B-cell immune dysregulation with low soluble CD22 levels in refractory seronegative myasthenia gravis.

Myasthenia gravis (MG), primarily caused by acetylcholine receptor (AChR) autoantibodies, is a chronic autoimmune disorder causing severe muscle weakness and fatigability. In particular, seronegative MG constitutes 10%-15% of MG cases and presents diagnostic challenges especially in early-onset female patients who often show severe disease and resistance to immunosuppressive therapy. Furthermore, the immunopathology of seronegative MG remains unclear. Thus, in this study, we aimed to elucidate the pathogenic mechanism of seronegative MG using scRNA-seq analysis and plasma proteome analysis; in particular, we investigated the relationship between immune dysregulation status and disease severity in refractory seronegative MG. Employing single-cell RNA-sequencing and plasma proteome analyses, we analyzed peripheral blood samples from 30 women divided into three groups: 10 healthy controls, 10 early-onset AChR-positive MG, and 10 refractory early-onset seronegative MG patients, both before and after intravenous immunoglobulin treatment. The disease severity was evaluated using the MG-Activities of Daily Living (ADL), MG composite (MGC), and revised 15-item MG-Quality of Life (QOL) scales. We observed numerical abnormalities in multiple immune cells, particularly B cells, in patients with refractory seronegative MG, correlating with disease activity. Notably, severe MG cases had fewer regulatory T cells without functional abnormalities. Memory B cells were found to be enriched in peripheral blood cells compared with naïve B cells. Moreover, plasma proteome analysis indicated significantly lower plasma protein levels of soluble CD22, expressed in the lineage of B-cell maturation (including mature B cells and memory B cells), in refractory seronegative MG patients than in healthy donors or patients with AChR-positive MG. Soluble CD22 levels were correlated with disease severity, B-cell frequency, and RNA expression levels of CD22. In summary, this study elucidates the immunopathology of refractory seronegative MG, highlighting immune disorders centered on B cells and diminished soluble CD22 levels. These insights pave the way for novel MG treatment strategies focused on B-cell biology.

Phenotypic Insights Into Anti-IgLON5 Disease in IgLON5-Deficient Mice.

BACKGROUND AND OBJECTIVES: Anti-IgLON5 disease is an autoimmune neurodegenerative disorder characterized by various phenotypes, notably sleep and movement disorders and tau pathology. Although the disease is known to be associated with the neuronal cell adhesion protein IgLON5, the physiologic function of IgLON5 remains elusive. There are conflicting views on whether autoantibodies cause loss of function, activation of IgLON5, or inflammation-associated neuronal damage, ultimately leading to the disease. We generated IgLON5 knockout (-/-) mice to investigate the functions of IgLON5 and elucidate the pathomechanism of anti-IgLON5 disease. METHODS: IgLON5 knockout (-/-) mice underwent behavioral tests investigating motor function, psychiatric function (notably anxiety and depression), social and exploratory behaviors, spatial learning and memory, and sensory perception. Histologic analysis was conducted to investigate tau aggregation in mice with tauopathy. RESULTS: IgLON5-/- mice had poorer performance in the wire hang and rotarod tests (which are tests for motor function) than wild-type mice. Moreover, IgLON5-/- mice exhibited decreased anxiety-like behavior and/or hyperactivity in behavior tests, including light/dark transition test and open field test. IgLON5-/- mice also exhibited poorer remote memory in the contextual fear conditioning test. However, neither sleeping disabilities assessed by EEG nor tau aggregation was detected in the knockout mice. DISCUSSION: These results suggest that IgLON5 is associated with activity, anxiety, motor ability, and contextual fear memory. Comparing the various phenotypes of anti-IgLON5 disease, anti-IgLON5 disease might partially be associated with loss of function of IgLON5; however, other phenotypes, such as sleep disorders and tau aggregation, can be caused by gain of function of IgLON5 and/or neuronal damage due to inflammation. Further studies are needed to elucidate the role of IgLON5 in the pathogenesis of anti-IgLON5 diseases.

Non-lesional white matter changes depicted by q-space diffusional MRI correlate with clinical disabilities in multiple sclerosis.

