TAK1 Limits Death Receptor Fas-Induced Proinflammatory Cell Death in Macrophages.

Fas, a member of the death receptor family, plays a central role in initiating cell death, a biological process crucial for immune homeostasis. However, the immunological and pathophysiological impacts to which enhanced Fas signaling gives rise remain to be fully understood. Here we demonstrate that TGF-ß-activated kinase 1 (TAK1) works as a negative regulator of Fas signaling in macrophages. Upon Fas engagement with high concentrations of FasL, mouse primary macrophages underwent cell death, and, surprisingly, Fas stimulation led to proteolytic cleavage of gasdermin (GSDM) family members GSDMD and GSDME, a hallmark of pyroptosis, in a manner dependent on caspase enzymatic activity. Remarkably, TAK1-deficient macrophages were highly sensitive to even low concentrations of FasL. Mechanistically, TAK1 negatively modulated RIPK1 kinase activity to protect macrophages from excessive cell death. Intriguingly, mice deficient for TAK1 in macrophages (TAK1mKO mice) spontaneously developed tissue inflammation, and, more important, the emergence of inflammatory disease symptoms was markedly diminished in TAK1mKO mice harboring a catalytically inactive RIPK1. Taken together, these findings not only revealed an unappreciated role of TAK1 in Fas-induced macrophage death but provided insight into the possibility of perturbation of immune homeostasis driven by aberrant cell death.

Combination therapy of modified electroconvulsive therapy and long-acting injectable aripiprazole for dopamine supersensitivity psychosis: a case report.

In the treatment of schizophrenia, long-term pharmacotherapy with D2-receptor antagonists can induce dopamine supersensitivity psychosis (DSP). We report a male patient with schizophrenia with suspected DSP due to excessive polypharmacy. He was hospitalized for several years. Most psychotropic drugs were reduced and subsequently stopped without the exacerbation of symptoms by administering modified electroconvulsive therapy (mECT). Aripiprazole was then selected as the main drug for treatment, which was subsequently changed to the long-acting injection formulation. He was eventually discharged and returned home. Combination therapy with mECT and aripiprazole, especially the long-acting injectable formulation, may help improve and prevent DSP.

Subjective achievement from psychiatry rotation in the Japanese postgraduate residency system: a longitudinal questionnaire study.

BACKGROUND: Psychiatry rotation has been mandatory in the Japanese postgraduate residency system since 2020. Some psychiatry-related competency items are stipulated as mandatory for residents. The current study aimed to clarify whether psychiatry rotation affected residents' subjective achievement of these competency items. METHODS: This longitudinal study was conducted among postgraduate residents who completed a rotation in the psychiatry department at Nagasaki University Hospital across two academic years (2020-2021). The survey was administered at the start and at the end of the psychiatry rotation. Residents evaluated their subjective understanding and confidence regarding initiating treatment for these competency items using a six-point Likert scale. The average scores for each item were compared between pre-rotation and post-rotation. RESULTS: In total, 99 residents (91.7%) responded to this survey. Residents had significantly higher scores at post-rotation compared with pre-rotation in all psychiatry-related competency items in both subjective understanding and confidence in initiating treatment. Additionally, strong effect sizes were found for many items. CONCLUSION: Residents improved learning about psychiatry-related competency items through psychiatry rotation. This finding suggests that it is reasonable for psychiatry rotation to be mandatory in the current Japanese postgraduate residency system. The importance of psychiatry is likely to increase in both undergraduate and postgraduate medical education in the future. It is necessary to continuously update educational strategies to meet changing social needs over time. As this study was conducted at a single institution, a multi-center study is needed to expand the current findings.

Postpolio Syndrome from Non-paralytic Poliovirus Infection.

A 73-year-old man presented with muscle weakness and atrophy of his right arm. Atrophy of his left brachia and left calf had occurred 13 years before without any improvement or deterioration. His sister and cousin had a history of paralytic poliomyelitis. Serum poliovirus type 2 neutralizing antibody was elevated to 128×. Electromyography revealed chronic denervation potentials not only in the muscles affected previously but also in the unaffected muscles. Acute and chronic denervation potentials were found in the newly affected muscle. Postpolio syndrome should be considered in patients with unilateral muscular atrophy even when they have no history of paralytic poliomyelitis.

Neuropathology of the spinal nerve roots, spinal cord, and brain in the first autopsied case of Charcot-Marie-Tooth disease 4F with a D651N mutation in the periaxin gene.

