Syk inhibitors reduce tau protein phosphorylation and oligomerization.

Spleen tyrosine kinase (Syk), a non-receptor-type tyrosine kinase, has a wide range of physiological functions. A possible role of Syk in Alzheimer's disease (AD) has been proposed. We evaluated the localization of Syk in the brains of patients with AD and control participants. Human neuroblastoma M1C cells harboring wild-type tau (4R0N) were used with the tetracycline off (TetOff) induction system. In this model of neuronal tauopathy, the effects of the Syk inhibitors-BAY 61-3606 and R406-on tau phosphorylation and oligomerization were explored using several phosphorylated tau-specific antibodies and an oligomeric tau antibody, and the effects of these Syk inhibitors on autophagy were examined using western blot analyses. Moreover, the effects of the Syk inhibitor R406 were evaluated in vivo using wild-type mice. In AD brains, Syk and phosphorylated tau colocalized in the cytosol. In M1C cells, Syk protein (72 kDa) was detected using western blot analysis. Syk inhibitors decreased the expression levels of several tau phosphoepitopes including PHF-1, CP13, AT180, and AT270. Syk inhibitors also decreased the levels of caspase-cleaved tau (TauC3), a pathological tau form. Syk inhibitors increased inactivated glycogen synthase kinase 3ß expression and decreased active p38 mitogen-activated protein kinase expression and demethylated protein phosphatase 2 A levels, indicating that Syk inhibitors inactivate tau kinases and activate tau phosphatases. Syk inhibitors also activated autophagy, as indicated by increased LC3II and decreased p62 levels. In vivo, the Syk inhibitor R406 decreased phosphorylated tau levels in wild-type mice. These findings suggest that Syk inhibitors offer novel therapeutic strategies for tauopathies, including AD.

Factors affecting the antimicrobial changes during treatment for acute otitis media in Japan: A retrospective cohort study using classification and regression trees (CART) analysis.

OBJECTIVES: Factors that affect the change of first-line antimicrobial agents were investigated to further promote their appropriate use. METHODS: This descriptive study used an electronic medical records database. Total 16,353 of the 199,896 patients enrolled between 1996 and 2019 met the inclusion criteria and formed the overall pediatric acute otitis media (AOM) cohort. The factors leading to the change in first-line antimicrobial agents within 14 days were analyzed using classification and regression trees (CART) analysis. RESULTS: This antimicrobial treatment cohort, involved 4860 cases of AOM alone and 9567 cases of AOM with other diseases. The size of the medical facility based on number of beds and historical duration of patient registration impacted on antimicrobial changes. CONCLUSIONS: The current results show that hospital-wide or nation-wide antimicrobial stewardship promotion could be the most influencing factor for antimicrobial changes. Particularly in cases of AOM where other diseases coexist, a more accurate diagnosis and definition of treatment failure of first-line drug are suggested to be important while establishing future treatment strategies. The current study is important to promote appropriate antimicrobial use for AOM treatment.

A case of anti-SAE1/2 antibody-positive dermatomyositis with extensive panniculitis: A possible cutaneous manifestation of treatment resistance.

Dermatomyositis constitutes a heterogeneous group of autoimmune inflammatory conditions with a wide variety of clinical outcomes. The symptomatic heterogeneity carries skin, muscle, and joint manifestations; pulmonary and cardiac involvements; and concomitant malignancy. Any of these symptoms often appear at different combinations and time courses, thus posing difficulty in early diagnosis and appropriate treatment choice. Recent progress in laboratory investigations explored the identification of several myositis-specific autoantibodies (MSAs) and myositis-associated autoantibodies, allowing precise characterization for a clinical perspective of the disease. MSAs can be detectable in approximately 80% of patients with whole dermatomyositis, some of which closely reflect unique clinical features in the particular disease subset(s), including the distribution and severity of organ involvement, treatment response, and prognosis. However, only limited evidence has been available in dermatomyositis-associated panniculitis, mostly that in anti- melanoma differentiation-associated protein 5 antibody-positive disease. We present a rare case of a patients with dermatomyositis with extensive panniculitis on the trunk whose serum IgG autoantibodies reacted with both subunits of small ubiquitin-like modifier activating enzymes (SAEs), SAE1 and SAE2. The onset of panniculitis coincided with increased disease activity, including disease-related skin manifestations, fever, dysphagia, and muscle weakness in the extremities. These symptoms responded well to a high dose of systemic steroid, but even upon receiving a high-dose intravenous immunoglobulin, the panniculitic lesions and pruritic erythema flared with tapering of steroid dose, further requiring tacrolimus and mycophenolate mofetil to achieve disease remission. To our knowledge, this is the third reported case of anti-SAE autoantibody-positive dermatomyositis with panniculitis. We aim to extend the understanding of the current limitation and further perspective in the clinical management of the extremely rare skin manifestation associated with dermatomyositis.

