Automated escape system: identifying prey's kinematic and behavioral features critical for predator evasion.

Identifying the kinematic and behavioral variables of prey that influence the evasion from predator attacks remains challenging. To address this challenge, we have developed an automated escape system that responds quickly to an approaching predator and pulls the prey away from the predator rapidly, as real prey. Reaction distance, response latency, escape speed, and other variables can be adjusted in the system. By repeatedly measuring the response latency and escape speed of the system, we demonstrated the system's ability to exhibit fast and rapid responses while maintaining consistency across successive trials. Using the live predatory fish species, Coreoperca kawamebari, we show that escape speed and reaction distance significantly affect the outcome of predator-prey interactions. These findings indicate that the developed escape system is useful for identifying kinematic and behavioral features of prey that are critical for predator evasion, as well as for measuring the performance of predators.

Characterization of BRAFThr599dup Mutation as a Targetable Driver Mutation Identified in Lung Adenocarcinoma by Comprehensive Genomic Profiling.

PURPOSE: Understanding the function of BRAF mutants is crucial for determining the best treatment strategy. This study aimed to characterize a rare BRAF variant, BRAFThr599dup, which was identified in a patient with lung adenocarcinoma (LUAD) by comprehensive genomic profiling. MATERIALS AND METHODS: We report a case of LUAD with BRAFThr599dup treated with dabrafenib and trametinib. We conditionally expressed wild-type BRAF, BRAFV600E, or BRAFThr599dup in Ba/F3 cells and BEAS-2B cells. Ba/F3 cells carrying double-mutant BRAF (BRAFThr599dup/R509H, BRAFV600E/R509H, or BRAFK601E/R509H) that lacked the dimerizing ability were also established. Knockout of endogenous BRAF or CRAF in Ba/F3-BRAFThr599dup cells and Ba/F3-BRAFV600E cells was performed using the CRISPR/Cas9 system. Cell viability, mitogen-activated protein kinase (MAPK) signaling activity, and sensitivity to dabrafenib and trametinib were evaluated. RESULTS: The patient was revealed to have BRAFThr599dup-positive tumor cells as a predominant clone, and dabrafenib and trametinib treatment showed modest efficacy. In Ba/F3 cells, both BRAFThr599dup and BRAFV600E similarly caused interleukin-3-independent proliferation and activated the MAPK pathway. Moreover, BRAFThr599dup and BRAFV600E similarly caused a significant increase in the anchorage-independent growth ability of BEAS-2B cells. Along with Ba/F3-BRAFV600E cells, Ba/F3-BRAFThr599dup cells were highly sensitive to a monomer-specific BRAF inhibitor, dabrafenib, with a half-maximal inhibitory concentration value of 29.7 nM. In the absence of wild-type BRAF, wild-type CRAF, or an intact dimer interface, the ability to induce oncogenic addiction and MAPK pathway activation in Ba/F3-BRAFThr599dup cells was not affected, which was in contrast to the findings in the BRAFK601E/R509H double-mutant model. CONCLUSION: BRAFThr599dup is a potent driver oncogene that activates the MAPK pathway without the requirement for dimerization in vitro. Because BRAFThr599dup has been recurrently reported across various cancer types, our findings should be further investigated both mechanistically and clinically.

Immunohistochemical and in situ hybridization analyses of glucose transporter 2 in pancreatic neuroendocrine tumors: Possible glucose transporter 2 association with neoplastic insulin production.

