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Background and Objective: Chronic graft versus host disease (GVHD)-associated myositis targeting skeletal muscle is a relatively rare but potentially debilitating complication following allogeneic hematopoietic stem cell transplantation (HSCT). We reviewed the clinicopathological features of GVHD-associated myositis among patients receiving allogeneic HSCT to elucidate the cellular pathogenesis., Methods: We retrospectively reviewed clinical data and muscle biopsy results from 17 consecutive patients diagnosed with GVHD-associated myositis at our institution between 1995 and 2019. Immunostaining findings of GVHD-associated myositis were compared to those of patients with anti-tRNA-synthetase antibody-associated myopathy (ASM) (n = 13) and dermatomyositis (DM) (n = 12)., Results: The majority of patients with GVHD-associated myositis showed subacute or chronic progression of mild to moderate limb weakness together with elevated serum creatine kinase. These patients also exhibited mild C-reactive protein elevation but were negative for myositis-related autoantibodies. Programmed death-1 (PD-1)-positive cells were observed in muscle interstitium adjacent to myofibers expressing human leukocyte antigen (HLA)-DR. The interstitium was also HLA-DR-positive, similar to biopsy samples from ASM patients but not DM patients. The proportions of HLA-DR-positive muscle fibers and PD-1-positive interstitial cells were significantly higher in GVHD and ASM samples than DM samples. The PD-1-positive cells were mostly CD-8-positive lymphocytes., Discussion: GVHD-associated myositis is characterized by HLA-DR-positive myofibers and infiltration of PD-1-positive lymphocytes. These features distinguish GVHD-associated myositis from DM but not from ASM., (© 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

An 84-year-old man was diagnosed with anti-acetylcholine receptor (AChR) antibody-positive ocular myasthenia gravis (OMG) at the age of 77 and received treatment. The patient was referred to our department with swelling and pain in his right upper arm, which had spread to other limbs. His serum anti-AChR antibody and creatine kinase levels were elevated, and MRI of the limbs displayed signal changes suggesting inflammation in the several muscles. Despite showing no sign of thymoma, he was positive for serum anti-titin and anti-Kv1.4 antibodies. We performed a muscle biopsy, which led to a diagnosis of inflammatory myopathy (IM). IM associated with OMG is relatively mild. Age-related immune dysregulation may cause both OMG and IM. Evaluation of disease activity with serum anti-AChR antibody levels, and assessment of prognosis with examining anti-striational antibodies are necessary for appropriate management of IM associated with MG.

Objective: Sporadic inclusion body myositis (sIBM) is the most common acquired myopathy in patients older than 50 years of age. sIBM is hardly responds to any immunosuppressing theraphies, and its pathophysiology remains elusive. This study aims to explore pathogenic pathways underlying sIBM and identify novel therapeutic targets using metabolomic and transcriptomic analyses., Methods: In this retrospective observational study, we analyzed biopsied muscle samples from 14 sIBM patients and six non-diseased subjects to identify metabolic profiles. Frozen muscle samples were used to measure metabolites with cation and anion modes of capillary electrophoresis time of flight mass spectrometry. We validated the metabolic pathway altered in muscles of sIBM patients through RNA sequencing and histopathological studies., Results: A total of 198 metabolites were identified. Metabolomic and transcriptomic analyses identified specific metabolite changes in sIBM muscle samples. The pathways of histamine biosynthesis and certain glycosaminoglycan biosynthesis were upregulated in sIBM patients, whereas those of carnitine metabolism and creatine metabolism were downregulated. Histopathological examination showed infiltration of mast cells and deposition of chondroitin sulfate in skeletal muscle samples, supporting the results of metabolomic and transcriptomic analyses., Interpretation: We identified alterations of several metabolic pathways in muscle samples of sIBM patients. These results suggest that mast cells, chondroitin sulfate biosynthesis, carnitine, and creatine play roles in sIBM pathophysiology., (© 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Introduction: Sporadic inclusion body myositis (sIBM) is often accompanied by signs suggestive of denervation on electromyography (EMG), which mimics neurogenic disorders. Hence, the current study aimed to assess reinnervation after denervation in sIBM and its clinical impllcation., Methods: We retrospectively examined consecutive muscle biopsy specimens collected from 109 sIBM patients who were referred to our institution for diagnostic muscle biopsy from 2001 to 2018. Reinnervation after denervation in sIBM patients was assessed via muscle biopsy and EMG. The levels of acetylcholine receptor subunit γ (Chrng) and muscle-specific kinase (MuSK) mRNA, which are markers of denervation, were examined using real-time polymerase chain reaction. Response to treatment was defined as an increase of grade 1 or higher in two or more muscle groups as assessed using the Medical Research Council scale., Results: In total, 93 (85.3%) of 109 sIBM patients had reinnervation after denervation on histological examination and/or EMG. The mean disease duration before biopsy was significantly longer in patients with reinnervation after denervation than in those without (p < 0.00001). Patients with denervation had significantly higher levels of Chrng and MuSK mRNA than those without. The proportion of patients who responded to immunosuppressive therapies was smaller in the patients with denervation than those without (p < 0.05). However, there was no significant difference regarding time from onset to using a walking aid between the two groups., Discussion: Reinnervation after denervation is associated with disease duration and short-term response to therapy in individuals with sIBM., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Patients with congenital heart disease who have a variety of cardiac/extracardiac problems are at high risk for deterioration. This study aimed to determine the effectiveness of post-intensive care unit (ICU) follow-up by a rapid response team (RRT) after congenital heart surgery. This before-and-after study was conducted at an urban regional tertiary hospital. We enrolled 572 consecutive patients who underwent congenital heart surgery and were transferred alive from the paediatric ICU (PICU) between April 2015 and March 2020. Post-ICU follow-up for 48 h was started in April 2018. The primary and secondary endpoints were unplanned ICU readmission and clinical outcomes at ICU readmission, respectively. Overall, 346 and 226 patients were analysed pre- and post-intervention, respectively. Patient demographics were similar between groups, but in the post-intervention group, patients tended to have had more complicated surgery. Unplanned ICU readmission rates within 30 days were similar between groups. Regarding the demographics and outcomes at ICU readmission, patients in the post-intervention group had lower predicted mortality rates (1.7% vs 5.3%, P = 0.001), required less ventilator days (median, 0.5 days [interquartile range (IQR) 0-1] vs median, 3 days [IQR 0.5-4], P = 0.02), and had a shorter ICU stay (median, 3 days [IQR 2-4] vs median, 6 days [IQR 3-9], P = 0.03), but there was no significant between-group difference in ICU mortality. Post-ICU follow-up by a RRT after congenital heart surgery did not decrease unplanned ICU readmission but improved several outcomes at ICU readmission., (© 2022. The Author(s).)

