Acute onset of constrictive pericarditis due to acute myelomonocytic leukemia: A case and literature review.

We herein present a fatal case of constrictive pericarditis (CP) due to acute myelomonocytic leukemia (AMML) in a patient who initially complained of an acute onset of chest pain two days after COVID-19 vaccination. An autopsy revealed pericardial infiltration of leukemic cells. CP is rarely associated with leukemia and only 14 cases have been reported in the literature. The etiology of CP in previous reports included leukemic infiltration, graft-versus-host disease, drug-induced, post-radiation, autoimmune, and otherwise unidentified. This case indicates that leukemic infiltration can cause CP and that clinicians should include leukemia in the differential diagnosis of CP.

Pla2g5 contributes to viral-like-induced lung inflammation through macrophage proliferation and LA/Ffar1 lung cell recruitment.

Macrophages expressing group V phospholipase A2 (Pla2g5) release the free fatty acid (FFA) linoleic acid (LA), potentiating lung type 2 inflammation. Although Pla2g5 and LA increase in viral infections, their role remains obscure. We generated Pla2g5flox/flox mice, deleted Pla2g5 by using the Cx3cr1cre transgene, and activated bone marrow-derived macrophages (BM-Macs) with poly:IC, a synthetic double-stranded RNA that triggers a viral-like immune response, known Pla2g5-dependent stimuli (IL-4, LPS + IFNγ, IL-33 + IL-4 + GM-CSF) and poly:IC + LA followed by lipidomic and transcriptomic analysis. Poly:IC-activated Pla2g5flox/flox;Cx3cr1cre/+ BM-Macs had downregulation of major bioactive lipids and critical enzymes producing those bioactive lipids. In addition, AKT phosphorylation was lower in poly:IC-stimulated Pla2g5flox/flox;Cx3cr1cre/+ BM-Macs, which was not restored by adding LA to poly:IC-stimulated BM-Macs. Consistently, Pla2g5flox/flox;Cx3cr1cre/+ mice had diminished poly:IC-induced lung inflammation, including inflammatory macrophage proliferation, while challenging Pla2g5flox/flox;Cx3cr1cre/+ mice with poly:IC + LA partially restored lung inflammation and inflammatory macrophage proliferation. Finally, mice lacking FFA receptor-1 (Ffar1)-null mice had reduced poly:IC-induced lung cell recruitment and tissue macrophage proliferation, not corrected by LA. Thus, Pla2g5 contributes to poly:IC-induced lung inflammation by regulating inflammatory macrophage proliferation and LA/Ffar1-mediated lung cell recruitment and tissue macrophage proliferation.

Neuronal DSCAM regulates the peri-synaptic localization of GLAST in Bergmann glia for functional synapse formation.

In the central nervous system, astrocytes enable appropriate synapse function through glutamate clearance from the synaptic cleft; however, it remains unclear how astrocytic glutamate transporters function at peri-synaptic contact. Here, we report that Down syndrome cell adhesion molecule (DSCAM) in Purkinje cells controls synapse formation and function in the developing cerebellum. Dscam-mutant mice show defects in CF synapse translocation as is observed in loss of function mutations in the astrocytic glutamate transporter GLAST expressed in Bergmann glia. These mice show impaired glutamate clearance and the delocalization of GLAST away from the cleft of parallel fibre (PF) synapse. GLAST complexes with the extracellular domain of DSCAM. Riluzole, as an activator of GLAST-mediated uptake, rescues the proximal impairment in CF synapse formation in Purkinje cell-selective Dscam-deficient mice. DSCAM is required for motor learning, but not gross motor coordination. In conclusion, the intercellular association of synaptic and astrocyte proteins is important for synapse formation and function in neural transmission.

Type 1 Cryoglobulinemic Vasculitis Due to Monoclonal Gammopathy of Undetermined Significance Successfully Treated by Bortezomib Plus Dexamethasone.