BACKGROUND: Pancreatic neuroendocrine tumors (PanNETs) are rare neoplasms. Additionally, glucose transporter 2 (GLUT2) is associated with insulin production and is essential for glucose transport to normal pancreatic ß-cells. Neoplastic cell GLUT2 expression may also influence insulin production by using this transporter. GLUT2 expression and its clinical significance remain unclear in PanNETs. This study aimed to provide GLUT2 expression profiles and evidence of correlation with insulin in PanNETs. METHODS: Clinical data were retrieved from 113 surgically resected paraffin-embedded PanNET tissue samples fixed with 10% formalin. PanNETs are categorized as insulinoma, non-functional (NF)-PanNET, or PanNET-not otherwise specified (NOS). A GLUT2 score was used to evaluate cytoplasmic GLUT2 immunoreactivity. The immunoreactive score (IRS) was used to determine membranous GLUT2, cytoplasmic insulin, and proinsulin immunoreactivities. A commercially available in situ hybridization (ISH) kit detected human SLC2A2 (GLUT2) mRNA on tissues in all seven positive- and 20 negative-GLUT2 IRS cases. RESULTS: GLUT2 and IRSs significantly differed among insulinoma, NF-PanNET, and PanNET-NOS. Insulinomas exhibited significantly higher GLUT2 scores and IRSs than did NF-PanNETs. GLUT2 IRS positive cases demonstrated significantly higher insulin and proinsulin IRSs than did negative cases. Additionally, GLUT2 ISH-positive cases demonstrated positive GLUT2 scores and IRSs, with significantly higher GLUT2 IRSs than did negative cases. PanNET histological grade categories did not significantly affect GLUT2 scores and IRSs. CONCLUSION: The first evidence of a correlation between GLUT2 expressions and insulin in PanNETs is shown in this study.

Challenges of pediatric pharmacotherapy: A narrative review of pharmacokinetics, pharmacodynamics, and pharmacogenetics.

PURPOSE: Personalized pharmacotherapy, including for the pediatric population, provides optimal treatment and has emerged as a major trend owing to advanced drug therapeutics and diversified drug selection. However, it is essential to understand the growth and developmental characteristics of this population to provide appropriate drug therapy. In recent years, clinical pharmacogenetics has accumulated knowledge in pediatric pharmacotherapy, and guidelines from professional organizations, such as the Clinical Pharmacogenetics Implementation Consortium, can be consulted to determine the efficacy of specific drugs and the risk of adverse effects. However, the existence of a large knowledge gap hinders the use of these findings in clinical practice. METHODS: We provide a narrative review of the knowledge gaps in pharmacokinetics (PK) and pharmacodynamics (PD) in the pediatric population, focusing on the differences from the perspective of growth and developmental characteristics. In addition, we explored PK/PD in relation to pediatric clinical pharmacogenetics. RESULTS: The lack of direct and indirect biomarkers for more accurate assessment of the effects of drug administration limits the current knowledge of PD. In addition, incorporating pharmacogenetic insights as pivotal covariates is indispensable in this comprehensive synthesis for precision therapy; therefore, we have provided recommendations regarding the current status and challenges of personalized pediatric pharmacotherapy. The integration of clinical pharmacogenetics with the health care system and institution of educational programs for health care providers is necessary for its safe and effective implementation. A comprehensive understanding of the physiological and genetic complexities of the pediatric population will facilitate the development of effective and personalized pharmacotherapeutic strategies.

Defective C3d caused by C3 p.W1034R in inherited atypical hemolytic uremic syndrome.

INTRODUCTION: Atypical hemolytic uremic syndrome (aHUS) is a rare form of thrombotic microangiopathy. Personal genome analyses have revealed numerous aHUS-causing variants, mainly complement-related genes. However, not all aHUS-causing variants have been functionally validated. METHODS: An exome sequence analysis of a Japanese multiplex family composed of three patients diagnosed with aHUS in infancy and showing frequent relapses clustered in a dominant transmission mode was performed. Protein interaction between the C3d and C-terminal domains of factor H was analyzed using a quartz crystal microbalance. RESULTS: Following filtering by heterozygous variants, amino acid substitutions, and allele frequency, the analysis revealed eight rare variants shared by the affected individuals. Variant prioritization listed C3 p.W1034R as the most likely candidate gene mutation in the affected individuals, despite being classified as a variant of uncertain significance. Binding of recombinant C3d harboring 1034R to recombinant short consensus repeats 15 to 20 of factor H was significantly suppressed compared with that of C3 with 1034W. CONCLUSION: C3 p.W1034R results in an inherited form of aHUS that often presents with recurrent episodes, possibly because of impaired interactions between the C3d and C-terminal domains of factor H. Following comprehensive genomic analysis, functional validation of C3 p.W1034R strengthens the molecular basis for aHUS pathophysiology.