Charcot-Marie-Tooth disease (CMT) 4F is an autosomal recessive, hereditary peripheral neuropathy, mostly caused by mutations in the periaxin gene (PRX). This article reports neuropathological findings of the spinal nerve roots, spinal cord, and brain of a patient with CMT4F and a D651N missense mutation in PRX. The patient was a 74-year-old woman who had a history of peripheral neuropathy with onset at the age of 30 years. She also had a history of infantile paralysis at the age of 18 months. The most pronounced autopsy finding was diffuse enlargement of anterior and posterior nerve roots, accentuated at the lumbo-sacral levels. On microscopy, the swollen nerve roots showed a loss of large-diameter myelinated fibers and formation of numerous onion bulbs. Most of the onion bulbs lacked the central, regenerating thin myelin sheaths, and in large-diameter nerve fibers whose axons had been lost, collagen fibers occupied the center of the onion bulbs. Some nerve roots formed glial bundles at the proximal end. The spinal cord showed degeneration of the gracile fascicles, and the lumbar segment anterior horn showed an asymmetric neuronal loss with rarefaction of the neuropil. The brain did not show any notable changes except for multiple foci of a radial microcolumnar arrangement of neurons in the cerebral cortex. Degeneration of the lumbar segment anterior horn is most likely secondary to the anterior radiculopathy, but a localized circulatory disturbance is another possibility.

Dystypia Associated with Diaschisis of the Middle Frontal Gyri after Left Angular Infarction.

Dystypia without aphasia, agraphia, or apraxia is a rare symptom and has been suggested to result from a lesion in the left middle frontal cortex. We herein describe a man with dystypia with agraphia due to infarction of the left angular gyrus. His dystypia seemed to result from the convergence failure of the kana into the alphabetical spellings. During dystypia, hypoperfusion of the bilateral middle frontal cortices was discovered. However, after his symptoms improved, blood flow in the middle frontal cortices returned to normal. This case suggests that the middle frontal cortex is downstream of the angular gyrus in the dictating pathway and a lesion in the left middle frontal cortex could cause pure dystypia.

Pathological evidence of demyelination in the recurrent laryngeal, phrenic, and oculomotor nerves in Charcot-Marie-Tooth disease 4F.

We present pathology of the peripheral nerves of a patient with Adult-onset Charcot-Marie-Tooth disease 4F caused by periaxin gene mutation p.D651N. The patient was a 72-year-old woman. She had hoarseness and underwent continuous positive airway pressure therapy at night due to sleep apnea. The patient died abruptly. Remarkable demyelination with tomacula formation was found in the phrenic nerve, vagal nerve, recurrent laryngeal nerve, and oculomotor nerves. The cause of death could have been insufficient reactivity to the aspiration or sudden onset of bilateral vocal cord palsy. We must pay attention to respiratory function and cranial nerve palsies in hereditary demyelinating neuropathies.

Long-read sequencing identifies GGC repeat expansions in NOTCH2NLC associated with neuronal intranuclear inclusion disease.

Neuronal intranuclear inclusion disease (NIID) is a progressive neurodegenerative disease that is characterized by eosinophilic hyaline intranuclear inclusions in neuronal and somatic cells. The wide range of clinical manifestations in NIID makes ante-mortem diagnosis difficult1-8, but skin biopsy enables its ante-mortem diagnosis9-12. The average onset age is 59.7 years among approximately 140 NIID cases consisting of mostly sporadic and several familial cases. By linkage mapping of a large NIID family with several affected members (Family 1), we identified a 58.1 Mb linked region at 1p22.1-q21.3 with a maximum logarithm of the odds score of 4.21. By long-read sequencing, we identified a GGC repeat expansion in the 5' region of NOTCH2NLC (Notch 2 N-terminal like C) in all affected family members. Furthermore, we found similar expansions in 8 unrelated families with NIID and 40 sporadic NIID cases. We observed abnormal anti-sense transcripts in fibroblasts specifically from patients but not unaffected individuals. This work shows that repeat expansion in human-specific NOTCH2NLC, a gene that evolved by segmental duplication, causes a human disease.

Gatekeeping in an inpatient rehabilitation facility to reduce morbidity and mortality due to cardiac disease: screening program using of BNP and ECG Auto-diagnosis.

The Kaifukuki-Rehabilitation Ward (KRW) is a type of inpatient rehabilitation facility in Japan. In the KRW of our institute, mortality and frequency of emergency referrals in 2013 were rather high, 2.6% and 4.3%, respectively. We aimed to investigate the usefulness of an original gatekeeping system to reduce mortality and morbidity from cardiac complications, and to improve the quality of medical care in the KRW. A total of 370 consecutive patients admitted to the KRW of Kobayashi Memorial Hospital between 1 May 2015 and 31 March 2016 were enrolled in this prospective observational study. All patients underwent a screening evaluation in which we defined patients as being screen positive (SC-positive) if they had at least one of 20 diagnostic ECG codes and/or BNP level over 140 pg/dL at admission. A cardiologist provided weekly interventions to those among SC-positive patients who needed cardiac disease treatment during hospitalization. In all, 129 patients were classified as SC-positive (mean age 80 years, 124 [32%] male), and weekly intervention was needed in 28 patients, including start of cardiac medication in 17 cases. Mortality and frequency of emergency transfer due to cardiac disease during hospital stay were 0.3% and 0.3%, respectively. Our gatekeeping system involving a screening evaluation at admission and weekly intervention in selected patients by a cardiologist may be useful in reducing mortality and rate of transfer due to cardiac disease and may improve quality of medical care in KRWs.