Cryoglobulins are immunoglobulins that precipitate in cold conditions. Type I cryoglobulinemic vasculitis is associated with hematological malignancies. We herein report a case of steroid-resistant type 1 cryoglobulinemic vasculitis associated with monoclonal gammopathy of undetermined significance (MGUS) in a 47-year-old woman. By immunofixation of cryoglobulin, we found that the main component of cryoglobulin was the M protein due to MGUS, so treatment of MGUS was needed. Bortezomib+dexamethasone therapy resulted in a rapid decrease in cryoglobulin and improvement in the symptoms of cryoglobulinemic vasculitis. In refractory type I cryoglobulinemic vasculitis, treatment of the underlying gammaglobulinopathy should be considered.

Identification of Key Genes and Immunological Features Associated with Copper Metabolism in Parkinson's Disease by Bioinformatics Analysis.

To explore diagnostic genes associated with cuproptosis in Parkinson's disease (PD) and to characterize immune cell infiltration by comprehensive bioinformatics analysis, three PD datasets were downloaded from the GEO database, two of which were merged and preprocessed as the internal training set and the remaining one as the external validation set. Based on the internal training set, differential analysis was performed to obtain differentially expressed genes (DEGs), and weighted gene co-expression network analysis (WGCNA) was conducted to obtain significant module genes. The genes obtained here were intersected to form the intersecting genes. The intersecting genes obtained from DEGs and WGCNA were intersected with cuproptosis-related genes (CRGs) to generate cuproptosis-related disease signature genes, and functional enrichment analysis was performed on Disease Ontology (DO), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG). Subsequently, LASSO analysis of the cuproptosis-related disease signature genes was performed to identify key genes and construct a diagnostic and predictive model. Then, single sample gene set enrichment analysis (ssGSEA) was performed on the internal training set to further analyze the correlation between key genes and immune cells. Lastly, the results were validated using an external validation set. A total of 405 DEGs were obtained by differential analysis, and 6 gene modules were identified by WGCNA analysis. The genes in the most significant modules were intersected with the DEGs to obtain 21 intersecting genes. The functions of the intersecting genes were mainly enriched in neurotransmitter transport, GABA-ergic synapse, synaptic vesicle cycle, serotonergic synapse, phenylalanine metabolism, tyrosine metabolism, tryptophan metabolism, etc. Subsequently, the intersecting genes were intersected with CRGs, and LASSO regression analysis was performed to screen 3 key cuproptosis-related disease signature genes, namely, SLC18A2, SLC6A3, and SV2C. The calibration curve of the nomogram model constructed based on these 3 key genes to predict PD showed good agreement, with a C-index of 0.944 and an area under the ROC (AUC) of 0.944 (0.833-1.000). It was also validated by the external dataset that the model constructed with these 3 key genes had good diagnostic and predictive power for PD. The ssGSEA analysis revealed that neutrophils might be the potential core immune cells and that SLC18A2, SLC6A3, and SV2C were significantly negatively correlated with neutrophils, which was also verified in the validation set. PD diagnosis and prediction model based on CRGs (SLC18A2, SLC6A3, and SV2C) has good diagnostic and predictive performance and could be a useful tool in the diagnosis of PD.

Astrocytes as Drivers and Disruptors of Behavior: New Advances in Basic Mechanisms and Therapeutic Targeting.

Astrocytes are emerging as key regulators of cognitive function and behavior. This review highlights some of the latest advances in the understanding of astrocyte roles in different behavioral domains across lifespan and in disease. We address specific molecular and circuit mechanisms by which astrocytes modulate behavior, discuss their functional diversity and versatility, and highlight emerging astrocyte-targeted treatment strategies that might alleviate behavioral and cognitive dysfunction in pathologic conditions. Converging evidence across different model systems and manipulations is revealing that astrocytes regulate behavioral processes in a precise and context-dependent manner. Improved understanding of these astrocytic functions may generate new therapeutic strategies for various conditions with cognitive and behavioral impairments.

Muscle belly ratio is the most suitable estimate of the activity of the torn supraspinatus muscle.

