Effects of the novel acaricide acynonapyr on the calcium-activated potassium channel.

Resistance to insecticides and acaricides is a major impediment to effectively controlling insect pests worldwide. These pests include the two-spotted spider mite Tetranychus urticae (T. urticae), which exists globally. This polyphagous herbivore causes major agricultural problems and can develop resistance to the agents above. Therefore, the continuous development of acaricides with new modes of action is important to circumvent the resistance of insects to pesticides. Acynonapyr is a novel class of acaricides containing an azabicyclo ring. In this study, we determined the activity of acynonapyr and its analogs on calcium-activated potassium (KCa2) channels in two-spotted spider mites using electrophysiological techniques (patch-clamp). We also examined their acaricidal efficacy against mites in the laboratory. The acynonapyr and analogs blocked T. urticae KCa2 (TurKCa2) channels in a concentration-dependent manner. A comparison of acaricidal activity against T. urticae with inhibitory activity against TurKCa2 revealed that TurKCa2 channels are the primary toxicological targets. Finally, we examined the effect of acynonapyr on Homo sapiens KCa2 (HsaKCa2.2) channels and demonstrated that the compound at 10 µM had a limited effect on the activity of this channel.

Use of endoscopic ultrasound-guided fine needle aspiration of the pancreas to diagnose a case of primary linitis plastica of the colon with retroperitoneal dissemination.

A 54-year-old man had previously undergone curative sigmoidectomy for poorly differentiated adenocarcinoma with a signet-ring cell component of the sigmoid colon, which was characterized morphologically by stenosis and inelasticity of the colon (linitis plastica). Six weeks after surgery, the patient developed stenosis of the right ureter. Disseminated sigmoid cancer was suspected, and chemotherapy was started. Nine months after initiation of chemotherapy, obstructive jaundice was observed which was due to stenosis of the distal bile duct (BD). Although computed tomography showed no evident metastatic lesion that could cause the stenosis, swelling of the entire pancreas was evident compared to that of 11 months earlier. Endoscopic ultrasound (EUS) also did not detect any focal masses in the head of the pancreas, although there was a diffuse hypoechoic change in the entire pancreas. Histopathology of the stenotic BD and biopsy specimen from the head of the pancreas showed no malignant cells. Two months after the initial endoscopic bile duct drainage, the patient was admitted again for epigastric pain. A second EUS fine needle aspiration (EUS-FNA) of the head of the pancreas was performed and showed poorly differentiated carcinoma with some signet-ring cells. This finding provided histological confirmation of a disseminated pancreatic lesion of the previously resected linitis plastica of the sigmoid colon. This is a rare case of disseminated pancreatic lesion from primary linitis plastica of the colon diagnosed by EUS-FNA.

Nationwide registry for patients with neuroendocrine neoplasm of pancreas, gastrointestinal tract, lungs, bronchi, or thymus in Japan.

BACKGROUND: Neuroendocrine neoplasm (NEN) is a comparatively rare tumor that has been considered indolent. Due to these characteristics, detailed epidemiological data have not been analyzed in Japan. To elucidate the present status of NEN diagnosis and treatment in Japan, we started a registry cohort study in January 2015. METHODS: Patients pathologically diagnosed with NENs of the pancreas, gastrointestinal tract, lungs, bronchi, or thymus after January 2012 were enrolled in this registry after the date of ethics review committee approval in each hospital or institute. Follow-up was continued for enrolled patients. RESULTS: During 5 years of enrollment between January 2015 and December 2019, a total of 1526 participants from 63 departments were enrolled in this registry (mean, 305.2 participants/year), covering approximately 5.8% of the annual incidence of NENs in Japan. For pancreatic NEN, 41.9% of patients had metastasis and the dominant metastatic site was the liver, at twice the rate of lymph node metastasis in the current registry. In contrast, the frequency of lymph node metastasis from gastrointestinal (GI)-NEN was similar to that of the liver. The distribution of WHO 2019-based grades varied according to the primary site. Low-to-intermediate grade (G1-G2) was dominant for duodenal, jejunal/ileal, rectal, and pancreatic NENs, whereas high grade (G3 or NEC) was dominant for esophageal, stomach, and colon NENs. For PanNENs, G3 and NEC accounted only for 1.6% and 2.9%, respectively. CONCLUSIONS: These cohort data provide crucial information for clinical research to clarify the characteristics of NENs in Japan.