The indications for using temporary epicardial pacing wires after pediatric cardiac surgery remain unclear. Post-procedure intracardiac pressure is valuable for detecting circulatory disturbances and residual lesions. This study aimed to examine the association between post-procedure intracardiac pressures and the use of temporary epicardial pacing wires. We performed a retrospective, case-control study at the pediatric intensive care unit of an urban regional tertiary hospital that included patients who had undergone congenital heart surgery between January 2015 and December 2016. We measured post-procedure intracardiac pressures, and data regarding baseline characteristics, procedures performed, and intraoperative variables were collected as covariates. Of the 186 included patients, 34 (18.3%) were treated using temporary epicardial pacing wires. The optimal cutoff values used to predict the use of pacing wires for central venous pressure, left atrial pressure, pulmonary arterial pressure/systemic blood pressure ratio, and right ventricular pressure/left ventricular pressure ratio were 11 mmHg (55.6% sensitivity, 86.2% specificity), 13 mmHg (50% sensitivity, 84.6% specificity), 0.39 (69.6% sensitivity, 78.7% specificity), and 0.51 (74.1% sensitivity, 64.2% specificity), respectively. Multivariable logistic regression analyses showed that the use of temporary epicardial pacing wires was significantly associated with left atrial pressure ≥ 11 mmHg (odds ratio 4.4; 95% confidence interval 1.01-18.9), and a pulmonary arterial pressure/systemic blood pressure ratio ≥ 0.39 (odds ratio 6.3; 95% confidence interval 1.3-31.4). High post-procedure intracardiac pressures were associated with the use of temporary epicardial pacing wires. These data can aid in the decision-making for the proper use of temporary epicardial pacing wires.

A 41-year-old woman presented with recurrent dizziness. After an attack of dizziness, she felt edematous sensations in her hands. However, according to photographs taken during the attack, the edema on the back of the patient's hands and fingers appeared mild. Laboratory examinations revealed a low C4 and C1 inhibitor (INH) activity. A direct sequencing analysis of C1INH revealed a pathogenic gene mutation. Based on these results, she was diagnosed with hereditary angioedema (HAE) type 1. These findings indicate that HAE can cause recurrent dizziness, and it should therefore be included in the differential diagnosis in patients with recurrent neurologic symptoms, even in the absence of severe edema.

We report the case of a 77-year-old woman with diabetic chorea, which presented as hemiballism of the right limbs. Initial blood examination revealed that sugar and hemoglobin A1c levels were 732 mg/dl and 12.2%, respectively. Thus, a diagnosis of hyperglycemic hyperosmolar syndrome was made at a previous hospital. Ballism of the right limbs developed after 10 days and progressively worsened. After a month, the patient was admitted to our hospital. Brain MRI (axial T 1 -weighted imaging) revealed a high-signal-intensity area in the left striatum. Dopamine transporter SPECT demonstrated reduced 123 I-ioflupane binding in the bilateral striatum with left side predominance. Although haloperidol and risperidone were ineffective for her involuntary movement, chlorpromazine had a little effect. Levodopa and gabapentin combination treatments were effective in decreasing the symptoms. It was considered that dopamine antagonist was the medical treatment for diabetic chorea and that levodopa could worsen neurological symptoms such as chorea-ballism. However, in our case, levodopa treatment was effective.

