[Abnormal posture of the trunk related to donepezil hydrochloride: report of 2 cases].

Patient 1, an 80-year-old woman with Alzheimer's disease, had been taking donepezil 5 mg for 2 years. Donepezil was increased to 10 mg, and 2 months later, the patient developed dropped head syndrome. MRI and needle EMG abnormality of the neck extensor muscles suggested focal myopathy, but the symptom disappeared within 2 months by discontinuing donepezil. Patient 2, a 78-year-old man with Lewy body dementia, had been taking levodopa and pramipexole (PPX). One month after tapering levodopa, donepezil 3 mg was introduced, and Pisa syndrome (bending of the trunk to the right anterior direction) developed 10 days later. Donepezil and PPX were discontinued and levodopa was increased. Within 5 months, his posture had almost recovered. Cholinesterase inhibitors can induce abnormal posture of the trunk, and clinicians should be aware of this uncommon but important side effect.

Tracheoarterial fistula in a patient with amyotrophic lateral sclerosis successfully managed by overinflation of the tracheostomy tube cuff alone: a case report.

BACKGROUND: Tracheoarterial fistula is the most devastating complication after tracheostomy, and its mortality, without definitive treatment, approaches 100%. In general, the combination of bedside emergency management, that is, overinflation of the tracheostomy tube cuff, and definitive treatment such as surgical or endovascular intervention is necessary to prevent the poor outcome. Patients with neuromuscular diseases such as amyotrophic lateral sclerosis are susceptible to tracheoarterial fistula because of long-term mechanical ventilation and muscle weakness. CASE PRESENTATION: We describe a case of tracheoarterial fistula in a Japanese 39-year-old patient with amyotrophic lateral sclerosis with long-term ventilator management. The patient was clinically diagnosed with a tracheoarterial fistula because of massive bleeding following sentinel hemorrhage. The massive hemorrhage was controlled by overinflation of the tracheostomy tube cuff alone, without definitive treatment. CONCLUSIONS: This case suggests overinflation of the tracheostomy tube cuff alone plays an important role, semi-permanently, in the management of tracheoarterial fistula, especially in cases where surgical or endovascular intervention is not indicated. Clinicians taking care of patients with tracheostomy undergoing long-term mechanical ventilation should be aware that tracheoarterial fistula might occur following tracheostomy.

Detection of SARS-CoV-2 Genome for over 100 Days after COVID-19 Onset.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), is spreading globally. Generally, the viral genome becomes undetectable within a couple of weeks after infection. Herein, we report a case of long-term detection of the SARS-CoV-2 genome in the same individual for 106 days. Whole genome sequencing was performed on specimens taken at the onset of the disease and 2 months after onset, and the B.1.1.7 lineage was detected in both samples. A comparison of the full-length sequences revealed a single-base difference and no amino acid mutations. This is the first case in Japan where the virus was detected over a long period, and the full-length sequences were compared.

Oral Administration of Mulberry (Morus alba L.) Leaf Powder Prevents the Development of Hepatocellular Carcinoma in Stelic Animal Model (STAM) Mice.

BACKGROUND/AIM: We examined the inhibitory effect of mulberry leaf (ML) (Morus alba L.) administration on the development of hepatocellular carcinoma (HCC) in stelic animal model (STAM) mice. This STAM mouse model of nonalcoholic steatohepatitis (NASH) closely resembles the progression from NASH to HCC in human clinical practice. MATERIALS AND METHODS: Streptozotocin (STZ, 200 µg) was administered to C57L/6J mice that were fed a high-fat diet (HFD; STAM mice) with 1% ML ad libitum. After sacrificing, the liver and blood were collected. Biochemical tests of plasma and histologic examination of the liver were performed. RESULTS: Pathologic examination of all (6/6) liver samples of the STAM mice showed HCC. On the contrary, in STAM mice that received ML, fat deposition and adenoma were observed in 6/6 and 2/6 of the liver samples, respectively, but there was no HCC. CONCLUSION: Administration of ML in STAM mice inhibited the progression from nonalcoholic hepatitis (NASH) to HCC. ML may be effective in preventing the development of HCC.

[Eosinophilic granulomatosis with polyangiitis presenting with ischemic optic neuropathy].

A 60-year-old man with a history of bronchial asthma and nasal polyp presented with loss of vision in the right eye. His visual loss progressed within a single day, and he presented to our hospital 5 days after the onset of the symptom. Fundoscopy showed swelling and hemorrhage of the right optic disc. Blood tests revealed increased eosinophils, C-reactive protein, and perinuclear anti-neutrophil cytoplasmic antibody. Cerebrospinal fluid was normal. Cranial MRI showed local enhancement of the right optic disc and posterior ciliary arteries. He was diagnosed with arteritic anterior ischemic optic neuropathy caused by eosinophilic granulomatosis with polyangiitis (EGPA). High dose intravenous methylprednisolone was started on presentation, but the patient showed no improvement in visual function. Although a rare complication, ischemic optic neuropathy associated with EGPA should be noted, as this is an emergent condition and requires prompt diagnosis and treatment.