A Nationwide Epidemiological Survey of Adolescent Patients With Diverse Symptoms Similar to Those Following Human Papillomavirus Vaccination: Background Prevalence and Incidence for Considering Vaccine Safety in Japan.

BACKGROUND: Since June 2013, Japan has suspended proactive recommendation of human papillomavirus (HPV) vaccination due to self-reported diverse symptoms, including pain and motor dysfunction, as possible serious adverse events following immunization. Although these symptoms may be seen in adolescents without HPV vaccination, their frequency, taking into account disease severity, has not been examined. METHODS: A two-stage, descriptive, nationwide epidemiological survey was conducted in 2016, with a 6-month target period from July 1 to December 31, 2015, to estimate the prevalence and incidence of diverse symptoms among Japanese adolescents without HPV vaccination. Participants were 11,037 medical departments in hospitals selected nationwide by stratified random sampling. Eligible patients had to satisfy four criteria: (1) aged 12-18 years upon visiting hospital; (2) having at least one of four symptoms/disorders (pain or sensory dysfunction, motor dysfunction, autonomic dysfunction, or cognitive impairment); (3) symptoms/disorders persisting for at least 3 months; and (4) both criteria (2) and (3) influence attendance at school or work. We then extracted data of patients with diverse symptoms similar to those after HPV vaccination while considering opinions of doctors in charge. RESULTS: Estimated 6-month period prevalence of diverse symptoms among girls aged 12-18 years without HPV vaccination was 20.2 per 100,000. Annual incidence was estimated to be 7.3 per 100,000. CONCLUSION: Adolescent Japanese girls without HPV vaccination also visited hospitals with diverse symptoms similar to those following HPV vaccination. Our findings predict the medical demands for coincident diverse symptoms, which are temporally associated with but not caused by HPV vaccination of Japanese adolescents.

Distinction in Prevalence of Atherosclerotic Embolic Sources in Cryptogenic Stroke With Cancer Status.

Background Cerebrovascular diseases are common comorbidities in patients with cancer. Although active cancer causes ischemic stroke by multiple pathological conditions, including thromboembolism attributable to Trousseau syndrome, the relationship between stroke and inactive cancer is poorly known. The aim of this study was to elucidate the different underlying pathogeneses of cryptogenic stroke in active and inactive patients with cancer, with detailed investigation by transesophageal echocardiography. Methods and Results CHALLENGE ESUS/CS (Mechanisms of Embolic Stroke Clarified by Transesophageal Echocardiography for Embolic Stroke of Undetermined Source/Cryptogenic Stroke) registry is a multicenter registry including data of patients initially diagnosed as having cryptogenic stroke and undergoing transesophageal echocardiography. Patients were divided into active cancer, inactive cancer, and noncancer groups, and their clinical features were compared. Of the total 667 enrolled patients (age, 68.7±12.8 years; 455 men), 41 (6.1%) had active cancer, and 51 (7.5%) had a history of inactive cancer. On multinomial logistic regression analysis, infarctions in multiple vascular territories (odds ratio [OR], 2.73; 95% CI, 1.39-5.40) and CRP (C-reactive protein) (OR, 1.10; 95% CI, 1.01-1.19) were independently associated with active cancer, whereas age (OR, 1.05; 95% CI, 1.01-1.08), contralateral carotid stenosis from the index stroke lesion (OR, 4.05; 95% CI, 1.60-10.27), calcification of the aortic valve (OR, 2.10; 95% CI, 1.09-4.05), and complicated lesion of the aortic arch (OR, 2.13; 95% CI, 1.11-4.10) were significantly associated with inactive cancer. Conclusions Patients with cancer were not rare in cryptogenic stroke. Although patients with active cancer had more multiple infarctions, patients with inactive cancer had more atherosclerotic embolic sources potentially causing arteriogenic strokes. Registration URL: https://www.umin.ac.jp/ctr/; Unique identifier: UMIN000032957.

JNETS clinical practice guidelines for gastroenteropancreatic neuroendocrine neoplasms: diagnosis, treatment, and follow-up: a synopsis.