Objective: The aim of this study was to investigate whether anodal transcranial direct current stimulation over the left temporoparietal area improved audioverbal memory performance in stroke patients., Design: Twelve stroke patients with audioverbal memory impairment participated in a single-masked, crossover, and sham-controlled experiment. The anodal or sham transcranial direct current stimulation was applied during the Rey Auditory Verbal Learning Test, which evaluates the ability to recall a list of 15 heard words over five trials. The number of correctly recalled words was compared between the anodal and sham conditions and the influence of transcranial direct current stimulation on serial position effect of the 15 words was also examined., Results: The increase in the number of correctly recalled words from the first to the fifth trial was significantly greater in the anodal condition than in the sham condition (P < 0.01). There was a significant difference (P < 0.01) between the anodal and sham conditions in the number of correctly recalled words within the first five words (primacy region) over the second to fifth trial trials, but not in the middle (next five words) or recency (last five words) regions., Conclusions: Anodal transcranial direct current stimulation over the left temporoparietal area improved audioverbal memory performance and induced the primacy effect in stroke patients.

A 51-year-old woman developed very severe aplastic anemia complicated by chronic renal failure. She underwent ATG therapy, resulting in a transient effect. Thereafter, renal insufficiency progressed, followed by the induction of CAPD therapy. Although rabbit ATG (rATG) was administered as the next immunotherapy for aplastic anemia, pancytopenia persisted and she experienced repeated episodes of severe infection including MRSA and fungal infections. She was transplanted with peripheral blood stem cells from her HLA-haploidentical son after a reduced-intensity conditioning regimen that included cyclophosphamide (three days of 30 mg/kg), fludarabine (two days of 20 mg/m(2)) and rATG (three days of 2.5 mg/kg). FK506 (0.03 mg/kg/24H) was administered for the prophylaxis of GVHD. Prompt trilineage engraftment occurred, resulting in the improvement of infections. Three months after grafting, she succumbed to cerebrovascular disease, although there was no apparent GVHD and she had remained well with stable hematopoiesis.

Kidney development and physiology require polarization of epithelia that line renal tubules. Genetic studies show that polarization of invertebrate epithelia requires the crumbs, partition-defective-3, and discs large complexes. These evolutionarily conserved protein complexes occur in mammalian kidney; however, their role in renal development remains poorly defined. Here, we find that mice lacking the small PDZ protein mammalian LIN-7c (MALS-3) have hypomorphic, cystic, and fibrotic kidneys. Proteomic analysis defines MALS-3 as the only known core component of both the crumbs and discs large cell polarity complexes. MALS-3 mediates stable assembly of the crumbs tight junction complex and the discs large basolateral complex, and these complexes are disrupted in renal epithelia from MALS-3 knockout mice. Interestingly, MALS-3 controls apico-basal polarity preferentially in epithelia derived from metanephric mesenchyme, and defects in kidney architecture owe solely to MALS expression in these epithelia. These studies demonstrate that defects in epithelial cell polarization can cause cystic and fibrotic renal disease.

Synapses are highly specialized intercellular junctions organized by adhesive and scaffolding molecules that align presynaptic vesicular release with postsynaptic neurotransmitter receptors. The MALS/Veli-CASK-Mint-1 complex of PDZ proteins occurs on both sides of the synapse and has the potential to link transsynaptic adhesion molecules to the cytoskeleton. In this study, we purified the MALS protein complex from brain and found liprin-alpha as a major component. Liprin proteins organize the presynaptic active zone and regulate neurotransmitter release. Fittingly, mutant mice lacking all three MALS isoforms died perinatally with difficulty breathing and impaired excitatory synaptic transmission. Excitatory postsynaptic currents were dramatically reduced in autaptic cultures from MALS triple knockout mice due to a presynaptic deficit in vesicle cycling. These findings are consistent with a model whereby the MALS-CASK-liprin-alpha complex recruits components of the synaptic release machinery to adhesive proteins of the active zone.