Background: A torn rotator cuff muscle deteriorates over time leading with an increase in muscle atrophy and fatty infiltration. There are several clinical assessments for evaluating the atrophy of the torn supraspinatus muscle. However, it is unclear which approach can more accurately estimate the activity of the torn supraspinatus muscle. The purpose of this study was to determine which magnetic resonance imaging-based muscle atrophy imaging assessment currently implemented in the clinical setting accurately estimates the activity of the torn supraspinatus muscle. Methods: Forty patients who were diagnosed with a rotator cuff tear and were candidates for repairs were selected for this study. Cross-sectional area, occupation ratio, and tangent sign were analyzed on T1-weighted oblique sagittal plane magnetic resonance images in which the scapular spine leads to the Y-section. Muscle belly ratio of the supraspinatus muscle was analyzed by calculating the ratio of the width of the muscle belly to the distance from the greater tubercle to the proximal end of the muscle on T1-weighted coronal plane magnetic resonance imaging images. Fatty infiltration was evaluated using the Goutallier classification system. Tear size was obtained intraoperatively by measuring the width and length of the tear and classified based on the Cofield's classification. To assess activity of the torn supraspinatus muscle, participants were first instructed to sit on a chair with the affected arm resting on a table and the shoulder abducted to 60° in the scapular plane with neutral rotation. Elasticity of the supraspinatus muscle belly was then obtained at rest and during isometric contraction using with real-time tissue elastography. Muscle activity, a surrogate for contractility, was defined as the difference between the elasticities measured at rest and during isometric contraction. A stepwise multiple regression analysis was used to investigate independent factors, such as sex, tear width, cross-sectional area, occupation ratio, tangent sign, and muscle belly ratio, related to muscle activity. Results: Stepwise multiple regression analysis (R2 = 0.522, P < .001) revealed that supraspinatus muscle activity was significantly correlated with muscle belly ratio (ß = 0.306, P = .044) and Goutallier stage (ß = -0.490, P = .002). Conclusion: Estimations of muscle belly ratio are most suitable for assessing the activity of a torn supraspinatus muscle compared to other clinical measurements.

Glucagon-like Peptide-1 Receptor Pathway Attenuates Platelet Activation in Aspirin-Exacerbated Respiratory Disease.

Platelets are key contributors to allergic asthma and aspirin-exacerbated respiratory disease (AERD), an asthma phenotype involving platelet activation and IL-33-dependent mast cell activation. Human platelets express the glucagon-like peptide-1 receptor (GLP-1R). GLP-1R agonists decrease lung IL-33 release and airway hyperresponsiveness in mouse asthma models. We hypothesized that GLP-1R agonists reduce platelet activation and downstream platelet-mediated airway inflammation in AERD. GLP-1R expression on murine platelets was assessed using flow cytometry. We tested the effect of the GLP-1R agonist liraglutide on lysine-aspirin (Lys-ASA)-induced changes in airway resistance, and platelet-derived mediator release in a murine AERD model. We conducted a prospective cohort study comparing the effect of pretreatment with liraglutide or vehicle on thromboxane receptor agonist-induced in vitro activation of platelets from patients with AERD and nonasthmatic controls. GLP-1R expression was higher on murine platelets than on leukocytes. A single dose of liraglutide inhibited Lys-ASA-induced increases in airway resistance and decreased markers of platelet activation and recruitment to the lung in AERD-like mice. Liraglutide attenuated thromboxane receptor agonist-induced activation as measured by CXCL7 release in plasma from patients with AERD and CD62P expression in platelets from both patients with AERD (n = 31) and nonasthmatic, healthy controls (n = 11). Liraglutide, a Food and Drug Administration-approved GLP-1R agonist for treatment of type 2 diabetes and obesity, attenuates in vivo platelet activation in an AERD murine model and in vitro activation in human platelets in patients with and without AERD. These data advance the GLP-1R axis as a new target for platelet-mediated inflammation warranting further study in asthma.

A short-term three dimensional culture-based drug sensitivity test is feasible for malignant bone tumors.