Neuroendocrine neoplasms (NENs) are rare neoplasms that occur in various organs and present with diverse clinical manifestations. Pathological classification is important in the diagnosis of NENs. Treatment strategies must be selected according to the status of differentiation and malignancy by accurately determining whether the neoplasm is functioning or nonfunctioning, degree of disease progression, and presence of metastasis. The newly revised Clinical Practice Guidelines for Gastroenteropancreatic Neuroendocrine Neoplasms (GEP-NENs) comprises 5 chapters-diagnosis, pathology, surgical treatment, medical and multidisciplinary treatment, and multiple endocrine neoplasia type 1 (MEN1)/von Hippel-Lindau (VHL) disease-and includes 51 clinical questions and 19 columns. These guidelines aim to provide direction and practical clinical content for the management of GEP-NEN preferentially based on clinically useful reports. These revised guidelines also refer to the new concept of "neuroendocrine tumor" (NET) grade 3, which is based on the 2017 and 2019 WHO criteria; this includes health insurance coverage of somatostatin receptor scintigraphy for NEN, everolimus for lung and gastrointestinal NET, and lanreotide for GEP-NET. The guidelines also newly refer to the diagnosis, treatment, and surveillance of NEN associated with VHL disease and MEN1. The accuracy of these guidelines has been improved by examining and adopting new evidence obtained after the first edition was published.

Increased BUB1B/BUBR1 expression contributes to aberrant DNA repair activity leading to resistance to DNA-damaging agents.

There has been accumulating evidence for the clinical benefit of chemoradiation therapy (CRT), whereas mechanisms in CRT-recurrent clones derived from the primary tumor are still elusive. Herein, we identified an aberrant BUB1B/BUBR1 expression in CRT-recurrent clones in bladder cancer (BC) by comprehensive proteomic analysis. CRT-recurrent BC cells exhibited a cell-cycle-independent upregulation of BUB1B/BUBR1 expression rendering an enhanced DNA repair activity in response to DNA double-strand breaks (DSBs). With DNA repair analyses employing the CRISPR/cas9 system, we revealed that cells with aberrant BUB1B/BUBR1 expression dominantly exploit mutagenic nonhomologous end joining (NHEJ). We further found that phosphorylated ATM interacts with BUB1B/BUBR1 after ionizing radiation (IR) treatment, and the resistance to DSBs by increased BUB1B/BUBR1 depends on the functional ATM. In vivo, tumor growth of CRT-resistant T24R cells was abrogated by ATM inhibition using AZD0156. A dataset analysis identified FOXM1 as a putative BUB1B/BUBR1-targeting transcription factor causing its increased expression. These data collectively suggest a redundant role of BUB1B/BUBR1 underlying mutagenic NHEJ in an ATM-dependent manner, aside from the canonical activity of BUB1B/BUBR1 on the G2/M checkpoint, and offer novel clues to overcome CRT resistance.

Hystero-epilepsy in the Tuesday Lessons and NMDA receptor function: A hypothesis for dissociative disorder.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis patients demonstrate characteristic multistage progression and movement disorders, which are analogous to hystero-epilepsy in Jean-Martin Charcot's Tuesday Lessons. First, based on a review of the Tuesday Lessons recorded by Charcot's pupils, we hypothesized that there were patients with anti-NMDAR encephalitis among those diagnosed with hystero-epilepsy in the nineteenth century. We found acute-onset multiple neuropsychiatric manifestations resembling anti-NMDAR encephalitis among patients with hystero-epilepsy. Patients with drug withdrawal syndrome, dissociative and conversion disorders and patients under hypnosis from the modern point of view were also identified. These results suggested that hystero-epilepsy in the Tuesday Lessons could encompass dissociative and conversion disorders, hypnosis, drug withdrawal syndrome, and anti-NMDAR encephalitis-like manifestations. Based on Charcot's observations and current progress in molecular biology, such as the identification of glutamate/NMDAR system dysfunction in drug withdrawal syndrome, we then hypothesized that patients with dissociative and conversion disorders and those under hypnosis could also have hypofunction of the glutamatergic system. The NMDAR hypofunction hypothesis is emerging as a pathogenesis of schizophrenia. NMDAR antagonists are known to evoke symptoms similar to schizophrenia, anti-NMDAR encephalitis and near-death experiences. In current clinical reports, spectrum disorders such as dissociative disorder and conversion disorder have been observed in patients with anti-NMDAR encephalitis. Our hypothesis will offer an expansion of the NMDAR hypofunction hypothesis from psychosis to functional neurological disorders and normal specific situations, such as hypnosis, thanatosis, and near-death experiences.

