Learning Curve Effect of Combined Technique Thrombectomy as First-Line Attempt for Acute Ischemic Stroke: A Single-Center Retrospective Study.

OBJECTIVES: We retrospectively examined the initial experience and learning curve after the introduction of thrombectomy with the combined technique using an aspiration catheter and a stent retriever as first-line attempt for acute ischemic stroke. METHODS: Consecutive patients undergoing thrombectomy for acute ischemic stroke at our institution between January 2020 and December 2022 were divided into 3 groups according to the year of thrombectomy. Patient characteristics and procedural, safety, and clinical outcomes were compared between the three year periods to determine predictors of favorable clinical outcome. RESULTS: In 2020, 2021, and 2022, the numbers of patients were 74, 70, and 90, respectively, with similar patient characteristics across the three years; successful recanalization rates were 79.7%, 97.1%, and 93.3%, respectively (P < 0.01 for the first 2 years); median procedure times were 67, 43, and 32 minutes, respectively (P < 0.01 for the first 2 years and P = 0.018 for the last 2 years); first pass effect rates were 20.3%, 41.4%, and 44.4%, respectively (P < 0.01 for the first 2 years); symptomatic intracranial hemorrhage rates were 14.9%, 2.9%, and 1.1%, respectively (P = 0.018 for the first 2 years); and percentages of modified Rankin Scale score 0-2 at 90 days were 24.3%, 42.9%, and 41.1%, respectively (P = 0.022 for the first 2 years). Procedure time (P = 0.038) and successful recanalization (P = 0.041) were independent predictors of favorable clinical outcome. CONCLUSIONS: The learning curve effect of the combined technique may be associated with better clinical outcome due to increased successful recanalization rates, shortened procedure time, and reduced symptomatic intracranial hemorrhage.

Roles of tumor necrosis factor-like ligand 1A in γδT-cell activation and psoriasis pathogenesis.

Background: Interleukin (IL)-17-producing γδT (γδT17) cells mediate inflammatory responses in barrier tissues. Dysregulated γδT17 cell activation can lead to the overproduction of IL-17 and IL-22 and the development of inflammatory diseases, including psoriasis. IL-23 and IL-1ß are known to synergistically activate γδT17 cells, but the regulatory mechanisms of γδT17 cells have not been fully elucidated. This study aimed to reveal the contribution of the inflammatory cytokine tumor necrosis factor-like ligand 1A (TL1A) to γδT17 cell activation and psoriasis development. Methods: Anti-TL1A antibody was injected into an imiquimod (IMQ)-induced murine psoriasis model. TL1A receptor expression was analyzed in splenic and dermal γδT cells. γδT cells were tested for cytokine production in vitro and in vivo under stimulation with IL-23, IL-1ß, and TL1A. TL1A was applied to a psoriasis model induced by intradermal IL-23 injection. Mice deficient in γδT cells were intradermally injected with IL-23 plus TL1A to verify the contribution of TL1A-dependent γδT-cell activation to psoriasis development. Results: Neutralization of TL1A attenuated γδT17 cell activation in IMQ-treated skin. TL1A induced cytokine production by splenic γδT17 cells in synergy with IL-23. Dermal γδT17 cells constitutively expressed a TL1A receptor at high levels and vigorously produced IL-22 upon intradermal IL-23 and TL1A injection but not IL-23 alone. TL1A exacerbated the dermal symptoms induced by IL-23 injection in wild-type but not in γδT cell-deficient mice. Conclusion: These findings suggest a novel regulatory mechanism of γδT cells through TL1A and its involvement in psoriasis pathogenesis as a possible therapeutic target.

Cavernous sinus dural arteriovenous fistula embolized through an occluded superior petrosal sinus: illustrative case.