Predictors of At-Home Death for Cancer Patients in Rural Clinics in Japan.

BACKGROUND: The prediction of at-home deaths has become an important topic in rural areas of Japan with an advanced aging society. However, there are no well-established predictors to explain how these factors influence intention. This study aims to investigate the possible predictors of at-home death for cancer patients in rural clinics in Japan. METHODS: This is a nationwide cross-sectional survey. A self-administered questionnaire was sent to 493 rural clinics in Japan. The main outcome was the realization of at-home deaths for cancer patients. RESULTS: Among the 264 clinics (54%) that responded to the survey, there were 194 clinics with the realization of at-home death. The use of a clinical pathway (adjusted odds ratio 4.19; 95% confidence interval 1.57-11.19) and the provision of organized palliative care (adjusted odds ratio 19.16; 95% confidence interval 7.56-48.52) were associated with the prediction of at-home death, irrespective of island geography or the number of doctors and nurses. CONCLUSIONS: Having a clinical pathway and systematizing palliative care could be important to determine the possibility of at-home deaths for cancer patients in rural clinics in Japan.

Effects of Kumaizasa (Sasa senanensis) Leaf Extract on Innate Immune Regulation in HEK293 Cells and Macrophages.

BACKGROUND/AIM: We investigated the effect of Kumaizasa leaf extract (KLE) on innate immunity using the HEK293 and RAW 264.7 cell lines. MATERIALS AND METHODS: KLE, lipopolysaccharides (LPS), or KLE with LPS were added to RAW 264.7 cells. The TNF-α and IL-1ß mRNA expression was then quantified. The expression of MAPKs, NFĸB, TNF-α and IL-1ß proteins was also quantified. In addition, KLE was added to HEK293 cells and the IL-8 concentration was measured. RESULTS: In RAW 264.7 cells, KLE increased the levels of TNF-α and IL-1ß mRNA. By contrast, when KLE and LPS were added to RAW 264.7 cells, the increase in TNF-α and IL-1ß mRNA was ameliorated. Similarly, the expression of JNK and ERK proteins was reduced. The addition of KLE to HEK293 cells induced IL-8 production. CONCLUSION: Based on these results, a KLE-mediated mechanism may regulate immunity by suppressing the expression of JNK and ERK, which are involved in inflammatory signal transduction.

Acute Brainstem Dysfunction Caused by Cavernous Sinus Dural Arteriovenous Fistula.

Symptoms of cavernous sinus dural arteriovenous fistula depend on the drainage patterns and are very diverse. Among these, brainstem dysfunction is a rare but serious complication. Here, we describe a case with isolated and rapidly progressive brainstem dysfunction due to cavernous sinus dural arteriovenous fistula. An 80-year-old woman presented with a 2-day history of progressive gait disturbance. Neurological examination revealed mild confusion, dysarthria, and left hemiparesis. Magnetic resonance imaging (MRI) revealed pontine swelling without evidence of infarction. Magnetic resonance angiography suggested a faint abnormality near the cavernous sinus. Dural arteriovenous fistula was suspected, and digital subtraction angiography was planned for the next day. Her condition had progressed to coma by the next morning. Pontine swelling worsened, and hyperintensity appeared on diffusion-weighted imaging. Digital subtraction angiography revealed a right-sided cavernous sinus dural arteriovenous fistula with venous reflux into the posterior fossa. Orbital or ocular symptoms had preceded brainstem symptoms in all nine previously reported cases, but brainstem symptoms were the only presentation in our case, making the diagnosis difficult. Some dural arteriovenous fistulas mimic inflammatory diseases when the clinical course is acute. Prompt diagnosis using enhanced computed tomography or MRI and emergent treatment are needed to avoid permanent sequelae.

Sanguisorba officinalis L. derived from herbal medicine prevents intestinal inflammation by inducing autophagy in macrophages.