Magnetic resonance imaging arterial spin labeling hypoperfusion with diffusion-weighted image hyperintensity is useful for diagnostic imaging of Creutzfeldt-Jakob disease.

Background and objectives: Magnetic resonance imaging with arterial spin labeling (ASL) perfusion imaging is a noninvasive method for quantifying cerebral blood flow (CBF). We aimed to evaluate the clinical utility of ASL perfusion imaging to aid in the diagnosis of Creutzfeldt-Jakob disease (CJD). Methods: This retrospective study enrolled 10 clinically diagnosed with probable sporadic CJD (sCJD) based on the National CJD Research & Surveillance Unit and EuroCJD criteria and 18 healthy controls (HCs). Diffusion-weighted images (DWIs), CBF images obtained from ASL, N-isopropyl-(123I)-p-iodoamphetamine (123IMP)-single-photon emission computed tomography (SPECT) images, and 18F-fluorodeoxyglucose (18FDG)-positron emission tomography (PET) images were analyzed. First, the cortical values obtained using volume-of-interest (VOI) analysis were normalized using the global mean in each modality. The cortical regions were classified into DWI-High (≥ +1 SD) and DWI-Normal (< +1 SD) regions according to the DWI-intensity values. The normalized cortical values were compared between the two regions for each modality. Second, each modality value was defined as ASL hypoperfusion (< -1 SD), SPECT hypoperfusion (< -1 SD), and PET low accumulation (< -1 SD). The overall agreement rate of DWIs with ASL-CBF, SPECT, and PET was calculated. Third, regression analyses between the normalized ASL-CBF values and normalized SPECT or PET values derived from the VOIs were performed using a scatter plot. Results: The mean values of ASL-CBF (N = 10), 123IMP-SPECT (N = 8), and 18FDG-PET (N = 3) in DWI-High regions were significantly lower than those in the DWI-Normal regions (p < 0.001 for all); however, HCs (N = 18) showed no significant differences in ASL-CBF between the two regions. The overall agreement rate of DWI (high or normal) with ASL-CBF (hypoperfusion or normal) (81.8%) was similar to that of SPECT (85.2%) and PET (78.5%) in CJD. The regression analysis showed that the normalized ASL-CBF values significantly correlated with the normalized SPECT (r = 0.44, p < 0.001) and PET values (r = 0.46, p < 0.001) in CJD. Discussion: Patients with CJD showed ASL hypoperfusion in lesions with DWI hyperintensity, suggesting that ASL-CBF could be beneficial for the diagnostic aid of CJD.

A Photoredox/Sulfide Dual Catalysis System That Uses Sulfide Radical Cations to Promote Alkene Chlorotrifluoromethylation.

Sulfides and their derivatives are among the most important class of reagent in synthetic chemistry. Despite the importance of such compounds, the use of sulfide radical cations in synthetic chemistry is underdeveloped. To address this issue, herein, we describe alkene chlorotrifluoromethylation reactions promoted by photoredox/sulfide dual catalysis systems, which involves sulfide radical cations generated through the oxidation of sulfides by a photoredox catalyst. The high functional group tolerance of this chemistry was demonstrated using natural products and drug molecules as substrate alkenes.

Magnetic resonance imaging findings of the lower limb muscles in anti-mitochondrial M2 antibody-positive myositis.

