Importance of IgE-Induced Unique Plasma Leakage in the Skin for Urticaria-Like Symptoms in an Anaphylaxis-Dependent Spotted Distribution of Immune Complex in Skin (ASDIS) Mouse Model.

INTRODUCTION: Allergic diseases, such as anaphylaxis and urticaria, pose significant health concerns. The quest for improved prognostic outcomes in these diseases necessitates the exploration of novel therapeutic avenues. To address this need, we have developed a novel mouse model of anaphylaxis, denoted as anaphylaxis-dependent spotted distribution of immune complex in skin (ASDIS). ASDIS manifests as distinct dotted symptoms in the skin, detectable through in vivo imaging, resembling urticarial symptoms. In this study, we investigated the potential underlying mechanisms giving rise to these dotted symptoms, exploring the role of vascular permeability and characterizing the ASDIS model as a new urticaria model. METHODS: We employed haired and hairless HR mice (BALB/c background) and hairless HR-1 mice (a commercially available hairless strain with an unidentified genetic background). ASDIS was induced by the simultaneous intravenous injection of anti-ovalbumin IgE and fluorescein isothiocyanate (FITC)-ovalbumin, along with Evans blue - a recognized vascular permeability indicator. Anaphylaxis and scratching behavior were monitored through rectal temperature decrease and optical observation, respectively. Histamine, platelet-activating factor, and compound 48/80 were injected with or without FITC-ovalbumin for comparative analysis. The effects of an α1 adrenergic receptor agonist applied to the skin were also examined. RESULTS: In hairless mice, the simultaneous injection of histamine, compound 48/80, or IgE with FITC-ovalbumin induced comparable rectal temperature decreases and vascular permeability. However, only the combination of FITC-ovalbumin and IgE triggered ASDIS, specifically the dotted urticaria-like symptom. Evans blue visualization and optical observation of dotted swelling confirmed that the vascular permeability mediated the phenomenon. Hairless mice exhibited a more pronounced temperature decrease than their haired counterparts when exposed to histamine, platelet-activating factor, compound 48/80, and IgE with FITC-ovalbumin. The application of an α1 adrenergic receptor agonist to the skin attenuated the topical urticaria-like symptom. CONCLUSION: Our experiments revealed four findings. The first is that ASDIS mirrors urticaria-like symptoms resulting from increased vascular permeability, akin to human urticaria. The second finding is that the development of dotted symptoms involves an IgE-induced, yet unidentified, mechanism not triggered by histamine or compound 48/80 alone. The third finding highlights the heightened susceptibility of hairless mice to ASDIS induction. The fourth finding demonstrates that the inhibition of ASDIS by the topical application of an α1 adrenergic receptor agonist hints at a potential anti-urticarial application for this vasoconstrictor. Further elucidation of these unidentified IgE-dependent mechanisms and the specific generation of dotted symptoms by IgE-immune complexes could provide novel insights into allergic response processes and therapeutic interventions for these conditions.

Association between aortic thrombi detected using non-obstructive general angioscopy and atrial fibrillation.

Atrial fibrillation (AF) is an independent risk factor for stroke and systemic embolism. Cardiogenic and aortogenic emboli are causes of stroke or systemic embolism. Non-obstructive general angioscopy (NOGA) can be used to diagnose aortic intimal findings, including thrombi and atherosclerotic plaques, but little is known about NOGA-derived aortic intimal findings in patients with AF. This study focused on aortic intimal findings in patients with AF and evaluated the association between AF and aortic thrombi detected using NOGA. We enrolled 283 consecutive patients with coronary artery disease who underwent NOGA of the aorta between January 2017 and August 2022. Aortic intimal findings were screened using NOGA after coronary arteriography. The patients were divided into two groups according to their AF history (AF, n = 50 and non-AF, n = 233). Patients in the AF group were older than those in the non-AF group. Sex, body mass index, and coronary risk factors were not significantly different between the two groups. In the NOGA findings, the presence of intense yellow plaques and ruptured plaques was not significantly different between the two groups. Aortic thrombi were more frequent in the AF group than in the non-AF group (92.0 vs. 71.6%, p < 0.001). Multivariate logistic regression found that AF was independently associated with aortic thrombi (odds ratio 3.87 [95% CI 1.28-11.6], p = 0.016). The presence of aortic thrombi observed using NOGA was associated with AF in patients with coronary artery disease. The roles of aortic thrombi as well as cardiogenic embolism may require clarification.