Passive Translocation of Phospholipids in Asymmetric Model Membranes: Solid-State 1H NMR Characterization of Flip-Flop Kinetics Using Deuterated Sphingomyelin and Phosphatidylcholine.

Although lateral and inter-leaflet lipid-lipid interactions in cell membranes play roles in maintaining asymmetric lipid bilayers, the molecular basis of these interactions is largely unknown. Here, we established a method to determine the distribution ratio of phospholipids between the outer and inner leaflets of asymmetric large unilamellar vesicles (aLUVs). The trimethylammonium group, (CH3)3N+, in the choline headgroup of N-palmitoyl-sphingomyelin (PSM) and 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC) gave rise to a relatively sharp signal in magic-angle spinning solid-state 1H NMR (MAS-ss-1H NMR). PSM and DOPC have the same headgroup structure, but one phospholipid was selectively observed by deuterating the trimethylammonium group of the other phospholipid. The addition of Pr3+ to the medium surrounding aLUVs selectively shifted the chemical shift of the (CH3)3N+ group in the outer leaflet from that in the inner leaflet, which allowed estimation of the inter-leaflet distribution ratio of the unlabeled lipid in aLUVs. Using this method, we evaluated the translocation of PSM and DOPC between the outer and inner leaflets of the cholesterol-containing aLUVs, with PSM and DOPC mostly distributed in the outer and inner leaflets, respectively, immediately after aLUV preparation; their flip and flop rates were approximately 2.7 and 6.4 × 10-6 s-1, respectively. During the passive symmetrization of aLUVs, the lipid translocation rate was decreased due to changes in the membrane order, probably through the formation of the registered liquid-ordered domains. Comparison of the result with that of symmetric LUVs revealed that lipid asymmetry may not significantly affect the lipid translocation rates, while the lateral lipid-lipid interaction may be a dominant factor in lipid translocation under these conditions. These findings highlight the importance of considering the effects of lateral lipid interactions within the same leaflet on lipid flip-flop rates when evaluating the asymmetry of phospholipids in the cell membrane.

Tumor Necrosis Factor and Interleukin-1ß Upregulate NRP2 Expression and Promote SARS-CoV-2 Proliferation.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), utilizes the host receptor angiotensin-converting enzyme 2 (ACE2) and the auxiliary receptor Neuropilin-1 (NRP1) to enter host cells. NRP1 has another isoform, NRP2, whose function in COVID-19 has seldom been reported. In addition, although patients with severe cases of COVID-19 often exhibit increased levels of proinflammatory cytokines, the relationship between these cytokines and SARS-CoV-2 proliferation remains unknown. The aim of this study is to clarify the roles of proinflammatory cytokines in Neuropilin expressions and in SARS-CoV-2 infection. To identify the expression patterns of NRP under inflamed and noninflamed conditions, next-generation sequencing (RNA-seq), immunohistochemistry, quantitative real-time PCR, and Western blotting were performed using primary cultured fibroblast-like synoviocytes, MH7A (immortalized cell line of human rheumatoid fibroblast-like synoviocytes), immortalized MRC5 (human embryonic lung fibroblast), and synovial tissues. To measure viral proliferative capacity, SARS-CoV-2 infection experiments were also performed. NRP2 was upregulated in inflamed tissues. Cytokine-stimulated human fibroblast cell lines, such as MH7A and immortalized MRC5, revealed that NRP2 expression increased with co-stimulation of tumor necrosis factor α (TNFα) and interleukin-1 beta (IL-1ß) and was suppressed with anti-TNFα antibody alone. TNFα and IL-1ß promoted SARS-CoV-2 proliferation and Spike protein binding. The viral proliferation coincided with the expression of NRP2, which was modulated through plasmid transfections. Our results revealed that proinflammatory cytokines, including TNFα, contribute to NRP2 upregulation and SARS-CoV-2 proliferation in host human cells.