Disturbed activation of autophagy is implicated in the pathogenesis of inflammatory bowel disease. Accordingly, several autophagy-related genes have been identified as Crohn's disease susceptibility genes. We screened the autophagy activators from a library including 3,922 natural extracts using a high-throughput assay system. The extracts identified as autophagy activators were administered to mice with 2% dextran sodium sulfate (DSS). Among the autophagy inducers, Sanguisorba officinalis L. (SO) suppressed DSS-induced colitis. To identify the mechanism by which SO ameliorates colitis, epithelial cell and innate myeloid cells-specific Atg7-deficient mice (Villin-cre; Atg7f/f and LysM-cre; Atg7f/f mice, respectively) were analyzed. SO-mediated inhibition of colitis was observed in Villin-cre; Atg7f/f mice. However, SO and a mixture of its components including catechin acid, ellagic acid, gallic acid, and ziyuglycoside II (Mix4) did not suppressed colitis in LysM-cre; Atg7f/f mice. In large intestinal macrophages (Mφ) of Atg7f/f mice, SO and Mix4 upregulated the expression of marker genes of anti-inflammatory Mφ including Arg1, Cd206, and Relma. However, these alterations were not induced in LysM-cre; Atg7f/f mice. These findings indicate that SO and its active components ameliorate DSS-induced colitis by providing intestinal Mφ with anti-inflammatory profiles via promotion of Atg7-dependent autophagy.

Difference in the Types of Treated Cancer between Clinics and Small-to-Middle-Sized Hospitals in Rural Communities of Japan.

Resolution of regional disparities in cancer mortality is global challenge. Establishing an equal system of cancer treatment throughout the country is required under the Cancer Control Act in Japan. The types of treated cancer may reflect practical experience at the institutions and cooperation to other institutions. This study investigated the types treated at the institutions in rural communities of Japan. A questionnaire survey was conducted for 811 public rural institutions (clinics and small-to-middle-sized hospitals [< 200 beds]) in 2013. The survey's items included the types of treated cancer (14 categories: stomach, colon, breast, liver, biliary tract, pancreatic, prostate, esophageal, lung, renal, urinary tract, testicular, hematopoietic, and others) and the first five types were defined as major cancers. The data were analyzed between hospitals and clinics. The response rate was about 60%, and of 177 hospitals and 281 clinics, 54 hospitals (30%) and 10 clinics (3%) reported the types of cancer. The median number of cancer types in hospitals was significantly greater than that of clinics (4 [interquartile range 3.0-7.8]) vs. 1 [1.0-1.8], P < 0.01). The prevalence of hospitals treating at least one of five major cancers was significantly greater than that of clinics (96% vs. 30%, P < 0.01). The prevalence of clinics treating prostate cancer was significantly greater than that of hospitals (31% vs. 70%, P = 0.03). In conclusion, most types of cancer are treated at small-to-middle-sized hospitals, except for prostate cancer, providing basic information about cancer treatment in rural communities of Japan.

Clinical characteristics of autoimmune disorders in the central nervous system associated with myasthenia gravis.

Myasthenia gravis (MG) is occasionally associated with autoimmune diseases in the central nervous system (CNS), such as neuromyelitis optica spectrum disorder (NMOSD), multiple sclerosis (MS), Morvan syndrome, and anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. Here, we report five original cases associated with autoimmune disorders in the CNS among 42 patients with MG in a single tertiary hospital in Japan (11.9%). In four of these five cases, the second disease developed when the preceding disease was unstable. Accurate diagnosis of the newly developing disease may be difficult in such cases, because some neurological symptoms can be seen in both disorders. This implies the great importance of recognizing the possible co-occurrence of MG and disorders in the CNS. In addition, a comprehensive review of the literature revealed distinct clinical characteristics depending on the associated disease in the CNS, including thymic pathology and temporal relationship between MG and associated CNS disorders. Notably, NMOSD usually develops after the onset of MG and thymectomy, in clear contrast to MS. Thymoma is highly prevalent among patients with Morvan syndrome, in contract to cases with NMOSD and MS. The analysis of clinical characteristics, representing the first such investigation to the best of our knowledge, suggests different pathogeneses of these autoimmune diseases in the CNS, and provides significant implications for clinical practice.

Sudden-onset C8 Radiculopathy due to a Plexiform Schwannoma of the Cervical Nerve Root.

Plexiform schwannoma is a rare variant of schwannomas and usually presents with chronic symptoms. We herein report a case of cervical nerve plexiform schwannoma that presented with unusually sudden severe left radiculopathy of the eighth cervical nerve after physical exercise. Coronal short-tau inversion recovery (STIR) magnetic resonance imaging (MRI) revealed a multinodular tumor along the eighth cervical nerve. The tumor was partially resected. A pathological analysis revealed that the tumor was a schwannoma, and we diagnosed the case as a plexiform schwannoma. The unusual sudden-onset presentation in this case was considered to be caused by the unusual localization of the tumor involving the nerve root and mechanical stress due to physical exercise.