The feasibility of a short-term, three-dimensional (3D) culture-based drug sensitivity test (DST) for surgically resected malignant bone tumors, including osteosarcoma (OS), was evaluated utilizing two OS cell line (KCS8 or KCS9)-derived xenograft (CDX) models. Twenty-three (KCS8) or 39 (KCS9) of 60 tested drugs were likely effective in OS cells derived from a cell line before xenografting. Fewer drugs (19: KCS8, 26: KCS9) were selected as effective drugs in cells derived from a CDX tumor, although the drug sensitivities of 60 drugs significantly correlated between both types of samples. The drug sensitivity of a CDX tumor was not significantly altered after the depletion of non-tumorous components in the sample. In a surgically resected metastatic tumor obtained from a patient with OS, for whom a cancer genome profiling test detected a pathogenic PIK3CA mutation, DST identified mTOR and AKT inhibitors as effective drugs. Of two CDX and six clinical samples of OS and Ewing's sarcoma, DST identified proteasome inhibitors (bortezomib, carfilzomib) and CEP-701 as potentially effective drugs in common. This unique method of in vitro drug testing using 3D-cell cultures is feasible in surgically resected tissues of metastatic malignant bone tumors.

GPCR-mediated calcium and cAMP signaling determines psychosocial stress susceptibility and resiliency.

Chronic stress increases the risk of developing psychiatric disorders, including mood and anxiety disorders. Although behavioral responses to repeated stress vary across individuals, the underlying mechanisms remain unclear. Here, we perform a genome-wide transcriptome analysis of an animal model of depression and patients with clinical depression and report that dysfunction of the Fos-mediated transcription network in the anterior cingulate cortex (ACC) confers a stress-induced social interaction deficit. Critically, CRISPR-Cas9-mediated ACC Fos knockdown causes social interaction deficits under stressful situation. Moreover, two classical second messenger pathways, calcium and cyclic AMP, in the ACC during stress differentially modulate Fos expression and regulate stress-induced changes in social behaviors. Our findings highlight a behaviorally relevant mechanism for the regulation of calcium- and cAMP-mediated Fos expression that has potential as a therapeutic target for psychiatric disorders related to stressful environments.

Multistep IgE Mast Cell Desensitization Is a Dose- and Time-Dependent Process Partially Regulated by SHIP-1.

Multistep mast cell desensitization blocks the release of mediators following IgE crosslinking with increasing doses of Ag. Although its in vivo application has led to the safe reintroduction of drugs and foods in IgE-sensitized patients at risk for anaphylaxis, the mechanisms of the inhibitory process have remained elusive. We sought to investigate the kinetics, membrane, and cytoskeletal changes and to identify molecular targets. IgE-sensitized wild-type murine (WT) and FcεRIα humanized (h) bone marrow mast cells were activated and desensitized with DNP, nitrophenyl, dust mites, and peanut Ags. The movements of membrane receptors, FcεRI/IgE/Ag, actin, and tubulin and the phosphorylation of Syk, Lyn, P38-MAPK, and SHIP-1 were assessed. Silencing SHIP-1 protein was used to dissect the SHIP-1 role. Multistep IgE desensitization of WT and transgenic human bone marrow mast cells blocked the release of ß-hexosaminidase in an Ag-specific fashion and prevented actin and tubulin movements. Desensitization was regulated by the initial Ag dose, number of doses, and time between doses. FcεRI, IgE, Ags, and surface receptors were not internalized during desensitization. Phosphorylation of Syk, Lyn, p38 MAPK, and SHIP-1 increased in a dose-response manner during activation; in contrast, only SHIP-1 phosphorylation increased in early desensitization. SHIP-1 phosphatase function had no impact on desensitization, but silencing SHIP-1 increased ß-hexoxaminidase release, preventing desensitization. Multistep IgE mast cell desensitization is a dose- and time-regulated process that blocks ß-hexosaminidase, impacting membrane and cytoskeletal movements. Signal transduction is uncoupled, favoring early phosphorylation of SHIP-1. Silencing SHIP-1 impairs desensitization without implicating its phosphatase function.