BACKGROUND: We previously developed an optimized q-space diffusional MRI technique (normalized leptokurtic diffusion [NLD] map) to delineate the demyelinated lesions of multiple sclerosis (MS) patients. Herein, we evaluated the utility of NLD maps to discern the white matter abnormalities in normal-appearing white matter (NAWM) and the abnormalities' possible associations with physical and cognitive disabilities in MS. METHODS: We conducted a retrospective observational study of MS patients treated at our hospital (Jan. 2012 to Dec. 2022). Clinical and MRI data were collected; Processing Speed Test (PST) data were obtained when possible. For a quantitative analysis of the NLD maps, we calculated the NLD index as GVROI/GVREF, where GV is a mean grayscale value in the regions of interest (ROIs) and the reference area (REF; cerebrospinal fluid). RESULTS: One hundred-one individuals with MS were included. The lower corpus callosum and non-lesional WM NLD index were associated with worse Expanded Disability Status Scale (EDSS) and PST scores. The NLD indexes in the corpus callosum (p < 0.0001) and non-lesional white matter (p < 0.0001) were significantly reduced in progressive MS compared to relapsing-remitting MS. We categorized MS severity as moderate/severe (EDSS score ≥ 4 points) and mild (EDSS score < 4 points). The NLD indexes in the corpus callosum (p < 0.0001) and non-lesional white matter (p < 0.0001) were significantly lower in the moderate/severe MS group compared to the mild MS group. CONCLUSION: The NLD map revealed abnormalities in the non-lesional white matter, providing valuable insights for evaluating manifestations in MS patients.

Prevalence of Primary Headache in Nurses in Japan: A Cross-sectional Single-center Study.

Objective This study examined the prevalence of migraine in nurses in Japan, which, to our knowledge, has not been documented in English. Methods From April to May 2021, we administered a questionnaire to 229 nurses working at Keio University Hospital to investigate the prevalence and characteristics of headache among nurses in Japan. Headaches were classified as migraine or tension-type headache (TTH) based on the International Classification of Headache Disorders-3 (ICHD-3). Results In total, 80 patients (34.9%) had primary headaches, including 47 (20.5%) with migraine and probable migraine and 33 (14.4%) with TTH and probable TTH. We found a significant difference in the Numerical Rating Scale score, nausea and vomiting, photophobia, phonophobia, and aggravation by routine physical activity between migraine and TTH. The specificities for a migraine diagnosis were 100% and 93.9% for nausea/vomiting and photophobia, respectively. Only 8.8% of patients had their headaches diagnosed by a physician. Conclusion Migraines have a high prevalence (>20%) among nurses and are often under-diagnosed. In many cases, headache-associated symptoms are more important than laterality or other characteristics for the diagnosis. Many nurses are treated for headaches without a correct diagnosis. Further education regarding primary headaches may be necessary for health practitioners as well as society.

Cerebral Venous Thrombosis Mimicking Limbic Encephalitis.

Cerebral venous thrombosis (CVT) is challenging to diagnose, as it presents with variable symptoms. We encountered a complicated case of CVT that mimicked limbic encephalitis due to sensory aphasia. Based on the characteristic magnetic resonance imaging findings, this 72-year-old Japanese man was later confirmed to have CVT, the cause of which was periodontitis due to Eikenella corrodens, a Gram-negative facultative anaerobic that is part of the mouth's normal flora. The symptoms improved without sequelae following anticoagulation treatment and antibiotics. Clinicians should consider CVT as a differential diagnosis when unexplainable neurological symptoms suggesting limbic encephalitis are observed.

COVID-19 vaccination elicited de novo and recurrence of cluster headache: A case series.

BACKGROUND: Recent pharmacovigilance studies suggested that cluster headache could be a potential adverse effect after coronavirus disease-2019 (COVID-19) vaccination; however, the possibility of coincidence could not be excluded. Detailed case studies might help elucidate their potential link and implicate potential pathogenic mechanisms. METHODS: Patients who developed cluster headache in close temporal relationship to COVID-19 vaccination were identified from two tertiary medical centers in Japan and Taiwan respectively through 2021-2022. Detailed characteristics of the headaches and time between the onset of the index cluster episode and antecedent COVID-19 vaccination were reported. In patients with previous cluster headaches, the duration from previous bout was also recorded. RESULTS: Six patients with new cluster headache bout 3-17 days after COVID-19 vaccination were identified. Two of them were de novo cases. The others either had been attack-free for a long time or developed new cluster bout in seasons atypical to prior bouts. The vaccines included mRNA, viral vector, or protein subunit vaccines. CONCLUSIONS: COVID-19 vaccines, regardless of vaccine types, may elicit de novo or relapse of cluster headache. Future studies are needed to confirm the potential causality and explore the potential pathogenic mechanism.