Seasonal Influence on Development of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: A Retrospective Cohort Study Conducted at Multiple Institutions in Japan (J-CANVAS).

OBJECTIVE: To clarify seasonal and other environmental effects on the onset of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). METHODS: We enrolled patients with new-onset eosinophilic granulomatosis with polyangiitis (EGPA), microscopic polyangiitis (MPA), and granulomatosis with polyangiitis (GPA) registered in the database of a Japanese multicenter cohort study. We investigated the relationship between environmental factors and clinical characteristics. Seasons were divided into 4 (spring, summer, autumn, and winter), and the seasonal differences in AAV onset were analyzed using Pearson chi-square test, with an expected probability of 25% for each season. RESULTS: A total of 454 patients were enrolled, with a mean age of 70.9 years and a female proportion of 55.5%. Overall, 74, 291, and 89 patients were classified as having EGPA, MPA, and GPA, respectively. Positivity for myeloperoxidase (MPO)-ANCA and proteinase 3 (PR3)-ANCA was observed in 355 and 46 patients, respectively. Overall, the seasonality of AAV onset significantly deviated from the expected 25% for each season (P = 0.001), and its onset was less frequently observed in autumn. In ANCA serotypes, seasonality was significant in patients with MPO-ANCA (P < 0.001), but not in those with PR3-ANCA (P = 0.97). Additionally, rural residency of patients with AAV was associated with PR3-ANCA positivity and biopsy-proven pulmonary vasculitis. CONCLUSION: The onset of AAV was influenced by seasonal variations and was less frequently observed in autumn. In contrast, the occurrence of PR3-ANCA was triggered, not by season, but by rural residency.

Purkinje Cardiomyocytes of the Adult Ventricular Conduction System Are Highly Diploid but Not Uniquely Regenerative.

Adult hearts are characterized by inefficient regeneration after injury, thus, the features that support or prevent cardiomyocyte (CM) proliferation are important to clarify. Diploid CMs are a candidate cell type that may have unique proliferative and regenerative competence, but no molecular markers are yet known that selectively identify all or subpopulations of diploid CMs. Here, using the conduction system expression marker Cntn2-GFP and the conduction system lineage marker Etv1CreERT2, we demonstrate that Purkinje CMs that comprise the adult ventricular conduction system are disproportionately diploid (33%, vs. 4% of bulk ventricular CMs). These, however, represent only a small proportion (3%) of the total diploid CM population. Using EdU incorporation during the first postnatal week, we demonstrate that bulk diploid CMs found in the later heart enter and complete the cell cycle during the neonatal period. In contrast, a significant fraction of conduction CMs persist as diploid cells from fetal life and avoid neonatal cell cycle activity. Despite their high degree of diploidy, the Purkinje lineage had no enhanced competence to support regeneration after adult heart infarction.

Primary Cilia Are Frequently Present in Small Cell Lung Carcinomas but Not in Non-Small Cell Lung Carcinomas or Lung Carcinoids.

Most human malignant neoplasms show loss of primary cilia (PC). However, PC are known to be retained and involved in tumorigenesis in some types of neoplasms. The PC status in lung carcinomas remains largely uninvestigated. In this study, we comprehensively assessed the PC status in lung carcinomas. A total of 492 lung carcinomas, consisting of adenocarcinomas (ACs) (n = 319), squamous cell carcinomas (SCCs) (n = 152), and small cell lung carcinomas (SCLCs) (n = 21), were examined by immunohistochemical analysis using an antibody against ARL13B, a marker of PC. The PC-positive rate was markedly higher in SCLCs (81.0%) than in ACs (1.6%) and SCCs (7.9%). We subsequently performed analyses to characterize the PC-positive lung carcinomas further. PC-positive lung carcinomas were more numerous and had longer PC than normal cells. The presence of PC in these cells was not associated with the phase of the cell cycle. We also found that the PC were retained even in metastases from PC-positive lung carcinomas. Furthermore, the hedgehog signaling pathway was activated in PC-positive lung carcinomas. Because ARL13B immunohistochemistry of lung carcinoids (n = 10) also showed a statistically significantly lower rate (10.0%) of PC positivity than SCLCs, we searched for a gene(s) that might be upregulated in PC-positive SCLCs compared with lung carcinoids, but not in PC-negative carcinomas. This search, and further cell culture experiments, identified HYLS1 as a gene possessing the ability to regulate ciliogenesis in PC-positive lung carcinomas. In conclusion, our findings indicate that PC are frequently present in SCLCs but not in non-SCLCs (ACs and SCCs) or lung carcinoids, and their PC exhibit various specific pathobiological characteristics. This suggests an important link between lung carcinogenesis and PC.