Cholesterol Crystal Embolism in a Patient with Spontaneous Ruptured Aortic Plaques Identified by Non-Obstructive General Angioscopy.

Cholesterol crystal (CC) embolism is a disease in which CCs from atherosclerotic lesions embolize peripheral arteries, causing organ dysfunction. In this case, a patient with spontaneously ruptured aortic plaques (SRAPs) identified by non-obstructive general angioscopy (NOGA) may have developed a CC embolism. This is the first report of a CC embolism in a patient with SRAPs identified using NOGA, which further supports the previously speculated pathogenesis of CC embolism due to SRAPs.

Development of a Novel IgG1 Anaphylaxis Mouse Model with Uniquely Characteristic Skin Manifestations Induced Through the FcγRIII-Histamine Pathway.

BACKGROUND: Studies of passive anaphylaxis, in which mouse immunoglobulin G (IgG) and its antigens are administered to mice, believe that platelet-activating factor (PAF) is more important than histamine and that basophils or macrophages are primarily involved. However, the full extent of IgG-dependent anaphylaxis is still unclear; that is, little agreement has been reached about the mechanism. METHODS: First, we established the novel model of IgG1 anaphylaxis induced by the intravenous administration of two types of IgG1 and a fluorescent dye-labeled antigen, as IgG1 immune complex in HR-1 hairless mice. Subsequently, pharmacological analysis was used to investigate the underlying mechanisms of IgG1 anaphylaxis in this established model. RESULTS: The novel IgG1 anaphylaxis model can induce the IgG-induced Anaphylaxis-dependent Spotted Distribution of fluorescently labeled Immune complexes in the Skin, named "G-ASDIS". Moreover, this model was triggered primarily by the FcγRIII-dependent histamine release, which is different from the conventional model in which PAF was involved in the development of IgG1 anaphylaxis. Basophils in the circulation and mast cells in the skin may participate in the development of IgG1 anaphylaxis and increased G-ASDIS. CONCLUSION: Our results propose that the novel axis, namely the FcγRIII-basophils and/or mast cell-histamine pathway, is important for IgG1 anaphylaxis. Further analysis of our model in addition to other models will lead to a broader analysis and understanding of the IgG1 anaphylaxis mechanism.

Co-induced Allergic Response to an Unrelated Allergen Exacerbates Imiquimod-Induced Psoriasis in Mice.

Psoriasis is classically regarded as a T-helper 1 (Th1) response-dominant disease believed to be antagonized by the Th2 response, which is responsible for allergic diseases, such as atopic dermatitis. The roles of these responses in psoriasis and the relationship between psoriasis and atopic dermatitis have received increasing attention because it is estimated that more than one million patients are concomitantly affected by psoriasis and atopic dermatitis. To address this, we attempted to determine the characteristics of imiquimod-induced psoriasiform lesions in mice with a concomitant allergic response after co-application of the unrelated allergen ovalbumin onto the skin. Imiquimod cream containing ovalbumin was successively applied to the right back skin of hairless HR female mice. Psoriasiform scores were determined for 11 d, and then, the resected skin thickness, spleen weight, and serum antibody levels were examined. In some experiments, mice were allowed free access to ovalbumin-containing water for 10 d before skin application to induce oral tolerance. Imiquimod cream induced psoriasis, and its severity increased upon simultaneous ovalbumin treatment. Increases in anti-ovalbumin immunoglobulin G2a (IgG2a) levels, a Th1 response indicator, and IgG1 and IgE levels, Th2 response indicators, were mediated by ovalbumin addition. Oral tolerance against ovalbumin effectively decreased ovalbumin-exacerbated imiquimod-induced psoriasis, in parallel with a decrease in levels of anti-ovalbumin antibodies. These results suggest that the concomitant allergic response induced by ovalbumin application exacerbates imiquimod-induced psoriasis. This implies that allergic responses to unrelated allergens might exacerbate psoriasis in humans and that modulating such responses could be an effective new approach to treat psoriasis.