Real-world evidence of galcanezumab for migraine treatment in Japan: a retrospective analysis.

OBJECTIVE: To evaluate the efficacy and safety of galcanezumab in patients with migraine in a real-world setting in Japan. BACKGROUND: Galcanezumab is the first anti-calcitonin gene-related peptide monoclonal antibody approved in Japan. To the best of our knowledge, no real-world studies on galcanezumab have been published in any international journal from Japan. METHODS: We retrospectively examined patients with migraine who received three doses of galcanezumab between August 2021 and February 2022 at the Keio University Hospital. We assessed changes in monthly migraine days, responder rate, and migraine-associated and premonitory symptoms. We also investigated injection site reactions and adverse events. RESULTS: Fifty-two patients received three doses of galcanezumab during the study period. Compared with those at baseline, the monthly migraine days decreased by 5.9 days (95% confidence interval, 4.2-7.7) at 3 months. The 50% responder rate was 61.5% at 3 months. A total of 64.9%, 50.0%, and 63.9% of patients showed improvement in the severity of photophobia, phonophobia, and nausea/vomiting, respectively. Premonitory symptoms without subsequent headache were reported in 62.5% of patients. Moreover, injection site reaction was the most common adverse event (34.6%). CONCLUSION: This study revealed the efficacy and safety of galcanezumab for migraineurs in Japan. Galcanezumab also improved migraine-associated symptoms. However, despite a reduction in headaches, premonitory symptoms without subsequent headache were reported in > 50% of the patients at 3 months.

Anemia in female patients with myasthenia gravis.

Myasthenia gravis (MG) is the most common autoimmune neuromuscular disorder, and is more common in women than in men. Anemia is also more common in women. The purpose of this study was to investigate factors associated with anemia and the negative impact of anemia in female MG patients. We investigated factors related to MG and anemia in 215 female patients with MG, who were attending the MG clinic of Keio Hospital between January and December 2021. We statistically evaluated clinical factors related to anemia in patients with and without anemia. Eighty-five patients (40%) had anemia in the past, and 130 patients did not have anemia in the past. There were no significant differences in age at study, age at MG onset, body mass index, or frequency of autoantibodies between the anemia and non-anemia groups. MG severity evaluated by the MG Foundation of America classification was greater in the anemia group than in the non-anemia group. History of anemia was associated with immunosuppressive treatment, such as prednisolone and calcineurin inhibitor treatment. There was a correlation between hemoglobin levels and the MG-quality of life score. Long term immunosuppressive therapy can cause anemia in female MG patients. Anemia may negatively affect the quality of life of female MG patients.

Immunodeficiency in patients with thymoma-associated myasthenia gravis.

Thymoma with immunodeficiency is sometimes accompanied by myasthenia gravis (MG), but the clinical characteristics have not been elucidated. This study aimed to characterize its clinical and immunological features. Of the 132 thymoma-associated MG patients, 9 patients presented with immunodeficiency. All suffered from severe pneumonia, and most had invasive thymoma and autoimmune disorders. DRB1*08:03 and DQB1*06:01 alleles were frequently detected. Compared to group without immunodeficiency, they showed no significant differences in the severity of MG, significantly lower IgG concentrations and higher mortality rate. Thymoma-associated MG with immunodeficiency is a distinct subset requiring special attention to prevent infection during the follow-up period.

Incidence of headache after COVID-19 vaccination in patients with history of headache: A cross-sectional study.