BACKGROUND: Transvenous embolization for cavernous sinus (CS) dural arteriovenous fistulas (CS-DAVFs) with limitations of the major access routes to the CS is challenging. OBSERVATIONS: A 74-year-old woman presented with left-sided conjunctival injection and exophthalmos. Cerebral angiography showed a left CS-DAVF draining into the left uncal vein and superior ophthalmic vein, with the fistulous point located in the posterosuperior compartment of the left CS. The left inferior petrosal sinus and internal jugular vein were occluded, and no drainage route from the left superior ophthalmic vein was seen. The anterior segment of the left superior petrosal sinus (SPS) was occluded, but the posterior segment was not. Microangiography from the posterior segment of the left SPS showed a beak-like orifice in the anterior segment of the left SPS toward the left CS. A micro-guidewire was guided through the beak-like orifice, and the microcatheter was advanced into the left CS. The left CS was packed and the DAVF was occluded. LESSONS: Transvenous embolization through an occluded SPS may be an option in the endovascular treatment of CS-DAVFs. Penetration along the beak-like orifice of the occluded SPS visualized by venography at the blind end of the SPS may be useful in reaching the CS via the SPS.

Factors related to white thrombi in acute ischemic stroke in cancer patients.

OBJECTIVES: Thrombi in cerebral large vessel occlusion associated with active cancer are often fibrin and platelet-rich white thrombi. However, evaluating the thrombus composition in a short time before thrombectomy is often ineffective. We sought to determine factors related to white thrombi in acute ischemic stroke due to large vessel occlusion in cancer patients. METHODS: Consecutive cancer patients undergoing thrombectomy for acute ischemic stroke due to large vessel occlusion between January 2018 and May 2022 were retrospectively reviewed. The patients were classified into white thrombus and red thrombus groups on the basis of the pathological findings of retrieved thrombi. Patient characteristics and laboratory findings were compared between the two groups. RESULTS: There were 12 patients in the white thrombus group and 11 patients in the red thrombus group. Active cancer was significantly more in the white thrombus group than in the red thrombus group (91.7% vs. 36.3%, p = 0.0094). Internal carotid artery occlusion was significantly less in the white thrombus group than in the red thrombus group (0% vs. 36.4%, p = 0.037). Among laboratory findings, D-dimer levels were an independent factor associated with white thrombi (odds ratio 8.97 [95% confidence interval 1.71-368.99], p < 0.0001). The cutoff value of D-dimer levels for predicting white thrombi was 3.5 µg/mL (83.3% sensitivity and 100% specificity). CONCLUSIONS: In acute ischemic stroke in cancer patients, active cancer, no internal carotid artery occlusion, and higher D-dimer levels (≥3.5 µg/mL) may be associated with occlusion with fibrin and platelet-rich white thrombi.

Membrane skeleton hyperstability due to a novel alternatively spliced 4.1R can account for ellipsoidal camelid red cells with decreased deformability.

The red blood cells (RBCs) of vertebrates have evolved into two basic shapes, with nucleated nonmammalian RBCs having a biconvex ellipsoidal shape and anuclear mammalian RBCs having a biconcave disk shape. In contrast, camelid RBCs are flat ellipsoids with reduced membrane deformability, suggesting altered membrane skeletal organization. However, the mechanisms responsible for their elliptocytic shape and reduced deformability have not been determined. We here showed that in alpaca RBCs, protein 4.1R, a major component of the membrane skeleton, contains an alternatively spliced exon 14-derived cassette (e14) not observed in the highly conserved 80 kDa 4.1R of other highly deformable biconcave mammalian RBCs. The inclusion of this exon, along with the preceding unordered proline- and glutamic acid-rich peptide (PE), results in a larger and unique 90 kDa camelid 4.1R. Human 4.1R containing e14 and PE, but not PE alone, showed markedly increased ability to form a spectrin-actin-4.1R ternary complex in viscosity assays. A similar facilitated ternary complex was formed by human 4.1R possessing a duplication of the spectrin-actin-binding domain, one of the mutations known to cause human hereditary elliptocytosis. The e14- and PE-containing mutant also exhibited an increased binding affinity to ß-spectrin compared with WT 4.1R. Taken together, these findings indicate that 4.1R protein with the e14 cassette results in the formation and maintenance of a hyperstable membrane skeleton, resulting in rigid red ellipsoidal cells in camelid species, and suggest that membrane structure is evolutionarily regulated by alternative splicing of exons in the 4.1R gene.