Isolation and Purification of Harpagogenin as an Nrf2-ARE Activator from the Tubers of Chinese Artichoke (Stachys sieboldii).

Chinese artichoke tuber (Stachys sieboldii Miq.) is used as an herbal medicine as well as edible food. This study examined the effect of the Chinese artichoke extracts on the nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway that induces the expression of antioxidant enzymes to explore its novel characteristics. Hot water extracts exhibited relatively high ARE activity. ARE activity was observed in two fractions when the hot water extracts were separated in the presence of trifluoroacetic acid using HPLC. Conversely, the highly active fraction disappeared when the hot water extracts were separated in the absence of trifluoroacetic acid. These results indicate that acidic degradation produces active ingredients. The structural analysis of the two active fractions identified harpagide, which is an iridoid glucoside, and harpagogenin. In vitro experiments revealed that harpagide was converted into harpagogenin under acidic conditions and that harpagogenin, but not harpagide, had potent ARE activity. Therefore, this study identified harpagogenin, which is an acid hydrolysate of harpagide, as an ARE activator and suggests that Nrf2-ARE pathway activation by Chinese artichoke contributes to the antioxidative effect.

Association between the Angle of the Left Subclavian Artery and Procedural Time for Percutaneous Coronary Intervention in Patients with Acute Coronary Syndrome.

Background: The effect of left subclavian artery tortuosity during percutaneous coronary intervention (PCI) in patients with acute coronary syndrome (ACS) remains unclear. Methods: Of 245 ACS patients (from November 2019 and May 2021), 79 who underwent PCI via a left radial approach (LRA) were included. We measured the angle of the left subclavian artery in the coronal view on CT imaging as an indicator of the tortuosity and investigated the association between that angle and the clinical variables and procedural time. Results: Patients with a left subclavian artery angle of a median of <70 degrees (severe tortuosity) were older (75.4 ± 11.7 vs. 62.9 ± 12.3 years, P < 0.001) and had a higher prevalence of female sex (42.1% vs. 14.6%, P=0.007), hypertension (94.7% vs. 75.6%, P=0.02), and subclavian artery calcification (73.7% vs. 34.2%, P < 0.001) than those with that ≥70 degrees. The left subclavian artery angle correlated negatively with the sheath cannulation to the first balloon time (ρ = -0.51, P < 0.001) and total procedural time (ρ = -0.32, P=0.004). A multiple linear regression analysis revealed that the natural log transformation of the sheath insertion to first balloon time was associated with a subclavian artery angle of <70 degrees (ß = 0.45, P < 0.001). Conclusion: Our study showed that lower left subclavian artery angles as a marker of the tortuosity via the LRA were strongly associated with a longer sheath insertion to balloon time and subsequent entire procedure time during the PCI.

TPNA10168, an Nrf-2 activator, attenuates inflammatory responses independently of Nrf2 in microglial BV-2 cells: Involvement of the extracellular-signal-regulated kinase pathway.