Subcutaneous Panniculitis-like T-cell Lymphoma Lacking Subcutaneous Tumor Mimicking Adult-onset Still's Disease.

We herein report a case of subcutaneous panniculitis-like T-cell lymphoma (SPTCL) resembling adult-onset Still's disease (AOSD). A 40-year-old woman presented with a fever, erythema, and painful subcutaneous nodules on the trunk. Laboratory data and a bone marrow analysis showed hemophagocytic syndrome. Although AOSD was suspected, based on a histopathological evaluation of the erythema, she was diagnosed with SPTCL. She was refractory to combination chemotherapy but achieved durable remission with cyclosporine monotherapy. Genetic testing revealed a homozygous HAVCR2 c.245A>G variant (rs184868814) that had caused NLRP3 inflammasome activation. SPTCL and AOSD share a pathogenesis in terms of NLRP3 inflammasome activation, so the clinical phenotype of SPTCL reasonably mimics AOSD.

Macrophage P2Y6 Receptor Signaling Selectively Activates NFATC2 and Suppresses Allergic Lung Inflammation.

Innate immune responses to innocuous Ags can either prevent or facilitate adaptive type 2 allergic inflammation, but the mechanisms are incompletely understood. We now demonstrate that macrophage UDP-specific type 6 purinergic (P2Y6) receptors selectively activate NFATC2, a member of the NFAT family, to drive an innate IL-12/IFN-γ axis that prevents type 2 allergic inflammation. UDP priming potentiated IL-12p40 production in bone marrow-derived macrophages (BMMs) stimulated by the house dust mite Dermatophagoides farinae (Df) in a P2Y6-dependent manner. Inhibitions of phospholipase C, calcium increase, and calcineurin eliminated UDP-potentiated Df-induced IL-12p40 production. UDP specifically induced nuclear translocation of NFATC2, but not NFATC1 and NFATC3, in BMMs in a P2Y6-dependent manner. UDP-potentiated IL-12p40 production by BMMs and Df-induced IL-12p40 gene expression by alveolar macrophages were abrogated in cells from Nfatc2 knockout mice. Pulmonary transplantation of wild-type but not Nfatc2 knockout macrophages increased Df-induced IL-12 production and IFN-γ expression in P2ry6 fl/fl/Cre/+ recipient mice. Finally, Nfatc2 knockout mice showed significantly increased indices of type 2 immunopathology in response to Df challenge, similar to P2ry6 fl/fl/Cre/+ mice. Thus, macrophage P2Y6 receptor signaling selectively utilizes NFATC2 to potentiate an innate IL-12/IFN-γ axis, a potential mechanism that protects against inappropriate type 2 immune responses.

Nucleoside Triphosphate Hydrolases Assay in Toxoplasm gondii and Neospora caninum for High-Throughput Screening using a Robot Arm.

Protozoan parasites infect humans and many warm-blooded animals. Toxoplasma gondii, a major protozoan parasite, is commonly found in HIV-positive patients, organ transplant recipients and pregnant women, resulting in the severe health condition, Toxoplasmosis. Another major protozoan, Neospora caninum, which bears many similarities to Toxoplasma gondii, causes serious diseases in animals, as does Encephalomyelitis and Myositis-Polyradiculitis in dogs and cows, resulting in stillborn calves. All these exhibited similar nucleoside triphosphate hydrolases (NTPase). Neospora caninum has a NcNTPase, while Toxoplasma gondii has a TgNTPase-I. The enzymes are thought to play crucial roles in propagation and survival. In order to establish compounds and/or extracts preventing protozoan infection, we targeted these enzymes for drug discovery. The next step was to establish a novel, highly sensitive, and highly accurate assay by combining a conventional biochemical enzyme assay with a fluorescent assay to determine ADP content. We also validated that the novel assay fulfills the criteria to carry out high-throughput screening (HTS) in the two protozoan enzymes. We performed HTS, identified 19 compounds and six extracts from two synthetic compound libraries and an extract library derived from marine bacteria, respectively. In this study, a detailed explanation has been introduced on how to carry out HTS, including information about the preparation of reagents, devices, robot arm, etc.