Impact of the COVID-19 Pandemic on the Quality of Life of Patients with Parkinson's Disease and Their Caregivers: A Single-Center Survey in Tochigi Prefecture.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has negatively affected the mental health of the general population. OBJECTIVE: We investigated the determinants of quality of life (QOL) in Parkinson's disease (PD) patients during the COVID-19 pandemic. METHODS: Impacts of lifestyle changes due to the COVID-19 pandemic on 100 patients with PD and their caregivers/spouses were assessed. The Hospital Anxiety and Depression Scale was used to assess anxiety and depression. The physical component summary (PCS) and mental component summary (MCS) scores of the short form (SF)-8 were used to evaluate health-related QOL. RESULTS: Regarding health-related QOL, physical function, role physical, general health, vitality and the PCS score were significantly worse in PD patients than in caregivers. Worsening of PD-related symptoms, increased stress, and decreased physical activity were observed in 29.0%, 37.0% and 44.0% of PD patients, respectively. Sixteen patients (16.0%) experienced problems with hospital access, but none reported medication shortages. Strong concerns about COVID-19 were reported by 47.0% of caregivers and 50.0% of PD patients. In PD patients, increased gait disturbance and rigidity, disease severity, smoking, the levodopa equivalent dose and decreased body weight predicted a worse PCS score; anxiety, depression, female sex, stress and long disease duration predicted a worse MCS score. In caregivers, age and smoking contributed to a worse PCS score; depression, stress and worsening patient mood contributed to a worse MCS score. CONCLUSION: We report the negative impacts of the COVID-19 pandemic on health-related QOL and its determinants in PD patients and their caregivers.

Association between preoperative tumor necrosis factor alpha inhibitor and surgical site infection after surgery for inflammatory bowel disease: a systematic review and meta-analysis.

Tumor necrosis factor-alpha inhibitor (TNFi) treatment is effective for ulcerative colitis (UC) and Crohn's disease (CD). Although several meta-analyses have been performed to evaluate the association between TNFi treatment and surgical morbidity, the results are controversial. We conducted a systematic review and meta-analysis of the prevention of surgical site infection (SSI) after surgery for UC and CD in patients on TNFis, based on literature published between January 2000 and May 2019 (registered on PROSPERO, No. CRD42019134156). Overall, 2175 UC patients in 13 observational studies (OBSs) and 7084 CD patients in 16 OBSs were included. The incidences of incisional (INC) SSI and organ/space (O/S) SSI after surgery for UC were 179/1985 (9.0%) and 176/2175 (8.1%), respectively. TNFi use was not associated with the incidences of INC SSI (odds ratio (OR) 1.04, 95% confidence interval (CI) (0.47-2.32) or O/S SSI (OR 1.85, 95% CI (0.82-4.20)) after surgery for UC. The INC SSI and O/S SSI incidences after surgery for CD were 289/3089 (9.4%) and 526/7,084 (7.4%), respectively. Preoperative TNFi use was not associated with INC SSI (OR 0.98, 95% CI (0.52-1.83)) or O/S SSI incidence (OR 1.09, 95% CI (0.78-1.52)) after surgery for CD. We did not find a significant association between preoperative TNFi use and SSI in surgery for UC or CD.

The Japan Society for Surgical Infection: guidelines for the prevention, detection, and management of gastroenterological surgical site infection, 2018.

BACKGROUND: The guidelines for the prevention, detection, and management of gastroenterological surgical site infections (SSIs) were published in Japanese by the Japan Society for Surgical Infection in 2018. This is a summary of these guidelines for medical professionals worldwide. METHODS: We conducted a systematic review and comprehensive evaluation of the evidence for diagnosis and treatment of gastroenterological SSIs, based on the concepts of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. The strength of recommendations was graded and voted using the Delphi method and the nominal group technique. Modifications were made to the guidelines in response to feedback from the general public and relevant medical societies. RESULTS: There were 44 questions prepared in seven subject areas, for which 51 recommendations were made. The seven subject areas were: definition and etiology, diagnosis, preoperative management, prophylactic antibiotics, intraoperative management, perioperative management, and wound management. According to the GRADE system, we evaluated the body of evidence for each clinical question. Based on the results of the meta-analysis, recommendations were graded using the Delphi method to generate useful information. The final version of the recommendations was published in 2018, in Japanese. CONCLUSIONS: The Japanese Guidelines for the prevention, detection, and management of gastroenterological SSI were published in 2018 to provide useful information for clinicians and improve the clinical outcome of patients.