Hemodynamic Change due to Vessel Straightening Immediately after LVIS Jr. Deployment for an Anterior Communicating Artery Aneurysm.

Objective: Stent-assisted coil embolization for cerebral aneurysms may lead to straightening of the parent vessel. However, detailed reports documenting the hemodynamic change in bifurcation type aneurysms due to straightening of the parent vessel immediately after stent deployment are scarce. Case Presentation: A 48-year-old woman with a history of polycystic kidney disease underwent aneurysm neck clipping with left frontotemporal craniotomy for a ruptured bifurcation-type anterior communicating artery (AComA) aneurysm. Angiography 18 days after clipping showed a recurrent AComA aneurysm, for which stent-assisted coil embolization was performed. Straightening of the parent vessel immediately after deployment of a low-profile visualized intraluminal support junior (LVIS Jr.) stent from the AComA to the A1 segment of the right anterior cerebral artery was confirmed by working projection angiography. The aneurysm was easily embolized with coils with the support of the stent covering the aneurysm neck. The embolization was finished with a slight dome filling of the aneurysm. The parent vessel angle in 3D angiography changed from 90° before stent deployment to 160° immediately after stent deployment. Angiography 2 months after embolization showed the aneurysm with a complete occlusion and the parent vessel angle of 170° in a 3D image. Conclusion: The hemodynamic change in a bifurcation-type AComA aneurysm due to straightening of the parent vessel immediately after the LVIS Jr. stent deployment led to the covering of the aneurysm neck, resulting in good coil embolization, to which the vessel mobility and the stenting method may have contributed.

Inferior Epigastric Artery Injury due to Femoral Venipuncture for Neuroendovascular Intervention: Two Cases Requiring Transcatheter Arterial Embolization.

Objective: Injury to the inferior epigastric artery (IEA) caused by femoral puncture may lead to retroperitoneal hematoma. We report on two cases of IEA injury due to femoral venipuncture for neuroendovascular intervention that resulted in hemorrhagic shock and required transcatheter arterial embolization. Case Presentations: A 67-year-old woman and a 71-year-old man receiving dual antiplatelet therapy sustained injury to a branch of the IEA in the process of right femoral venipuncture for neuroendovascular intervention. In both cases, stent placement in the intracranial artery was accomplished as intended with systemic heparinization throughout the procedure; however, the patients became hypotensive during the procedure, and contrast-enhanced CT scans taken after the stenting revealed extravasation of contrast from the IEA and retroperitoneal hematoma. Transcatheter arterial embolization of the bleeding branch of the IEA was performed with the left femoral approach, and subsequent angiography confirmed the disappearance of the extravasation of contrast. Conclusion: Femoral venipuncture for neuroendovascular intervention in patients receiving antithrombotic agents may cause IEA injury requiring transcatheter arterial embolization. The risk of IEA injury may be reduced by using the femoral head as a reference, performing ultrasound-guided puncture, and confirming the course of the IEA by femoral angiography before venipuncture.

REV-ERB agonist suppresses IL-17 production in γδT cells and improves psoriatic dermatitis in a mouse model.

Psoriasis is a chronic inflammatory skin disease characterized by epidermal hyperplasia and cellular infiltration. Studies have shown that disease development depends on proinflammatory cytokines, such as interleukin (IL)-23 and IL-17. It has been suggested that IL-23 produced by innate immune cells, such as macrophages, stimulates a subset of helper T cells to release IL-17, promoting neutrophil recruitment and keratinocyte proliferation. However, recent studies have revealed the crucial role of γδT cells in psoriasis pathogenesis as the primary source of dermal IL-17. The nuclear receptors REV-ERBs are ligand-dependent transcription factors recognized as circadian rhythm regulators. REV-ERBs negatively regulate IL-17-producing helper T cells, whereas the involvement of REV-ERBs in regulating IL-17-producing γδT (γδT17) cells remains unclear. Here we revealed the regulatory mechanism involving γδT17 cells through REV-ERBs. γδT17 cell levels were remarkably elevated in the secondary lymphoid organs of mice that lacked an isoform of REV-ERBs. A synthetic REV-ERB agonist, SR9009, suppressed γδT17 cells in vitro and in vivo. Topical application of SR9009 to the skin reduced the inflammatory symptoms of psoriasiform dermatitis in mice. The results of this study provide a novel therapeutic approach for psoriasis targeting REV-ERBs in γδT17 cells.