Strong Polarization of a J=1/2 to 1/2 Transition Arising from Unexpectedly Large Quantum Interference.

We experimentally show that the 1s^{2}2s^{2}2p_{1/2}-1s2s^{2}2p_{1/2}^{2} transition in Pb^{77+} emitted in dielectronic recombination of Pb^{78+} is strongly polarized, although it is an intrinsically unpolarized J=1/2 to 1/2 transition. This unanticipated polarization is shown to be due to quantum interference with radiative recombination. The interference effect has been studied on an asymmetric resonance profile but has never been studied on polarization. In this Letter, we show that the effect on polarization can arise from a different cross term than that responsible for asymmetry, resulting in unexpectedly large polarization even for a nearly symmetric resonance suggesting a small interference.

Somatostatin receptor 2 in 10 different types of human non-neoplastic gastrointestinal neuroendocrine cells.

Somatostatin is known to inhibit the secretion of various hormones by acting on endocrine cells through the somatostatin receptor 2 (SSTR2). Immunohistochemical evaluation of SSTR2 has become increasingly important in clinical practice to determine treatment strategies for patients with a neuroendocrine tumor (NET). Gastrointestinal (GI) tracts contain various neuroendocrine cells that constitute a diffuse endocrine system and some NETs are derived from those cells. In addition, NETs have been well known to express a variable spectrum of proteins shared by their normal cell counterparts of the specific anatomical sites. Thus, we may derive the kinetics of SSTR2 expression of NETs, including de novo expression, from the SSTR2 expression of the corresponding normal neuroendocrine cells. Therefore, a detailed study on the distribution of SSTR2 in normal human neuroendocrine cells may contribute to understanding the expression of SSTR2 in GI-NETs. However, the detailed cellular localization of SSTR2 in non-neoplastic neuroendocrine cells remains unknown. Therefore, we immunolocalized SSTR2 in neuroendocrine cells of normal human GI tracts, including the stomach, duodenum, ileum, and rectum, obtained from 41 surgically resected tissue specimens. Double immunohistochemistry of SSTR2 and hormones or hormone-associated proteins was performed. In all GI neuroendocrine cells, cell types other than D- and EC-cells demonstrated a high percentage of SSTR2-positive cases or a high double-positive ratio. In particular, EC-cells showed lower SSTR2-positive ratios in all sites. Midgut NETs, which often produce serotonin, are excellent targets for somatostatin analogs and are positive for SSTR2. Thus, we speculated that EC-cell NETs might lead to the de novo expression of SSTR2. In addition, a previous report showed high SSTR2 expression in ECL-cell NETs and gastrinomas, which could be because they are derived from neuroendocrine cells with high SSTR2 expression. This study may contribute to understanding the expression of SSTR2 in GI-NETs.

Assessing fluid volume and determining outcomes of acute heart failure using plasma human atrial natriuretic peptide.