Global Liver Gene Expression Analysis on a Murine Hepatic Steatosis Model Treated with Mulberry (Morus alba L.) Leaf Powder.

BACKGROUND/AIM: Mulberry (Morus alba L.) leaves (ML) contain many functional components, such as 1-deoxynojirimycin, flavonoids (rutin, quercetin, kaempferol). It is well known that 1-deoxynojirimycin functions to suppress increases in blood glucose level by α-glucosidase inhibitory activity. Thus, the molecular mechanism underlying the protective and therapeutic effects of ML supplementation was investigated on a mouse model of high-calorie diet (Western diet: WD)-induced hepatic steatosis (HS). MATERIALS AND METHODS: The C57BL/6J mouse was used for the HS model. The mice were divided into three groups: control (normal diet: ND), WD, and WD + 1% ML groups. The WD group was fed a high-calorie (high carbohydrate and high fat) diet for 12 weeks to develop HS. At week 12, all mice were sacrificed, blood was collected for biochemical tests, and the liver was obtained for histological examination and RNA sequencing (RNA-Seq). RESULTS: Liver weight, plasma triglycerides (TG), alanine aminotransferase (ALT), and alanine aminotransferase (AST) levels of both ML groups were significantly lower than those of the WD group. On histological examination of the liver, the area of fatty deposits was found to be suppressed by ML administration. In the gene expression analysis of the liver of WD- versus ML-fed mice by RNA-Seq, 722/45,706 genes exhibited a significant change in expression (corrected p-value<0.05). Gene network analysis of these genes showed that genes related to liver inflammation were inactivated and those related to regeneration of liver were activated in the ML group. CONCLUSION: ML functions to suppress HS in WD-fed mice and regulates genes related to inflammation and regeneration of liver cells.

Duplication and deletion upstream of LMNB1 in autosomal dominant adult-onset leukodystrophy.

OBJECTIVE: To characterize the genetic and clinical features of patients with autosomal dominant adult-onset demyelinating leukodystrophy (ADLD) carrying duplication and deletion upstream of lamin B1 (LMNB1). METHODS: Ninety-three patients with adult-onset leukoencephalopathy of unknown etiology were genetically analyzed for copy numbers of LMNB1 and its upstream genes. We examined LMNB1 expression by reverse transcription-qPCR using total RNA extracted from peripheral leukocytes. Clinical and MRI features of the patients with ADLD were retrospectively analyzed. RESULTS: We identified 4 patients from 3 families with LMNB1 duplication. The duplicated genomic regions were different from those previously reported. The mRNA expression level of LMNB1 in patients with duplication was significantly increased. The clinical features of our patients with LMNB1 duplication were similar to those reported previously, except for the high frequency of cognitive impairment in our patients. We found 2 patients from 1 family carrying a 249-kb genomic deletion upstream of LMNB1. Patients with the deletion exhibited relatively earlier onset, more prominent cognitive impairment, and fewer autonomic symptoms than patients with duplication. The presence of cerebellar symptoms and lesions may be characteristic in our patients with the deletion compared with the previously reported family with the deletion. Magnetic resonance images of patients with the deletion exhibited a widespread distribution of white matter lesions including the anterior temporal region. CONCLUSIONS: We identified 4 Japanese families with ADLD carrying duplication or deletion upstream of LMNB1. There are differences in clinical and MRI features between the patients with the duplication and those with the deletion upstream of LMNB1.

Overexpressed wild-type superoxide dismutase 1 exhibits amyotrophic lateral sclerosis-related misfolded conformation in induced pluripotent stem cell-derived spinal motor neurons.

Amyotrophic lateral sclerosis (ALS) is a late-onset, fatal disorder in which motor neurons selectively degenerate. Superoxide dismutase 1 (SOD1) was found to be a causative gene of familial ALS, and mutant SOD1 transgenic mice recapitulated ALS phenotypes. Analysis of these mice showed accumulation of misfolded SOD1 protein in motor neurons. Misfolded SOD1 accumulation was found in spinal motor neurons of both familial ALS patients with the SOD1 mutation and sporadic ALS patients. However, it is unclear what condition causes wild-type SOD1 misfolding in patients without the SOD1 mutation. Here, we generated induced pluripotent stem cells from mutant SOD1 transgenic mice, wild-type SOD1 transgenic mice, and control mice, and differentiated them into spinal motor neurons to analyze misfolded SOD1 accumulation. We found that misfolded SOD1 protein was accumulated in spinal motor neurons of both mutant and wild-type SOD1 transgenic mice as detected by a specific antibody against the misfolded conformation of SOD1. These results suggest that an increased expression level of wild-type SOD1 may accelerate the ALS pathology and that our in vitro model would be a useful tool for misfolded SOD1 research.