Some chemical Nrf2 inducers possess antioxidant and anti-inflammatory properties. TPNA10168, which was identified from a chemical library as a potential activator of the Keap1-Nrf2-ARE pathway, exhibits a neuroprotective effect against oxidative stress-induced injury. However, it has not been investigated as an anti-inflammatory agent. Here we examined the effect of TPNA10168 on interferon-γ-induced proinflammatory gene expression in mouse microglial BV-2 cells. TPNA10168 significantly reduced the transcription of inflammatory genes, including TNF-α, IL-1ß, IL-6, and iNOS; however, the inhibition of proinflammatory cytokine gene expression was not attenuated by inhibitors of Nrf2-regulated enzymes. Furthermore, TPNA10168 showed anti-inflammatory effects, even in Nrf2-deficient cells, and inhibited interferon-γ-induced phosphorylation of extracellular-signal-regulated kinase (ERK). Studies with an ERK pathway inhibitor demonstrated a role for ERK in the transcription of inflammatory genes. These results suggest that TPNA10168 attenuates microglial proinflammatory activation independently of Nrf2, at least in part, by suppressing interferon-γ-induced ERK signaling.

Protective effect of the Impella on the left ventricular function after acute broad anterior wall ST elevation myocardial infarctions with cardiogenic shock: cardiovascular magnetic resonance imaging strain analysis.

BACKGROUND: The clinical efficacy of the Impella for high-risk percutaneous coronary intervention (PCI) and cardiogenic shock remains under debate. We thus sought to investigate the protective effects on the heart with the Impella's early use pre-PCI using cardiac magnetic resonance imaging (CMRI). METHODS: We retrospectively evaluated the difference in the subacute phase CMR imaging results (19 ± 9 days after admission) between patients undergoing an Impella (n = 7) or not (non-Impella group: n = 18 [12 intra-aortic balloon pumps (1 plus veno-arterial extracorporeal membrane oxygenation) and 6 no mechanical circulation systems]) in broad anterior ST-elevation myocardial infarction (STEMI) cases. A mechanical circulation system was implanted pre-PCI. RESULTS: No differences were found in the door-to-balloon time, peak creatine kinase, and hospital admission days between the Impella and non-Impella groups; however, the CMRI-derived left ventricular ejection fraction was significantly greater (45 ± 13% vs. 34 ± 7.6%, P = 0.034) and end-diastolic and systolic volumes smaller in the Impella group (149 ± 29 vs. 187 ± 41 mL, P = 0.006: 80 ± 29 vs. 121 ± 40 mL, P = 0.012). Although the global longitudinal peak strain did not differ, the global radial (GRS) and circumferential peak strain (GCS) were significantly higher in the IMPELLA than non-IMPELLA group. Greater systolic and diastolic strain rates (SRs) in the Impella than non-Impella group were observed in non-infarcted rather than infarcted areas. CONCLUSIONS: Early implantation of an Impella before PCIs for STEMIs sub-acutely prevented cardiac dysfunction through preserving the GRS, GCS, and systolic and diastolic SRs in the remote myocardium. This study provided mechanistic insight into understanding the usefulness of the Impella to prevent future heart failure.

Purification of Emu IgY for Therapeutic and Diagnostic Use Based on Monoclonal Secondary Antibodies Specific to Emu IgY.

The emu is the second largest ratite; thus, their sera and egg yolks, obtained after immunization, could provide therapeutic and diagnostically important immunoglobulins with improved production efficiency. Reliable purification tools are required to establish a pipeline for supplying practical emu-derived antibodies, the majority of which belongs to the immunoglobulin Y (IgY) class. Therefore, we generated a monoclonal secondary antibody specific to emu IgY. Initially, we immunized an emu with bovine serum albumin multiply haptenized with 2,4-dinitrophenyl (DNP) groups. Polyclonal emu anti-DNP antibodies were partially purified using conventional precipitation method and used as antigen for immunizing a BALB/c mouse. Splenocytes were fused with myeloma cells and a hybridoma clone secreting a desirable secondary antibody (mAb#2-16) was established. The secondary antibody bound specifically to emu-derived IgY, distinguishing IgYs from chicken, duck, ostrich, quail, and turkey, as well as human IgGs. Affinity columns immobilizing the mAb#2-16 antibodies enabled purification of emu IgY fractions from sera and egg yolks via simple protocols, with which we succeeded in producing IgYs specific to the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) spike protein with a practical binding ability. We expect that the presented purification method, and the secondary antibody produced in this study, will facilitate the utilization of emus as a novel source of therapeutic and diagnostic antibodies.