A 79-year-old woman, with no immune deficit, had presented progressive visual disturbance, diplopia and ptosis of her left eye over 2 weeks. T1-weighted MR images with gadolinium showed a heterogeneously enhanced lesion extending from the left orbital apex along the optic nerve to the cavernous sinus. Although we could not detect fungus by a transsphenoidal biopsy, we suspected fungal infection because of high level of galactomanan antigen in serum. Despite antifungal chemotherapy, her symptoms did not improve. CT image on day 40 showed an aneurysm in the left internal carotid artery, on day 43 cerebral infarction in the left internal carotid artery distribution and on day 45 she died. Autopsy disclosed that aspergillus hyphae invaded the left sphenoid sinus, cavernous sinus and wall of the aneurysm. In this case, fungal infection in the frontal skull base including orbital apex caused mycotic aneurysm in the intracavernous portion of the left internal carotid artery. Skull base aspergillosis presenting orbital apex syndrome is itself rare and in addition, the occurrence of cerebral infarction in the mycotic aneurysm has hardly been reported. We should have cerebrovascular disease in mind as a complication of CNS aspergillosis.

Iodine123-labeled metaiodobenzylguanidine, a radioiodinated analogue of norepinephrine, is a tracer for evaluating sympathetic function. We used iodine123-labeled metaiodobenzylguanidine myocardial scintigraphy and sympathetic skin response to study autonomic nervous functions in 19 patients with Machado-Joseph disease (MJD) and 20 control subjects. Planar imaging of all the participants was done to evaluate myocardial scintigraphy. The ratio of average counts in the heart to average counts in the mediastinum was calculated for both early and delayed images, the latter of which reflects the cardiac neural uptake of the tracer. Single photon emission computed tomography also was done on 12 patients with MJD to examine regional tracer uptake to the heart. The mean ratio of counts in the heart to counts in the mediastinum in the delayed images was lower for the patients with MJD than for the control subjects (p <0.01). Abnormal sympathetic skin response was present in 6 patients with MJD whose mean ratio of counts in the heart to counts in the mediastinum was lower than that of patients with MJD who had normal sympathetic skin response (p <0.01). A single photon emission computed tomography study showed significantly lower accumulation of the tracer in patients with MJD than in the control subjects in the anterior lateral sectors predominantly innervated by sympathetic nerves but not in the inferior septal sectors reported to be under main innervation by parasympathetic fibers. These results show that MJD is accompanied by cardiac sympathetic dysfunction, as detected by iodine123-labeled metaiodobenzylguanidine myocardial scintigraphy, which appears to be correlated with sudomotor sympathetic dysfunction.

We identified two polymorphisms out of all coding regions of the dopamine transporter gene. One existed in exon 9 (1215A/G) and another in exon 15 (1898T/C). The 1215G was significantly less frequent among patients with Parkinson's disease than the controls. Although the polymorphism caused no amino acid substitution, we concluded that it was associated with decreasing the susceptibility to Parkinson's disease through mechanisms other than the protein function of dopamine transporter.

Iodine-123-labeled meta-iodobenzylguanidine ([123I]MIBG), an analogue of guanetidine, is used as a tracer for evaluation of the function of sympathetic neurons. To investigate cardiac sympathetic function in Machado-Joseph disease (MJD), [123I] MIBG myocardial scintigraphy was performed in 12 patients with MJD and 20 controls. In planar imaging studies, the heart to the mediastinum of the average count ratio (H/M) was calculated for both early and delayed images. The mean values of H/M in delayed images of MJD was lower than those of controls (p < 0.01), but this did not correlate with duration of the illness. The mean values of H/M in MJD patients with abnormal sympathetic skin response (SSR) was lower than that with normal SSR (p < 0.05). The decrease of H/M in delayed image is more sensitive than abnormal SSR. The increase of heart rate after standing in the patients with low H/M was lower than those with normal H/M. Abnormal cardiac sympathetic function revealed by [123I]MIBG myocardial scintigraphy in MJD can be seen earlier than abnormal sudomotor system detected by SSR.

Objective: To clarify the characteristic magnetic resonance imaging (MRI) findings in patients with Machado-Joseph disease (MJD) diagnosed by genetic analysis., Patients and Methods: Using MRI, we examined 31 patients genetically diagnosed as having MJD, 20 patients with sporadic olivopontocerebellar atrophy, and 26 control subjects., Results: The MRIs of patients with MJD disclosed remarkably reduced width of the superior cerebellar peduncles, atrophy in the frontal and temporal lobes, diminished transverse diameter of the globus pallidus, and decreased anteroposterior and transverse diameters of the pons, which correlated with the width of the middle cerebellar peduncle. The width of the superior cerebellar peduncles also correlated with the diameter of the dentate or red nucleus in patients with MJD, but not in controls or in patients with sporadic olivopontocerebellar atrophy. On T2- and/or proton-weighted axial MR imaging, a high signal intensity in the transverse pontine fibers was observed in 14 (45.2%) of 31 patients with MJD and in all patients with sporadic olivopontocerebellar atrophy, but not in any controls., Conclusion: Affected afferent and efferent cerebellar tracts and atrophy of the frontal and temporal lobes and globus pallidus are characteristics of MRI of patients with MJD.