Endoscope-assisted microsurgical repair in trigeminal meningocele: case report.

Trigeminal meningocele is a rare disease that results in rhinorrhea. Treatments with endoscopic approaches and open craniotomies have high recurrence rates, and controversy regarding the most effective surgical strategy for trigeminal meningocele is ongoing. The authors report a case of a 13-year-old female patient with a diagnosis of trigeminal meningocele determined after she presented with a history of intermittent headaches, suspected rhinorrhea, and recurrent meningitis. In addition to the conventional method of covering the efflux point of CSF and filling the inside of the meningocele with fascial tissues, the authors selectively closed the influx point of CSF from the prepontine cistern to the meningocele using an anterior transpetrosal approach. On the basis of the preoperative images, the authors hypothesized that the influx point of CSF could not be observed under the microscopic direct view and instead used a flexible endoscope. A check valve-like structure with one-way communication of CSF from the prepontine cistern into the cystic cavity was identified and was closed. At the time of this report, 36 months postoperatively, the patient had no indications of recurrence. Although cases of trigeminal meningoceles are infrequently encountered and require a tailored approach, the results in this case thus far indicate that the use of an endoscope and open craniotomy is an effective strategy for surgical treatment.

The thymoproteasome hardwires the TCR repertoire of CD8+ T cells in the cortex independent of negative selection.

The thymoproteasome expressed specifically in thymic cortical epithelium optimizes the generation of CD8+ T cells; however, how the thymoproteasome contributes to CD8+ T cell development is unclear. Here, we show that the thymoproteasome shapes the TCR repertoire directly in cortical thymocytes before migration to the thymic medulla. We further show that the thymoproteasome optimizes CD8+ T cell production independent of the thymic medulla; independent of additional antigen-presenting cells, including medullary thymic epithelial cells and dendritic cells; and independent of apoptosis-mediated negative selection. These results indicate that the thymoproteasome hardwires the TCR repertoire of CD8+ T cells with cortical positive selection independent of negative selection in the thymus.

ROR agonist hampers the proliferation and survival of postactivated CD8+ T cells through the downregulation of cholesterol synthesis-related genes.

Cholesterol is a major component of the lipid bilayers of cellular membranes. The synthesis of cholesterol is acutely elevated during T-cell activation to support T-cell growth and proliferation. There is a limited understanding of cholesterol metabolism reprogramming during T-cell activation. Retinoic acid receptor-related orphan receptors (RORs) are ligand-activated nuclear receptors that regulate the transcription of target genes. In this study, we demonstrated that the activation of RORs by a synthetic agonist (SR1078) impairs the proliferation and survival of postactivated CD8+ T cells. The inhibitory effects of SR1078 on CD8+ T-cell proliferation and survival were attributed to cholesterol depletion and downregulated expression of cholesterol metabolism-related genes. The overexpression of RORα or RORγt promoted apoptosis in the postactivated CD8+ T cells in vitro. The expression of RORα (but not that of RORγt) was markedly upregulated in the CD8+ T cells upon stimulation with an antigen in vivo. The functional deficiency of RORα enhanced CD8+ T-cell expansion during the response to bacterial infection. These results suggest that RORs are involved in the regulation of CD8+ T-cell-mediated immune response through the regulation of cholesterol metabolism, which can be modulated by a synthetic ROR agonist. The findings of this study can aid in the development of immunotherapeutic methods that target nuclear receptors.

Cholesterol-binding protein TSPO2 coordinates maturation and proliferation of terminally differentiating erythroblasts.