Immunoglobulin a suppresses B cell receptor-mediated activation of mouse B cells with differential inhibition of signaling molecules.

CONTEXT: We previously reported that monoclonal mouse immunoglobulin (Ig) A, OA-4, attenuates sensitization in mice by suppressing B cell activation. OBJECTIVE: Here, it is demonstrated for the first time that mouse IgA inhibits mouse B cell activation in vitro under natural conditions (i.e. in the absence of chemical, physical, and genetic modifications of IgA and B cells). MATERIALS AND METHODS: Mouse splenocytes were stimulated with anti-B cell receptor (BCR) antibody or lipopolysaccharide (LPS) in the presence or absence of OA-4. Splenic B cell proliferation and the activation of several intracellular signaling molecules were measured. RESULTS: Anti-BCR antibody-induced proliferation was markedly inhibited by OA-4 or the commercially available mouse IgA S107, whereas LPS-induced proliferation was weakly attenuated by a high concentration of OA-4. Moreover, OA-4 markedly decreased the anti-BCR antibody-induced phosphorylation of p44/42 mitogen-activated protein kinase (ERK) and CD22 and decreased phosphorylated phospholipase (PLC) γ2 and intracellular Ca2+ levels moderately, whereas protein kinase B (Akt) phosphorylation was not affected by OA-4. The MAPK/ERK kinase-ERK and phosphoinositide 3-kinase-Akt pathways were found to play a role in the proliferation of splenocytes induced by anti-BCR antibody based on experiments with their inhibitors. In contrast to that in splenic B cells, ERK phosphorylation induced by anti-BCR antibody in A20 cells was not inhibited by OA-4. The modulatory effects of IgA were different among the cell types and signaling pathways. CONCLUSION: IgA is a potential immunoregulatory drug utilizing new mechanisms that affect splenic B cells but not A20 lymphomas.

Prognostic Significance of a Combination of Cardiogenic Shock and the Critical Culprit Lesion Location in ST-Elevation Myocardial Infarctions.

Both cardiogenic shock (CS) and critical culprit lesion locations (CCLLs), defined as the left main trunk and proximal left anterior descending coronary artery, are associated with worse outcomes in ST-elevation myocardial infarctions (STEMIs). We aimed to examine how the combination of CS and/or CCLLs affected the prognosis in Japanese STEMI patients in the primary percutaneous coronary intervention era (PPCI-era). The subjects included 624 STEMI patients admitted to our hospital between January 2013 and April 2020. They were divided into four groups according to the combination of CS and CCLLs: CS (-) CCLL (-) group [n = 405], CS (-) CCLL (+) group [n = 150], CS (+) CCLL (-) group [n = 25], and CS (+) CCLL (+) group [n = 44]. The cumulative incidences of all-cause death at 30 days and 1 year were 3.5% and 6.4% in the CS (-) CCLL (-), 3.3% and 5.6% in the CS (-) CCLL (+), 32.0% and 32.0% in the CS (+) CCLL (-), and 50.0% and 65.9% in the CS (+) CCLL (+) group, respectively. After a multivariate adjustment, the CS (+) CCLL (+) group was independently associated with all-cause death (hazard ratio: 17.00, 95% confidence interval: 7.12-40.59 versus the CS (-) CCLL (-) group). In the CS (+) CCLL (+) group, compared to years 2013-2017, the IMPELLA begun to be used (44.4% versus 0%), and intra-aortic balloon pumps significantly decreased (44.4% versus 92.3%) during years 2018-2020, while the medications upon discharge did not significantly differ. The 30-day mortality was numerically lower during years 2018-2020 than years 2013-2017 (Log-rank test, P = 0.092). In conclusion, the prognosis of STEMIs varies greatly depending on the combination of CS and CCLLs, and in particular, patients with both CS and CCLLs had the poorest prognosis during the modern PPCI-era.