Central sensitization in migraine is related to restless legs syndrome.

OBJECTIVE: We hypothesized that, in migraine patients, central sensitization (CS) could be associated with comorbid restless legs syndrome (RLS). METHODS: We conducted a case-control study including 186 migraine patients and 186 age- and sex-matched healthy controls. Symptoms related to CS syndrome were assessed by the Central Sensitization Inventory (CSI). Individuals with CSI Part A (CSI-A) scores ≥ 40 were defined as having CS. For patients with migraine, the Brief Pain Inventory (BPI) and Patient Health Questionnaire (PHQ)-9 were administered. In the patient group, RLS and migraine were diagnosed through face-to-face interviews. RESULTS: Among migraine patients, 26 (14.0%) suffered from chronic migraine. The mean disease duration was 23.7 ± 11.8 years. Migraine patients showed a higher rate of CS (21.0% vs. 8.6%) than healthy controls, with an adjusted odds ratio (AOR) of 3.039 (95% confidence interval (CI) 1.560-5.992; p = 0.001). Migraine patients in the CS group had higher rates of smoking, chronic migraine and RLS and higher BPI and PHQ-9 scores than migraine patients in the non-CS group. The use of acute and preventive treatment for migraine did not significantly differ between the CS and non-CS groups. Multivariable analysis identified the presence of RLS (AOR, 28.471; 95% CI 6.438-125.918; p < 0.001) and the BPI pain interference score (AOR, 1.398; 95% CI 1.061-1.843; p = 0.017) as the significant determinants of CS among migraine patients. CONCLUSION: Migraine patients were 3 times more likely to have CS than healthy controls. Our study results showed an association between RLS and CS in migraine patients.

A family with adult-onset myofibrillar myopathy with BAG3 mutation (P470S) presenting with axonal polyneuropathy.

We report a family with adult-onset myofibrillar myopathy with BAG3 mutation who presented peroneal weakness and axonal polyneuropathy, mimicking axonal Charcot-Marie-Tooth disease. The male proband noticed difficulty in tiptoeing at age 34. At age 42, the examination showed muscle weakness and atrophy in distal lower extremities with diminished patellar and Achilles tendon reflexes. Thermal and vibration sensations were also impaired in both feet. The serum CK level was 659 U/L. On muscle imaging, predominant semitendinosus muscle atrophy coexisted with atrophies in the quadriceps, gastrocnemius and lumbar paraspinal muscles. The muscle biopsy showed myofibrillar myopathy with fiber type grouping. His 68-year-old mother also had suffered from distal leg weakness and sensory impairment since her forties. A heterozygous mutation in BAG3 (P470S) was identified in both patients. Clinical features of myofibrillar myopathy with axonal polyneuropathy were consistent with BAG3-related myopathy. Our patients showed remarkably mild presentations without cardiomyopathy, unlike the majorities of previously reported cases.

[A patient with neurosarcoidosis presenting with easy falling and dysphagia].

A 68-year-old woman was referred to our hospital for progressive dizziness, gait disturbances and weight loss for 18 months. The patient was alert and showed dysphagia and a marked tendency to fall backward. Electronystagmography showed bilateral vestibular dysfunction and audiometry showed right sensorineural hearing disturbance. Cerebrospinal fluid exam showed mononuclear pleocytosis and elevated protein levels. On 18F-FDG PET/CT, abnormal uptake was observed in the mediastinal lymph nodes, from which biopsy specimens were obtained. Histological findings showed non-caseous granuloma and a diagnosis of bilateral vestibulocochlear, glossopharyngeal and vagal nerve palsies due to neurosarcoidosis was made. Steroid therapy resulted in improvement in her clinical symptoms. Neurosarcoidosis should be included in the differential diagnosis of patients showing progressive easy falling and dysphagia.