TSPO2 (translocator protein 2) is a transmembrane protein specifically expressed in late erythroblasts and has been postulated to mediate intracellular redistribution of cholesterol. We identified TSPO2 as the causative gene for the HK (high-K+) trait with immature red cell phenotypes in dogs and investigated the effects of the TSPO2 defects on erythropoiesis in HK dogs with the TSPO2 mutation and Tspo2 knockout (Tspo2-/-) mouse models. Bone marrow-derived erythroblasts from HK dogs showed increased binucleated and apoptotic cells at various stages of maturation and shed large nuclei with incomplete condensation when cultured in the presence of erythropoietin, indicating impaired maturation and cytokinesis. The canine TSPO2 induces cholesterol accumulation in the endoplasmic reticulum and could thereby regulate cholesterol availability by changing intracellular cholesterol distribution in erythroblasts. Tspo2-/- mice consistently showed impaired cytokinesis with increased binucleated erythroblasts, resulting in compensated anemia, and their red cell membranes had increased Na,K-ATPase, resembling the HK phenotype in dogs. Tspo2-deficient mouse embryonic stem cell-derived erythroid progenitor (MEDEP) cells exhibited similar morphological defects associated with a cell-cycle arrest at the G2/M phase, resulting in decreased cell proliferation and had a depletion in intracellular unesterified and esterified cholesterol. When the terminal maturation was induced, Tspo2-/- MEDEP cells showed delays in hemoglobinization; maturation-associated phenotypic changes in CD44, CD71, and TER119 expression; and cell-cycle progression. Taken together, these findings imply that TSPO2 is essential for coordination of maturation and proliferation of erythroblasts during normal erythropoiesis.

Enhanced Immunotherapeutic Efficacy of Anti-PD-L1 Antibody in Combination with an EP4 Antagonist.

Combination treatment approaches are increasingly considered to overcome resistance to immunotherapy targeting immunoinhibitory molecules such as programmed death (PD)-1 and PD-ligand 1 (PD-L1). Previous studies have demonstrated that the therapeutic efficacy of anti-PD-L1 Abs is enhanced by combination treatment with cyclooxygenase-2 inhibitors, through downregulation of the immunosuppressive eicosanoid PGE2, although the underlying mechanism remains unclear. In this study, we show that serum PGE2 levels are upregulated after anti-PD-L1 Ab administration in a bovine model of immunotherapy and that PGE2 directly inhibits T cell activation via its receptor E prostanoid (EP) 4. Additionally, anti-PD-L1 Ab induces TNF-α production and TNF-α blockade reduces PGE2 production in the presence of anti-PD-L1 Ab, suggesting that anti-PD-L1 Ab-induced TNF-α impairs T cell activation by PGE2 upregulation. Our studies examining the therapeutic potential of the dual blockade of PD-L1 and EP4 in bovine and murine immune cells reveal that the dual blockade of PD-L1 and EP4 significantly enhances Th1 cytokine production in vitro. Finally, we show that the dual blockade decreases tumor volume and prolongs survival in mice inoculated with the murine lymphoma cell line EG7. Altogether, these results suggest that TNF-α induced by anti-PD-L1 Ab treatment is associated with T cell dysfunction via PGE2/EP4 pathway and that the dual blockade of PD-L1 and EP4 should be considered as a novel immunotherapy for cancer.

TCR Affinity for In Vivo Peptide-Induced Thymic Positive Selection Fine-Tunes TCR Responsiveness of Peripheral CD8+ T Cells.

The affinity for TCR interactions with self-peptide/MHC complexes (pMHC) in the thymus critically affects immature thymocytes that newly express TCRs. Previous fetal thymus organ culture experiments have indicated that difference in the affinity for thymic TCR/pMHC interactions not only determines thymocyte fate between positive and negative selection, but also affects Ag responsiveness of positively selected thymocytes. In the current study, we examined whether TCR/pMHC affinity during positive selection in the thymus would further affect Ag responsiveness of mature T cells in the periphery. To do so, OVA peptide variants were in vivo administered to TAP1-deficient OT-I/TCR-transgenic mice in which T cell development was otherwise arrested at CD4+CD8+ thymocytes because of the lack of self-pMHC presentation in thymic APCs. We found that a group of peptide variants induced the transient generation of OT-I CD8+ T cells in the thymus and the periphery. We also noticed that the affinity threshold for positive and negative selection detected in adult mice in vivo was higher than that measured in fetal thymus organ culture experiments in vitro. Interestingly, we further found that the affinity for positively selecting peptides proportionally affected TCR responsiveness of peripheral naive CD8+ T cells. These results indicate that in vivo administration of a peptide can promote T cell selection in the thymus and the affinity for TCR/pMHC interaction during positive selection fine-tunes Ag responsiveness of peripheral T cells.