[Aortic Regurgitation due to Rupture of a Fibrous Strand in Fenestrated Aortic Valve:Report of a Case].

Fenestration of the aortic valve cusps rarely causes aortic regurgitation. A 54-year-old woman was diagnosed with aortic regurgitation secondary to a ruptured fibrous strand in a fenestrated aortic valve cusp. Diastolic murmur was pointed out during health checkup five months earlier, and transthoracic echocardiography revealed severe aortic valve regurgitation with a mobile mass attached to the aortic valve cusp. The patient underwent aortic valve replacement. Intraoperatively, we observed a ruptured fibrous strand attached to the non-coronary cusp and cusp laceration, both of which caused severe aortic regurgitation. Histopathological examination of the resected specimen showed myxomatous degeneration. The patient's postoperative course was uneventful, and she was discharged in a stable condition on postoperative day 14.

Late kidney injury after transcatheter aortic valve replacement.

BACKGROUND: Information on early to late-phase kidney damage in patients who underwent transcatheter aortic valve replacement (TAVR) is scarce. We aimed to identify the predictive factors for late kidney injury (LKI) at 1-year and patient prognosis beyond 1-year after TAVR. METHODS: We retrospectively reviewed 1,705 patients' data from the Japanese TAVR multicenter registry. Acute kidney injury (AKI) and LKI, defined as an increase of at least 0.3 mg/dL in creatinine level, a relative 50% decrease in kidney function from baseline to 48 hours and 1-year, were evaluated. The patients were categorized into the 4 groups as AKI-/LKI- (n = 1.362), AKI+/LKI- (n = 95), AKI-/LKI+ (n = 199), and AKI+/LKI+ (n = 46). RESULTS: The cumulative 3-year mortality rates were significantly increased across the four groups (12.5%, 15.8%, 24.6%, 25.8%, P < .001). Multivariate analysis revealed that chronic kidney disease, coronary artery disease, periprocedural AKI, and heart failure-related re-admission within 1-year were significantly associated with LKI. The Cox regression analysis revealed that AKI-/LKI+ and AKI+/LKI+ were independent predictors of increased late mortality beyond 1-year after TAVR (P = .001 and P = .01). CONCLUSIONS: LKI was influenced by adverse cardio-renal events and was associated with increased risks of late mortality beyond 1-year after TAVR.

Endothelin ETB Receptor-Mediated Astrocytic Activation: Pathological Roles in Brain Disorders.

In brain disorders, reactive astrocytes, which are characterized by hypertrophy of the cell body and proliferative properties, are commonly observed. As reactive astrocytes are involved in the pathogenesis of several brain disorders, the control of astrocytic function has been proposed as a therapeutic strategy, and target molecules to effectively control astrocytic functions have been investigated. The production of brain endothelin-1 (ET-1), which increases in brain disorders, is involved in the pathophysiological response of the nervous system. Endothelin B (ETB) receptors are highly expressed in reactive astrocytes and are upregulated by brain injury. Activation of astrocyte ETB receptors promotes the induction of reactive astrocytes. In addition, the production of various astrocyte-derived factors, including neurotrophic factors and vascular permeability regulators, is regulated by ETB receptors. In animal models of Alzheimer's disease, brain ischemia, neuropathic pain, and traumatic brain injury, ETB-receptor-mediated regulation of astrocytic activation has been reported to improve brain disorders. Therefore, the astrocytic ETB receptor is expected to be a promising drug target to improve several brain disorders. This article reviews the roles of ETB receptors in astrocytic activation and discusses its possible applications in the treatment of brain disorders.