Anti-mitochondrial M2 antibody (AMA-M2)-positive myositis is an idiopathic inflammatory myopathy (IIM). Of all patients with myositis, 2.5-19.5% have AMA-M2 antibodies. However, the detailed distribution of muscles affected in AMA-positive myositis is unknown. Therefore, we examined lower muscle magnetic resonance imaging (MRI) findings of patients with AMA-positive myositis. Among the 63 patients with IIM at our institute, 5 (7.9%) were positive for AMA-M2 antibodies. However, one was also positive for anti-Jo1 antibodies; therefore, four patients were finally participated in this study. All patients had high-intensity MRI signals in the proximal muscles, including the gluteus maximus and iliopsoas muscles, and in the thigh muscles, including the vastus lateralis, vastus medialis, adductor magnus, and semimembranosus muscles. Lower leg muscles were relatively spared. Fascial edema was observed in all patients and was also present in the lower leg muscles. Subcutaneous edema was observed, particularly in the proximal portion of the lower limbs. In AMA-positive myositis, proximal muscles, including the gluteus maximus, vastus lateralis, adductor magnus, and the semimembranosus, were markedly affected, while the lower leg muscles were relatively preserved. Additionally, fascial edema was evident even in lower leg muscles. Therefore, muscle MRI can be a useful diagnostic aid for AMA-positive myositis.

Regional cortical hypoperfusion and atrophy correlate with striatal dopaminergic loss in Parkinson's disease: a study using arterial spin labeling MR perfusion.

PURPOSE: To investigate the relationship of the striatal dopamine transporter density to changes in the gray matter (GM) volume and cerebral perfusion in patients with Parkinson's disease (PD). METHODS: We evaluated the regional cerebral blood flow (CBF) and GM volume, concurrently measured using arterial spin labeling and T1-weighted magnetic resonance imaging, respectively, as well as the striatal specific binding ratio (SBR) in 123I-N-ω-fluoropropyl-2ß-carboxymethoxy-3ß-(4-iodophenyl)nortropane (123I-FP-CIT) single-photon emission computed tomography in 30 non-demented patients with PD (15 men and 15 women; mean age, 67.2 ± 8.8 years; mean Hoehn-Yahr stage, 2.2 ± 0.9). Voxel-wise regression analyses using statistical parametric mapping (SPM) were performed to explore the brain regions that showed correlations of the striatal SBR to the GM volume and CBF, respectively, with a height threshold of p < 0.0005 at the voxel level and p < 0.05 family-wise error-corrected at the cluster level. RESULTS: SPM analysis showed a significant positive correlation between the SBR and GM volume in the inferior frontal gyrus (IFG). Whereas, a positive correlation between the SBR and CBF was widely found in the frontotemporal and parietotemporal regions, including the IFG. Notably, the opercular part of the IFG showed significant correlations in both SPM analyses of the GM volume (r2 = 0.90, p < 0.0001) and CBF (r2 = 0.88, p < 0.0001). CONCLUSION: The voxel-wise analyses revealed the brain regions, mainly the IFG, that showed hypoperfusion and atrophy related to dopaminergic loss, which suggests that the progression of dopaminergic neurodegeneration leads to regional cortical dysfunction in PD.

Arterial spin labeling imaging for the detection of cerebral blood flow asymmetry in patients with corticobasal syndrome.

PURPOSE: Corticobasal syndrome (CBS) and Parkinson's disease (PD) both present with asymmetrical extrapyramidal symptoms, often leading to a diagnostic dilemma. Patients with CBS frequently show cerebral blood flow (CBF) asymmetry alongside asymmetrical cortical atrophy. This study aimed to evaluate the clinical utility of arterial spin labeling (ASL) magnetic resonance imaging (MRI) to detect CBF asymmetry in patients with CBS. METHODS: We retrospectively investigated asymmetries of regional CBF and cortical volume, measured using ASL and T1-weighted MRI, in 13 patients with CBS and 22 age-matched patients with PD. Regional CBF and cortical volume values were derived from nine brain regions on each side. CBF and volume asymmetries were calculated as %difference in each region, respectively. RESULTS: CBF asymmetry showed significantly greater differences in seven of nine regions, such as the perirolandic area (- 8.7% vs. - 1.4%, p < 0.001) and parietal cortex (- 9.7% vs. - 1.3%, p < 0.001) in patients with CBS compared with patients with PD. In contrast, significant differences in volume asymmetry were observed in three regions included within the seven regions showing CBF asymmetry, which indicated that CBF asymmetry has greater sensitivity than volume asymmetry to detect asymmetricity in CBS. CONCLUSION: ASL imaging showed significant CBF asymmetry in a wider range of brain regions in patients with CBS, which suggests that noninvasive MRI with ASL imaging is a promising tool for the diagnosis of CBS, with advantages that include the simultaneous evaluation of asymmetrical hypoperfusion in addition to focal atrophy.