A Rare Case of Giant Solid Hemangioblastoma Accompanied with Hemophilia Type A.

The surgical removal of giant solid hemangioblastoma involves a high risk of perioperative bleeding and requires attentive hemostasis. Here, we present a case of a giant solid hemangioblastoma accompanied with hemophilia which was previously undiagnosed. A 35-year-old man without any past medical history was admitted with diplopia and ocular motility disorder. computed tomography (CT) and magnetic resonance imaging (MRI) revealed obstructive hydrocephalus and a solid giant tumor of more than 4.0 cm in diameter in the right cerebellopontine angle (CPA). Hemangioblastoma was suspected on cerebral angiography. After ventriculoperitoneal shunt for obstructive hydrocephalus, oozing from the skin incision continued for several days. Hemophilia type A was diagnosed based on the result of laboratory blood coagulability examination. Supplemental administration of factor VIII and coil embolization of the feeding arteries of the lesion on the CPA were performed, and the tumor was subtotally resected without hemorrhagic complications. The histopathological diagnosis was hemangioblastoma. We report this case to emphasize the importance not to overlook previously undiagnosed coagulopathy before surgical excision of hemangioblastoma. And, with appropriate perioperative management for coagulopathy, surgical treatment involving a high risk of perioperative bleeding can be safely undertaken.

Metronidazole Induced Encephalopathy Mimicking an Acute Ischemic Stroke Event.

Metronidazole induced encephalopathy (MIE), an encephalopathy brought by an antibiotic, is characterized with cerebellar dysfunction, altered mental status and extrapyramidal symptoms. MIE can result in an acute manifestation, but MIE has not been reported as a stroke mimic. An 86-year-old patient undergoing metronidazole therapy for Clostridium difficile enteritis presented to our hospital with sudden disoriented status and motor weakness of the left extremities. Computed tomography (CT) was unrevealing of intracranial hemorrhagic change, and CT angiography did not show any apparent major occlusion or stenosis of the intracranial vessels. However, CT perfusion (CTP) revealed a decrease in peripheral blood flow in the right cerebral hemisphere, and tissue plasminogen activator was administrated for a possible acute ischemic stroke. The findings of follow-up magnetic resonance imaging (MRI) were typical for MIE, revealing areas of hyperintensity on fluid attenuated inversion recovery (FLAIR) signal intensity in the dentate nuclei, the splenium of the corpus callosum, and in the dorsal midbrain. The degree of hyperintensity was stronger in the left dentate nucleus than in the right left dentate on FLAIR and the apparent diffusion coefficient map. The asymmetric findings of the left dentate nucleus on MRI were considered to be responsible for the clinical symptoms and the findings of CTP. We report a rare case of MIE mimicking an acute ischemic stroke, and hypothesize the relationship between the findings of CTP and that of MRI based on the anatomical connection of the dentate nucleus and the cerebral hemisphere.

Histopathological Correlations between Mediastinal Fat-Associated Lymphoid Clusters and the Development of Lung Inflammation and Fibrosis following Bleomycin Administration in Mice.