Pathophysiological Responses and Roles of Astrocytes in Traumatic Brain Injury.

Traumatic brain injury (TBI) is immediate damage caused by a blow to the head resulting from traffic accidents, falls, and sporting activity, which causes death or serious disabilities in survivors. TBI induces multiple secondary injuries, including neuroinflammation, disruption of the blood-brain barrier (BBB), and brain edema. Despite these emergent conditions, current therapies for TBI are limited or insufficient in some cases. Although several candidate drugs exerted beneficial effects in TBI animal models, most of them failed to show significant effects in clinical trials. Multiple studies have suggested that astrocytes play a key role in the pathogenesis of TBI. Increased reactive astrocytes and astrocyte-derived factors are commonly observed in both TBI patients and experimental animal models. Astrocytes have beneficial and detrimental effects on TBI, including promotion and restriction of neurogenesis and synaptogenesis, acceleration and suppression of neuroinflammation, and disruption and repair of the BBB via multiple bioactive factors. Additionally, astrocytic aquaporin-4 is involved in the formation of cytotoxic edema. Thus, astrocytes are attractive targets for novel therapeutic drugs for TBI, although astrocyte-targeting drugs have not yet been developed. This article reviews recent observations of the roles of astrocytes and expected astrocyte-targeting drugs in TBI.

Endothelin-1 stimulates expression of cyclin D1 and S-phase kinase-associated protein 2 by activating the transcription factor STAT3 in cultured rat astrocytes.

Brain injury-mediated induction of reactive astrocytes often leads to glial scar formation in damaged brain regions. Activation of signal transducer and activator of transcription 3 (STAT3), a member of the STAT family of transcription factors, plays a pivotal role in inducing reactive astrocytes and glial scar formation. Endothelin-1 (ET-1) is a vasoconstrictor peptide, and its levels increase in brain disorders and promote astrocytic proliferation through ETB receptors. To clarify the mechanisms underlying ET-1-mediated astrocytic proliferation, here we examined its effects on STAT3 in cultured rat astrocytes. ET-1 treatment stimulated Ser-727 phosphorylation of STAT3 in the astrocytes, but Tyr-705 phosphorylation was unaffected, and ET-induced STAT3 Ser-727 phosphorylation was reduced by the ETB antagonist BQ788. ET-1 stimulated STAT3 binding to its consensus DNA-binding motifs. Monitoring G1/S phase cell cycle transition through bromodeoxyuridine (BrdU) incorporation, we found that ET-1 increases BrdU incorporation into the astrocytic nucleus, indicating cell cycle progression. Of note, STAT3 chemical inhibition (with stattic or 5,15-diphenyl-porphine (5,15-DPP)) or siRNA-mediated STAT3 silencing reduced ET-induced BrdU incorporation. Moreover, ET-1 increased astrocytic expression levels of cyclin D1 and S-phase kinase-associated protein 2 (SKP2), which were reduced by stattic, 5,15-DPP, and STAT3 siRNA. ChIP-based PCR analysis revealed that ET-1 promotes the binding of SAT3 to the 5'-flanking regions of rat cyclin D1 and SKP2 genes. Our results suggest that STAT3-mediated regulation of cyclin D1 and SKP2 expression underlies ET-induced astrocytic proliferation.

Angiopoietin-1/Tie-2 signal after focal traumatic brain injury is potentiated by BQ788, an ETB receptor antagonist, in the mouse cerebrum: Involvement in recovery of blood-brain barrier function.