A case report of cryptococcal meningitis associated with ruxolitinib.

We herein report a 76-year-old Japanese man with myelofibrosis who developed cryptococcal meningitis. After treatment for 5 months with ruxolitinib, the patient presented with fever and disturbance of consciousness. Marked nuchal stiffness was noted. The magnetic resonance imaging results of the brain were normal. Lumbar puncture showed an opening cerebrospinal fluid (CSF) pressure of 110 mm H2O, pleocytosis (85 mononuclear cells and 222 polymorphonuclear cells/µL), decreased CSF/serum glucose ratio (43%), and elevated protein (194 mg/dL). Blood and CSF cultures grew no bacteria or fungi. However, cryptococcal antigen was detected in the blood and CSF samples. We discontinued ruxolitinib and started administration of amphotericin B. His condition improved gradually 1 week after initiation of treatment. There have been only a few reports on cryptococcal meningitis associated with ruxolitinib. Physicians should consider the possibility of cryptococcal meningitis in patients receiving ruxolitinib.

[Two adult patients with acute necrotizing encephalopathy following influenza virus infection].

Influenza encephalopathy is characterized by high fever, disturbance of consciousness following influenza virus infection. We encountered 2 adult patients with influenza-associated acute necrotizing encephalopathy (Case 1, a 70-year-old woman with diabetes; Case 2, a 49-year-old woman with multiple myeloma), showing hemorrhagic lesions in the bilateral thalamus. Case 1 presented with fever and disturbance of consciousness followed by status epilepticus, and Case 2 developed fever and drowsiness as initial manifestation. Influenza type A was positive in Case 1 and influenza type B was positive in Case 2. In the acute phase, 2 patients required respiratory ventilation and were treated with anti-influenza drug, steroid and immunoglobulin. Cognitive impairment remained in the both patients in the chronic phase. When acute necrotizing encephalopathy is suspected, intensive treatment should be started as early as possible to improve clinical outcome of patients.

Plasma prostaglandin D2 synthase levels in sleep and neurological diseases.

BACKGROUND: Prostaglandin D2 (PGD2) induces sleep and may play a role in sleep and neurological disorders. We investigated PGD synthase (PGDS) levels in various sleep and neurological disorders. METHODS: Sixty-three patients with neurological or sleep disorders (Parkinson's disease with excessive daytime sleepiness (PDS), n = 19; PD without sleepiness (PDWS), n = 14; Alzheimer's disease (AD), n = 10; narcolepsy (NA), n = 10; sleep apnea syndrome (SAS), n = 10) and 21 healthy controls were included in this study. Plasma lipocalin-type PGDS (L-PGDS) and glutathione-dependent hematopoietic PGDS (H-PGDS) levels were assessed using an enzyme-linked immunosorbent assay. RESULTS: H-PGDS levels were not significantly different among the groups. Compared with healthy controls, the PDWS, PDS and AD groups had higher levels of L-PGDS. Neither H-PGDS nor L-PGDS levels correlated with scores on the Epworth Sleepiness Scale or Pittsburgh Sleep Quality Index in any group. CONCLUSION: We found higher levels of L-PGDS in patients with neurodegenerative diseases such as PD and AD. Whether increased L-PGDS levels reflect underlying sleepiness or the pathophysiology of neurodegenerative diseases needs further study.

Battey's operation as a treatment for hysteria: a review of a series of cases in the nineteenth century.

Ovarian resection as a treatment for hysteria, called 'Battey's operation' or 'normal ovariotomy', was performed in the nineteenth century. Battey later reported that the resected ovaries appeared to have 'cystic degeneration'. Currently, patients with acute neuropsychiatric symptoms are screened for teratomas for the differential diagnosis of anti-NMDA receptor encephalitis. There is now a hypothesis that ovarian lesions resulting in paraneoplastic encephalitis were among the patients who underwent Battey's operation. We identified 94 published cases of Battey's operation for neuropsychiatric symptoms in the late nineteenth century. Among 36 cases with detailed descriptions, we found 3 patients who showed acute onset neuropsychiatric symptoms with macropathological ovarian findings that were compatible with teratoma. They showed favourable prognoses after surgery and might have motivated the surgeons to perform the operation.