BACKGROUND: The post-dialysis plasma level of human atrial natriuretic peptide (hANP) reflects the fluid volume in patients on hemodialysis. The threshold hANP level is reportedly 100 pg/mL; however, the clinical usefulness of the threshold hANP level for volume control has not been sufficiently studied. METHODS: We conducted a single-center, retrospective, observational study that included 156 hemodialysis patients without atrial fibrillation. First, we examined the usefulness of the threshold hANP level (100 pg/mL) for predicting hypoxemia due to congestion in a short-term observational study from December 30, 2015 to January 5, 2016. Subsequently, we conducted a 5-year follow-up study wherein the outcomes were hospitalization due to acute heart failure (AHF), development of cardiovascular diseases (CVD), and all-cause death. Finally, we collected echocardiography data to investigate the relationship between cardiac function and hANP. RESULTS: Our short-term observational study showed that patients with an hANP level ≥ 100 pg/mL developed hypoxemia due to congestion (odds ratio, 3.52; 95% confidence interval, 1.06-11.71; P = 0.040). At the 5-year follow-up, patients with an hANP level ≥ 100 pg/mL had significantly higher rates of hospitalization due to AHF, CVD, and all-cause death based on the log-rank test (P = 0.003, P = 0.019, P < 0.001, respectively). Cardiac disfunctions were significantly associated with the high hANP level. CONCLUSIONS: The hANP level is indicative of both fluid volume and cardiac dysfunction. A threshold hANP level of 100 pg/mL can serve as a predictive marker for AHF and a practical indicator for volume control.

Pulmonary vasodilator therapies in pulmonary arterial hypertension associated with CHD: a systematic review and network meta-analysis.

The optimal treatment strategy using pulmonary vasodilators in pulmonary arterial hypertension associated with CHD (PAH-CHD) remains controversial. We aimed to compare the efficacy and safety of pulmonary vasodilators in PAH-CHD. PubMed and EMBASE databases were searched through May 2022 and a network meta-analysis was conducted. The primary outcomes were mean difference of changes in 6-minute walk distance, NYHA functional class, and N-terminal pro-brain natriuretic peptide. The secondary outcomes included pulmonary vascular resistance, mean pulmonary arterial pressure, and resting oxygen saturation. We identified 14 studies, yielding 807 patients with PAH-CHD. Bosentan and sildenafil were associated with a significant increase in 6-minute walk distance from baseline compared with placebo (MD 48.92 m, 95% CI 0.32 to 97.55 and MD 59.70 m, 95% CI 0.88 to 118.53, respectively). Bosentan, sildenafil, and combination of bosentan and sildenafil were associated with significant improvement in NYHA functional class compared with placebo (MD -0.33, 95% CI -0.51 to -0.14, MD -0.58, 95% CI -0.75 to -0.22 and MD -0.62, 95% CI -0.92 to -0.31, respectively). Bosentan and sildenafil were also associated with significant improvements in secondary outcomes. These findings were largely confirmed in the subgroup analysis. Various adverse events were reported; however, serious adverse event rates were relatively low (4.8-8.7%), including right heart failure, acute kidney injury, respiratory failure, hypotension, and discontinuation of pulmonary vasodilators. In conclusion, bosentan and sildenafil were the most effective in improving prognostic risk factor such as 6-minute walk distance and NYHA class. Overall, pulmonary vasodilators were well tolerated in PAH-CHD.

Pathogenic variants of Alport syndrome and monogenic diabetes identified by exome sequencing in a family.

We present a family of two female Alport syndrome patients with a family history of impaired glucose tolerance. Whole exome sequencing identified a novel heterozygous variant of COL4A5 NM_033380.3: c.2636 C > A (p.S879*) and a rare variant of GCK NM_001354800.1: c.1135 G > A (p.A379T) as the causes of Alport syndrome and monogenic diabetes, respectively. Two independent pathogenic variants affected the clinical phenotypes. Clinical next-generation sequencing is helpful for identifying the causes of patients' manifestations.

Expression of factor XIII originating from synovial fibroblasts and macrophages induced by interleukin-6 signaling.