Requirement of CRMP2 Phosphorylation in Neuronal Migration of Developing Mouse Cerebral Cortex and Hippocampus and Redundant Roles of CRMP1 and CRMP4.

The mammalian cerebral cortex is characterized by a 6-layer structure, and proper neuronal migration is critical for its formation. Cyclin-dependent kinase 5 (Cdk5) has been shown to be a critical kinase for neuronal migration. Several Cdk5 substrates have been suggested to be involved in ordered neuronal migration. However, in vivo loss-of-function studies on the function of Cdk5 phosphorylation substrates in neuronal migration in the developing cerebral cortex have not been reported. In this study, we demonstrated that Cdk5-mediated phosphorylation of collapsing mediator protein (CRMP) 2 is critical for neuronal migration in the developing cerebral cortex with redundant functions of CRMP1 and CRMP4. The cerebral cortices of triple-mutant CRMP1 knock-out (KO); CRMP2 knock-in (KI)/KI; and CRMP4 KO mice showed disturbed positioning of layers II-V neurons in the cerebral cortex. Further experiments using bromodeoxyuridine birthdate-labeling and in utero electroporation implicated radial migration defects in cortical neurons. Ectopic neurons were detected around the CA1 region and dentate gyrus in CRMP1 KO; CRMP2 KI/KI; and CRMP4 KO mice. These results suggest the importance of CRMP2 phosphorylation by Cdk5 and redundancy of CRMP1 and CRMP4 in proper neuronal migration in the developing cerebral cortex and hippocampus.

Convulsive Seizure Due to Hypomagnesemia Caused by Short-term Vonoprazan Intake.

A 71-year-old woman was admitted for the treatment of diffuse large B-cell lymphoma of the ileum. She had been taking lansoprazole but was switched to vonoprazan due to epigastric discomfort. Three weeks after starting vonoprazan intake, she had a convulsive seizure, and a blood test showed hypomagnesiemia. The cause of hypomagnesemia was considered to be malabsorption of magnesium from the intestinal tract associated with vonoprazan. After discontinuation of vonoprazan, the magnesium level quickly recovered, and the seizures did not relapse. It is important to consider the risk of hypomagnesemia in patients taking vonoprazan, even for a short period of time.

Using the in vitro drug sensitivity test to identify candidate treatments for transient abnormal myelopoiesis.

Approximately 20% of patients with transient abnormal myelopoiesis (TAM) die due to hepatic or multiorgan failure. To identify potential new treatments for TAM, we performed in vitro drug sensitivity testing (DST) using the peripheral blood samples of eight patients with TAM. DST screened 41 agents for cytotoxic properties against TAM blasts. Compared with the reference samples of healthy subjects, TAM blasts were more sensitive to glucocorticoids, the mitogen-activated protein kinase kinase (MAP2K) inhibitor trametinib, and cytarabine. Our present results support the therapeutic potential of glucocorticoids and the role of the RAS/MAP2K signalling pathway in TAM pathogenesis.

New-onset Evans syndrome associated with systemic lupus erythematosus after BNT162b2 mRNA COVID-19 vaccination.

Evans syndrome presents as concurrent autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP). Systemic lupus erythematosus (SLE) is the most frequent autoimmune disorder associated with Evans syndrome. We herein report a case of new-onset Evans syndrome associated with SLE after BNT162b2 mRNA coronavirus disease 2019 (COVID-19) vaccination in a 53-year-old woman. Blood examination at diagnosis showed hemolytic anemia with a positive Coombs test and thrombocytopenia. Hypocomplementemia and the presence of lupus anticoagulant indicated a strong association with SLE. Prednisolone administration rapidly restored hemoglobin level and platelet count. This case suggests that mRNA COVID-19 vaccination may cause an autoimmune disorder. Physicians should be aware of this adverse reaction by mRNA COVID-19 vaccination and should consider the benefits and risks of vaccination for each recipient.