Autoimmune basal ganglia encephalitis associated with anti-recoverin antibodies: A case report.

Autoimmune basal ganglia encephalitis causes neurological symptoms such as parkinsonism associated with basal ganglia lesions. Here, we report a case of autoimmune basal ganglia encephalitis without retinal lesions or malignancy harboring anti-recoverin antibodies. The patient was a 67-year-old Japanese woman who developed anorexia, parkinsonism, and disturbance of consciousness 7 days before admission. Brain magnetic resonance imaging showed hyperintense bilateral basal ganglia lesions on fluid-attenuated inversion recovery images. 18F-fluorodeoxyglucose-positron emission tomography showed no malignancy in the trunk, and dopamine transporter single-photon emission computed tomography with dopamine transporters revealed reduced radiotracer uptake in the basal ganglia. Further, anti-recoverin IgG antibodies were detected in serum immunoblot. Based on the clinical and imaging findings, the patient was diagnosed with autoimmune basal ganglia encephalitis with anti-recoverin antibodies and administered high-dose immunoglobulins (HD-IVIG), which led to an improvement in clinical symptoms. Anti-recoverin antibodies are paraneoplastic antibodies that explicitly bind to Ca2+-binding proteins in the retina and cause retinopathy. This pathological sequence is defined as cancer-associated retinopathy (CAR). However, in our case, autoimmune basal ganglia encephalitis developed without CAR syndrome or malignancy. Clinicians should be aware of the possibility of autoimmune basal ganglia encephalitis showing anti-recoverin antibodies but no CAR syndrome or malignancy, which should be treated with HD-IVIG therapy.

Clioquinol Decreases Levels of Phosphorylated, Truncated, and Oligomerized Tau Protein.

The neuropathological hallmarks of Alzheimer's disease (AD) are senile plaques (SPs), which are composed of amyloid ß protein (Aß), and neurofibrillary tangles (NFTs), which consist of highly phosphorylated tau protein. As bio-metal imbalance may be involved in the formation of NFT and SPs, metal regulation may be a direction for AD treatment. Clioquinol (CQ) is a metal-protein attenuating compound with mild chelating effects for Zn2+ and Cu2+, and CQ can not only detach metals from SPs, but also decrease amyloid aggregation in the brain. Previous studies suggested that Cu2+ induces the hyperphosphorylation of tau. However, the effects of CQ on tau were not fully explored. To examine the effects of CQ on tau metabolism, we used a human neuroblastoma cell line, M1C cells, which express wild-type tau protein (4R0N) via tetracycline-off (TetOff) induction. In a morphological study and ATP assay, up to 10 µM CQ had no effect on cell viability; however, 100 µM CQ had cytotoxic effects. CQ decreased accumulation of Cu+ in the M1C cells (39.4% of the control), and both total and phosphorylated tau protein. It also decreased the activity of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK) (37.3% and 60.7% levels of the control, respectively), which are tau kinases. Of note, activation of protein phosphatase 2A (PP2A), which is a tau phosphatase, was also observed after CQ treatment. Fractionation experiments demonstrated a reduction of oligomeric tau in the tris insoluble, sarkosyl soluble fraction by CQ treatment. CQ also decreased caspase-cleaved tau, which accelerated the aggregation of tau protein. CQ activated autophagy and proteasome pathways, which are considered important for the degradation of tau protein. Although further studies are needed to elucidate the mechanisms responsible for the effects of CQ on tau, CQ may shed light on possible AD therapeutics.

A case of eosinophilic fasciitis without skin manifestations: a case report in a patient with lupus and literature review.