Angiopoietin-1, an angiogenic factor, stabilizes brain microvessels through Tie-2 receptor tyrosine kinase. In traumatic brain injury, blood-brain barrier (BBB) disruption is an aggravating factor that induces brain edema and neuroinflammation. We previously showed that BQ788, an endothelin ETB receptor antagonist, promoted recovery of BBB function after lateral fluid percussion injury (FPI) in mice. To clarify the mechanisms underlying BBB recovery mediated by BQ788, we examined the involvements of the angiopoietin-1/Tie-2 signal. When angiopoietin-1 production and Tie-2 phosphorylation were assayed by quantitative reverse transcription polymerase chain reaction and western blotting, increased angiopoietin-1 production and Tie-2 phosphorylation were observed in 7-10 days after FPI in the mouse cerebrum, whereas no significant effects were obtained at 5 days. When BQ788 (15 nmol/day, i.c.v.) were administered in 2-5 days after FPI, increased angiopoietin-1 production and Tie-2 phosphorylation were observed. Immunohistochemical observations showed that brain microvessels and astrocytes contained angiopoietin-1 after FPI, and brain microvessels also contained phosphorylated Tie-2. Treatment with endothelin-1 (100 nM) decreased angiopoietin-1 production in cultured astrocytes and the effect was inhibited by BQ788 (1 µM). Five days after FPI, increased extravasation of Evans blue dye accompanied by reduction in claudin-5, occludin, and zonula occludens-1 proteins were observed in mouse cerebrum while these effects of FPI were reduced by BQ788 and exogenous angiopoietin-1 (1 µg/day, i.c.v.). The effects of BQ788 were inhibited by co-administration of a Tie-2 kinase inhibitor (40 nmol/day, i.c.v.). These results suggest that BQ788 administration after traumatic brain injury promotes recovery of BBB function through activation of the angiopoietin-1/Tie-2 signal.

Prognostic impact and periprocedural complications of chronic steroid therapy in patients following transcatheter aortic valve replacement: Propensity-matched analysis from the Japanese OCEAN registry.

OBJECTIVE: This study aimed to assess the effect of chronic steroid use on periprocedural complications and clinical outcomes after transcatheter aortic valve replacement (TAVR). BACKGROUND: Chronic steroid use increases the risk of periprocedural complications and mortality during surgery. METHODS: We investigated 1,313 consecutive patients with aortic stenosis who underwent transfemoral (TF)-TAVR using data from a Japanese multicenter registry. The baseline characteristics, periprocedural complications including vascular complications (VCs), access route related VCs, and clinical outcomes were compared between patients in the steroid group and nonsteroid group. RESULTS: Major VCs and access route VCs occurred more in the steroid group than in the nonsteroid group (13.4 vs. 5.8%, p = .019; 20.9% vs. 9.8%, p = .004). Especially in the surgical cut-down group, the rate of access route VCs was differed between the two groups (28.0% vs. 7.5%, p = .003). The 30-day mortality rates were similar between the two groups (0% vs. 1.4%, p = .39). In the propensity score-matched model, the higher incidence of major VCs in the steroid group was maintained, although early mortality was similar in the two groups. CONCLUSIONS: Although chronic steroid therapy is not associated with increased early mortality, chronic steroid use may affect periprocedural VCs and access route VCs mainly due to surgical cut-down in patients following TF-TAVR.

How to anastomose a patch to avoid residual leak in the infarct exclusion method.

BACKGROUND AND AIM: Postinfarction ventricular septal defect is a potentially lethal complication of acute myocardial infarction for which surgical repair is mandatory. The infarct exclusion method has contributed to improving surgical outcomes, but a certain percentage of residual leakage continues to be reported. We considered possible mechanisms of residual leakage and modified the sewing method to overcome these mechanisms. METHOD: A bovine pericardial patch and a Teflon felt strip between the patch and endocardium to achieve good fit were used. The patch and felt were anchored with U stay sutures and reinforced with a running suture. RESULTS: Use of the modified method in seven cases showed improved outcomes. Only one patient had trivial leakage, compared to nine cases using the older method; six of nine patients had residual leaks, including three minor ones. CONCLUSIONS: Our method is a rational approach that effectively reduces residual leakage.