BACKGROUND: Headache is an adverse event of coronavirus 2019 (COVID-19) vaccination. Whether patients with history of headache suffer more from vaccination-induced headaches is unknown. We aimed to uncover if headache patients develop more headaches after COVID-19 mRNA vaccination than healthy controls. METHODS: We performed a questionnaire survey for nursing staff in our hospital from April to May 2021. Based on baseline characteristics, we divided the participants into migraine, non-migrainous headache, and healthy control, and examined the occurrence and features of headache after COVID-19 vaccinations. RESULTS: We included 171 participants (15.2% migraine and 24.6% non-migrainous headache). Headache incidence after vaccinations was significantly higher in the migraine (69.2%) and non-migrainous headache (71.4%) groups than in the healthy control (37.9%) group. The incidence of headaches was significantly higher after the second dose compared to the first (45.6% vs. 20.5%). CONCLUSION: Migraineurs and non-migrainous headache participants developed more headaches compared to the healthy controls after COVID-19 vaccination.

Meningitis caused by Listeria monocytogenes in a locally advanced cervical cancer patient with pyometra: A case report.

Locally advanced cervical cancer occasionally induces pyometra, but there have been no reports of meningitis where pyometra is the cause of infection. Here, we report a case of Listeria monocytogenes meningitis related to pyometra during concurrent chemoradiotherapy (CCRT) in a cervical cancer patient. The patient, a 77-year-old woman, was diagnosed with Stage IIB (FIGO 2018) cervical adenocarcinoma, and CCRT was initiated. Pyometra was exacerbated during CCRT, and after her first brachytherapy, she presented at our hospital with fever and decreased consciousness level. After admission to the Intensive Care Unit, the patient lost consciousness and experienced frequent seizures; tracheal intubation was required. Whole-body computed tomography revealed pyometra; therefore, transvaginal removal of the abscess was performed. Laboratory tests and vital signs indicated septic shock, and meropenem was administered. L. monocytogenes was detected in the abscess from the uterine cavity and the blood cultures on the third day of hospitalization. A lumbar puncture was performed on the same day to investigate whether the patient had meningitis. A FilmArray meningitis/encephalitis panel test of the spinal fluid revealed L. monocytogenes. After the diagnosis of meningitis with L. monocytogenes, ampicillin and gentamicin were started, and the blood test results gradually improved. Five months after the initial episode, her consciousness recovered, however she still received mechanical ventilatory support. L. monocytogenes infections can occur in patients undergoing chemotherapy, even without the use of steroids or immunosuppressive agents. In cases with pyometra, intrauterine manipulation can increase the risk of severe infection.

Three port logic gate using forward volume spin wave interference in a thin yttrium iron garnet film.

We demonstrate a logic gate based on interference of forward volume spin waves (FVSWs) propagating in a 54 nm thick, 100 µm wide yttrium iron garnet waveguide grown epitaxially on a garnet substrate. Two FVSWs injected by coplanar waveguides were made to interfere constructively and destructively by varying their phase difference, showing an XNOR logic function. The reflected and resonant waves generated at the edges of the waveguide were suppressed using spin wave absorbers. The observed isolation ratio was 19 dB for a magnetic field of ~2.80 kOe ( = 223 kA m-1) applied perpendicular to the film. The wavelength and device length were ~8.9 µm and ~53 µm, respectively. Further, the interference state of the SWs was analyzed using three-dimensional radio frequency simulations.

Spin-wave propagation in cubic anisotropy materials.

The information carrier of modern technologies is the electron charge whose transport inevitably generates Joule heating. Spin-waves, the collective precessional motion of electron spins, do not involve moving charges and thus avoid Joule heating [1-3]. In this respect, magnonic devices in which the information is carried by spin-waves attract interest for low-power computing. However implementation of magnonic devices for practical use suffers from low spin-wave signal and on/off ratio. Here we demonstrate that cubic anisotropy materials can enhance spin-wave signals by improving spin-wave amplitude as well as group velocity and attenuation length. Furthermore, cubic anisotropy material shows an enhanced on/off ratio through a laterally localized edge mode, which closely mimics the gate-controlled conducting channel in traditional field-effect transistors. These attractive features of cubic anisotropy materials will invigorate magnonics research towards wave-based functional devices.

The role of Snell's law for a magnonic majority gate.