BACKGROUND: Blood coagulation factor XIII (FXIII) promotes cross-linking between fibrin molecules at the final stage of the blood coagulation cascade. However, its expression in cells or tissues and function, particularly factor XIII subunit B (FXIII-B), remains controversial. Hemorrhagic FXIII deficiency following anti-interleukin-6 (IL-6) receptor antibody treatment has been reported in patients with rheumatoid arthritis (RA). Patients receiving this biologics have reduced FXIII activity when compared to the activity in those treated with other biologics. The relationship between pro-inflammatory cytokines and FXIII expression remains unknown. METHODS: To investigate the expression pattern of FXIII in synovial tissues, immunohistochemistry, RT-qPCR, and western blotting were performed. FXIII-A expressed monocyte-derived macrophages were treated with recombinant IL-6 and anti-IL-6 receptor antibody. RNA sequencing of FXIII-B-overexpressing cells was performed to clarify the function of FXIII-B. RESULTS: The immunohistochemical analysis of synovial tissues revealed that factor XIII subunit A (FXIII-A) was expressed in M2 macrophages, and FXIII-B was expressed in fibroblast-like synoviocytes. IL-6 stimulation upregulated FXIII-A expression in IL-4-induced monocyte-derived macrophages, and the anti-IL-6 receptor antibody suppressed FXIII-A expression. FXIII-B was more abundantly secreted in the supernatant of fibroblast-like synoviocytes compared with that of other cells. RNA sequencing showed that FXIII-B elevated the expression of genes associated with anti-apoptotic molecules and chemokines. CONCLUSIONS: Our findings highlight that synovial tissue is one of the sources of FXIII production. We also have demonstrated IL-6-dependent FXIII-A expression and the novel potential functions of FXIII-B.

Appearance of anti-MDA5 antibody-positive dermatomyositis after COVID-19 vaccination.

The direct causes of dermatomyositis, a common autoimmune disease, have not yet been accurately identified, but several studies have linked this condition to various patient-associated and environmental factors, such as viral infections and area of residence. In the present report, we describe our experience with a patient presenting with anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive dermatomyositis, which developed after vaccination against coronavirus disease 2019 (COVID-19). This patient was simultaneously diagnosed with anti-glutamic acid decarboxylase antibody-positive slowly progressive insulin-dependent diabetes (SPIDDM); her human leucocyte antigen test revealed that she expressed the DRB1*04:05 allele. This is important as this genotype is known to increase susceptibility to both anti-MDA5 antibody-positive dermatomyositis and type I diabetes. To the best of our knowledge, this is the first case of dermatomyositis complicated by SPIDDM identified after COVID-19 vaccination against COVID-19 and presenting with an underlying susceptible genotype. The patient's genetic predisposition may also be important for the development of autoimmune disease after COVID-19 vaccination.

Safe Introduction of Hydroxychloroquine Focusing on Early Intolerance Due to Adverse Drug Reactions in Patients with Systemic Lupus Erythematosus.

Objective This study explored the predictors of hydroxychloroquine intolerance and propose appropriate methods to initiate hydroxychloroquine in patients with systemic lupus erythematosus. Methods This retrospective study registered consecutive patients who were diagnosed with systemic lupus erythematosus and started treatment with hydroxychloroquine between 2015 and 2021. Any adverse events that required dose reduction or cessation of hydroxychloroquine, indicating intolerance to the drug, were recorded for up to 26 weeks after initiation of hydroxychloroquine. Results A total of 130 patients were included. Hydroxychloroquine intolerance due to adverse drug reactions was observed in 28 patients (21.5%), including gastrointestinal symptoms in 15 (11.5%) and cutaneous reactions in 7 (5.4%). Furthermore, the intolerance was observed more frequently in the maintenance group (patients treated daily with <20 mg prednisolone) than in the induction group (7.1% vs. 25.5%, p=0.04), and none of the patients in the induction group developed cutaneous reactions. The initial dose of hydroxychloroquine per ideal body weight was associated with hydroxychloroquine intolerance in a dose-dependent manner. Multivariable analyses revealed that the hydroxychloroquine dose per ideal body weight and higher levels of C4 predicted hydroxychloroquine intolerance. In particular, C4 levels were positively correlated with cutaneous reactions, whereas the dose of prednisolone was negatively correlated with gastrointestinal reactions. Conclusion Low-dose hydroxychloroquine may be optimal for induction in patients with systemic lupus erythematosus who have high C4 levels or are taking low doses of steroids.