Eosinophilic fasciitis (EF) is a rare connective tissue disease that causes inflammation and fibrosis of the fascia, inducing pain and motor dysfunction. Characteristic skin manifestations, such as edema, erythema, induration, peau d'orange appearance, and the groove sign, are of diagnostic significance and observed in the majority of patients with EF. We herein report a case of EF without these characteristic skin manifestations. A 66-year-old Japanese woman developed progressive limb pain and motor dysfunction. No skin changes were observed. We diagnosed the patient with EF based on the clinical course, magnetic resonance imaging, and en bloc biopsy containing fascia and muscle. Oral prednisolone therapy markedly attenuated limb pain and motor dysfunctions. Through a systemic search of the medical literature, we retrieved 4 juvenile cases and 8 adult cases of EF without characteristic skin manifestations during the clinical course. We herein present a systemic review on EF without skin manifestations and discuss differences between the two proposed sets of diagnostic criteria of EF.

Two Japanese LGMDR25 patients with a biallelic recurrent nonsense variant of BVES.

We report two Japanese patients with autosomal recessive limb-girdle muscular dystrophy type R25 (LGMDR25), harboring a novel recurrent homozygous nonsense variant of BVES. Muscle symptoms manifested from childhood to adulthood, initiated in the proximal or distal muscles of the lower limbs, and displayed asymmetric muscle involvement. Similar to the patients in previous reports, these patients also lost ambulation in late middle age. The posterior compartment of the lower limb muscles (biceps femoris, adductor magnus, gastrocnemius, and soleus) was preferentially affected as was the paraspinal muscle. Muscles in the anterior compartment of the thigh were affected in more advanced stages. Both patients had symptomatic atrioventricular block. The POPDC1 protein was undetectable in the muscles of the patients. As observed by transmission electron microscopy, one of the patient samples had fewer caveolae along the sarcolemma than a control sample.

Autoimmune Encephalitis Associated with Anti-gamma-aminobutyric Acid B Receptor Antibodies Mimicking Syncope.

Autoimmune encephalitis associated with autoantibodies to the gamma-aminobutyric acid B receptor (GABABR-AE) typically involves limbic symptoms with limbic abnormalities visible in brain magnetic resonance imaging (MRI). We herein report a case of a 48-year-old man with GABABR-AE whose initial presentation was limited to syncope without limbic symptoms or MRI abnormalities. Interestingly, serial MRI also revealed no abnormalities even after the appearance of limbic symptoms. Our findings suggest that GABABR-AE can initially mimic common syncope and that MRI findings may remain normal throughout the clinical course. Even if patients have normal MRI findings, GABABR-AE should be considered if limbic symptoms worsen.

A case of anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase antibody-positive paraneoplastic necrotizing myopathy associated with advanced gastric cancer that responded to intravenous immunoglobulin therapy.

A 49-year-old woman presented with progressive muscle weakness of the limbs and dysphagia. Her past and family medical history were unremarkable and she did not take statins or any other medications. Laboratory tests showed that serum levels of creatine kinase were elevated (13,565 IU/l) and anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibodies were detected in the serum. Other autoantibodies to the nuclear (ANA), RNP, aminoacyl-tRNA synthetases (ARS), and signal recognition particle (SRP) were negative. Pathological analysis of the left biceps muscle revealed minimal lymphocytic infiltration into the muscle fibers together with many necrotic and regenerated fibers, which corresponded to necrotizing myopathy. Abdominal CT and upper gastrointestinal endoscopy showed an advanced gastric cancer with lymph node metastasis. The patient was subsequently diagnosed with anti-HMGCR antibody-positive paraneoplastic necrotizing myopathy associated with advanced gastric cancer. The patient underwent radical surgery to remove the cancer and was initially treated with oral prednisolone and intravenous methylprednisolone pulse therapy; however, her symptoms worsened and she became bedridden. After an additional treatment with intravenous immunoglobulin (IVIg), she showed noticeable improvements in muscle strength and dysphagia and became ambulatory. This case and recent case-series studies suggest that anti-HMGCR antibody-positive necrotizing myopathy may be included in paraneoplastic syndrome and that physicians should screen for malignant tumors in patients with anti-HMGCR antibody-positive necrotizing myopathy. Moreover, IVIg can be a useful therapy in patients with anti-HMGCR antibody-positive paraneoplastic necrotizing myopathy who show refractoriness to tumor resection and corticosteroid therapies.