In the fifty years since the postulation of Moore's Law, the increasing energy consumption in silicon electronics has motivated research into emerging devices. An attractive research direction is processing information via the phase of spin waves within magnonic-logic circuits, which function without charge transport and the accompanying heat generation. The functional completeness of magnonic logic circuits based on the majority function was recently proved. However, the performance of such logic circuits was rather poor due to the difficulty of controlling spin waves in the input junction of the waveguides. Here, we show how Snell's law describes the propagation of spin waves in the junction of a Ψ-shaped magnonic majority gate composed of yttrium iron garnet with a partially metallized surface. Based on the analysis, we propose a magnonic counterpart of a core-cladding waveguide to control the wave propagation in the junction. This study has therefore experimentally demonstrated a fundamental building block of a magnonic logic circuit.

Demonstration of a robust magnonic spin wave interferometer.

Magnonics is an emerging field dealing with ultralow power consumption logic circuits, in which the flow of spin waves, rather than electric charges, transmits and processes information. Waves, including spin waves, excel at encoding information via their phase using interference. This enables a number of inputs to be processed in one device, which offers the promise of multi-input multi-output logic gates. To realize such an integrated device, it is essential to demonstrate spin wave interferometers using spatially isotropic spin waves with high operational stability. However, spin wave reflection at the waveguide edge has previously limited the stability of interfering waves, precluding the use of isotropic spin waves, i.e., forward volume waves. Here, a spin wave absorber is demonstrated comprising a yttrium iron garnet waveguide partially covered by gold. This device is shown experimentally to be a robust spin wave interferometer using the forward volume mode, with a large ON/OFF isolation value of 13.7 dB even in magnetic fields over 30 Oe.

Characterization of a human isolate of Tritrichomonas foetus (cattle/swine genotype) infected by a zoonotic opportunistic infection.

Tritrichomonas species flagellates (IMC strain) were isolated from the biliary tract of an individual who had developed cholecystitis as a complication of acquired agammaglobulinemia. Sequence analysis of Tritrichomonas sp. (IMC clone 2 (cl2)) was performed for several genetic regions including the ITS1-5.8S rDNA-ITS2 region, the cysteine protease (CP)-1, CP-2 and CP-4 to CP-9 genes, and the cytosolic malate dehydrogenase 1 gene. In addition to comparison of the variable-length DNA repeats in the isolate clone with those in T. foetus (Inui cl2) and the T. mobilensis (U.S.A.: M776 cl2) reference strains, this analysis showed that the Tritrichomonas sp. (IMC cl2) was T. foetus (cattle/swine genotype). Injection of T. foetus (IMC cl2) directly into the livers of CBA mice resulted in liver abscess formation on Day 7. Moreover, inoculation via orogastric intubation caused infection in the cecum on Day 5 in CBA mice co-infected with Entamoeba histolytica (HM-1: IMSS cl6). T. foetus (IMC cl2) was able to grow in YI-S medium for over 20 days, even at 5°C. These results indicate that the T. foetus isolate is able to survive in the feces and edible organ meat of the definitive host for a prolonged period of time, and it is possible that the parasite could infect humans.

System of laser pump and synchrotron radiation probe microdiffraction to investigate optical recording process.

We have developed a system of laser-pump and synchrotron radiation probe microdiffraction to investigate the phase-change process on a nanosecond time scale of Ge2Sb2Te5 film embedded in multi-layer structures, which corresponds to real optical recording media. The measurements were achieved by combining (i) the pump-laser system with a pulse width of 300 ps, (ii) a highly brilliant focused microbeam with wide peak-energy width (ΔE∕E ~ 2%) made by focusing helical undulator radiation without monochromatization, and (iii) a precise sample rotation stage to make repetitive measurements. We successfully detected a very weak time-resolved diffraction signal by using this system from 100-nm-thick Ge2Sb2Te5 phase-change layers. This enabled us to find the dependence of the crystal-amorphous phase change process of the Ge2Sb2Te5 layers on laser power.

Time-domain measurement of current-induced spin wave dynamics.

The performance of spintronic devices critically depends on three material parameters, namely, the spin polarization in the current (P), the intrinsic Gilbert damping (α), and the coefficient of the nonadiabatic spin transfer torque (ß). However, there has been no method to determine these crucial material parameters in a self-contained manner. Here we show that P, α, and ß can be simultaneously determined by performing a single series of time-domain measurements of current-induced spin wave dynamics in a ferromagnetic film.