Akinetopsia on Driving.

Akinetopsia is a quite rare symptom. Two types of akinetopsia have been reported: one is cinematographic vision, and the other is invisibility of moving objects. These symptoms are thought to occur due to dysfunction of the MT/V5 area at the occipitoparietal region. I herein describe a 54-year-old man who collided with a car parked on the left side of the road while driving. He complained that the parked car looked to be moving forwards and he could not stop his car when he noticed that it was parked. Magnetic resonance imaging disclosed the fresh infarction on the right temporoparietal region involving the MT/V5 area. His symptom during driving was considered cinematographic vision and it was the cause of the traffic accident. Akinetopsia resulted in illusory kinetopsia on driving and the traffic accident.

[A case of stiff-limb syndrome with anti-glycine receptor antibody].

A 48-year-old woman with a 3-month history of spontaneously resolving stiff leg symptom at the age of 43 years presented with progressive onset of leg rigidity, walking difficulty, and myoclonic jerks. On admission she had marked stiffness in her foot joints with symmetric sustained dorsiflexion of the ankles and toes, with spontaneous and reflex myoclonic jerks easily provoked by knee tendon tap. She appeared to have a spastic gait due to stiffness in her legs. Needle electromyogram (EMG) examination revealed continuous motor unit activity in the tibialis anterior muscle at rest even when voluntary contraction of the gastrocnemius muscle was instructed, but no myokimic discharge or acute denervation sign was seen. The laboratory tests were unremarkable, including glutamic acid decarboxylase antibody. Cerebrospinal fluid (CSF) examination was also normal, without oligoclonal bands or elevated IgG index. She was diagnosed with stiff-limb syndrome based on neurologic examination and needle EMG findings, and she was treated with intravenous high-dose methylprednisolone (500 mg/day, 3 days), resulting in marked improvement in her symptoms. Anti-glycine receptor antibodies were subsequently identified in her archived serum and CSF obtained before immunotherapy. She was then started on oral prednisolone (30 mg/day) and had been free of symptoms.

Cortical Hyperintensity on Diffusion-weighted Images as the Presymptomatic Marker of Sporadic Creutzfeldt-Jakob Disease.

We herein report a sporadic Creutzfeldt-Jakob disease (sCJD) patient followed from the presymptomatic phase to death. A 67-year-old woman had abnormal hyperintense cortical lesions on diffusion-weighted magnetic resonance imaging (MRI) one year before the onset. The levels of 14-3-3 protein and total tau protein, and findings from a real-time quaking-induced conversion test were normal at first but became abnormal after disease onset. Although there are four reports of presymptomatic sCJD identified by MRI, this is the first case report in which all three biomarkers had been assessed before and after the disease onset. MRI might be the most sensitive modality for detecting presymptomatic sCJD patients.

Revival of Historical Kana Orthography in a Patient with Allographic Agraphia.

Japanese people born before World War II learned Japanese kana (Japanese syllabograms) writing in a style that is not currently used. These individuals had to learn the current style of kana orthography after the war. An 85-year-old man was taken to our hospital by his family who were surprised by his diary. It was written with kanji (Japanese ideograms) and katakana using the prewar style. A neuropsychological examination revealed impaired recall of hiragana. Neuroimaging studies revealed atrophy of the left fronto-parietal lobe and hypoperfusion of the left frontal lobe. His allographic agraphia might have resulted from the disturbance of the current style of kana orthography.

Clinical and genetic features of Charcot-Marie-Tooth disease 2F and hereditary motor neuropathy 2B in Japan.

Mutations in small heat shock protein beta-1 (HspB1) have been linked to Charcot-Marie-Tooth (CMT) disease type 2F and distal hereditary motor neuropathy type 2B. Only four cases with HSPB1 mutations have been reported to date in Japan. In this study between April 2007 and October 2014, we conducted gene panel sequencing in a case series of 1,030 patients with inherited peripheral neuropathies (IPNs) using DNA microarray, targeted resequencing, and whole-exome sequencing. We identified HSPB1 variants in 1.3% (13 of 1,030) of the patients with IPNs, who exhibited a male predominance. Based on neurological and electrophysiological findings, seven patients were diagnosed with CMT disease type 2F, whereas the remaining six patients were diagnosed with distal hereditary motor neuropathy type 2B. P39L, R127W, S135C, R140G, K141Q, T151I, and P182A mutations identified in 12 patients were described previously, whereas a novel K123* variant with unknown significance was found in 1 patient. Diabetes and impaired glucose tolerance were detected in 6 of the 13 patients. Our findings suggest that HSPB1 mutations result in two phenotypes of inherited neuropathies and extend the phenotypic spectrum of HSPB1-related disorders.