Bleomycin (BLM) has been reported to induce lung inflammation and fibrosis in human and mice and showed genetic susceptibility. Interestingly, the C57BL/6 (B6) mice had prominent mediastinal fat-associated lymphoid cluster (MFALCs) under healthy condition, and showed susceptibility to development of lung fibrosis following BLM administration. However, the pathogenesis of lung lesion progression, and their correlation with MFALC morphologies, remain to be clarified. To investigate the correlations between MFALC structures and lung injuries in B6 mice, histopathological examination of mediastinal fat tissues and lungs was examined at 7 and 21 days (d) following a single 50 µL intranasal (i.n.) instillation of either BLM sulfate (5 mg/kg) (BLM group) or phosphate-buffered saline (control group). The lung fibrosis was examined by Masson's trichrome (MT) stain of paraffin sections and mRNA expression levels of Col1a1, Col3a1, and Acta2 in different frozen lung samples. Furthermore, immunohistochemistry for CD3, B220, Iba1, Gr1, BrdU, LYVE-1, and peripheral node addressin (PNAd) was performed to detect T- and B-cells, macrophages, granulocytes, proliferating cells, lymph vessels (LVs), and high endothelial venules (HEVs). We found that MFALCs were more abundant in the BLM group as compared to the control group. The lung of BLM group developed pneumonitis with severe cellular infiltrations at 7 days and significant collagen deposition (MT) and higher expression of Col1a1, and Col3a1 at 21 days post-administration. Numerous immune cells, proliferating cells, HEVs, and LVs were observed in both MFALCs and lungs of the BLM group. Interestingly, PNAd + HEVs were observed in the lungs of the BLM group, but not the control group. Moreover, numerous Gr1 + polymorphonuclear and mononuclear-like ring cells were found in the MFALCs and lungs of the BLM group. Interestingly, flow cytometric analysis revealed a significant increase of B-cell populations within the MFALCs of BLM group suggesting a potential proliferative induction of B-cells following inflammation. Furthermore, significant positive correlations were observed between quantitative parameters of these immune cells in both the lungs and MFALCs. Thus, we suggest a potentially important role for MFALCs and HEVs in the progression of lung disease, especially in inflammatory lung disease.

Morphology of brood pouch formation in the pot-bellied seahorse Hippocampus abdominalis.

BACKGROUND: The reproductive strategies of vertebrates are diverse. Seahorses (Pisces: Syngnathidae) possess the unique characteristic of male pregnancy; i.e., males, not females, incubate embryos in a specialized structure called a 'brood pouch'. The brood pouch is formed along the ventral midline of the tail. The lumen of the brood pouch is surrounded by loose connective tissue, called pseudoplacenta, and dermis. RESULTS: We visualized and evaluated the morphology of brood pouch formation in Hippocampus abdominalis to gain generalizable insights into this process in seahorses. First, we employed several staining methods to characterize the pseudoplacenta and dermis of the brood pouch of mature male seahorses. The pseudoplacenta is composed mainly of reticular fibers, while the dermis is composed mainly of collagenous fibers. Further observations showed that pouch formation is initiated by linear projections of epithelia on both ventrolateral sides of the body. These projections elongated toward the ventral midline, eventually fused together, and then formed a baggy structure composed of a single dermis layer with neither smooth muscle nor pseudoplacenta. Finally, the pseudoplacenta was formed, together with two layers of dermis and smooth muscle. Thus, a fully developed brood pouch was established. The morphology of the luminal epithelium also changed during pouch formation. We analyzed the localization of C-type lectins as markers; haCTL II was localized in both the outer and luminal epithelia of the brood pouch throughout development in the male seahorse, whereas haCTL IV, which was not detected in the early stage of seahorse development, became localized only in the luminal epithelium as development proceeded. CONCLUSIONS: We categorized the processes of brood pouch formation during male seahorse development into three stages: (1) the early stage, characterized by formation of a baggy structure from the primordium; (2) the middle stage, characterized by the differentiation and establishment of brood pouch-specific tissues; and (3) the late stage, characterized by a fully formed pouch with developing blood vessels and a pouch fold ultimately capable of carrying and incubating embryos.

Antigen processing and presentation in the thymus: implications for T cell repertoire selection.

The processing and presentation of major histocompatibility complex (MHC)-associated antigens depend on the intracellular digestion of self- and nonself-proteins, the loading of digested peptides onto MHC molecules, and the traffic of peptide-MHC complexes to plasma membrane surface for display to interacting T cells. Recent studies have revealed unique machineries for antigen processing and presentation in thymic antigen-presenting cells that display self-antigens to developing thymocytes for the formation of functionally competent yet self-tolerant T cell repertoire. Here, we briefly summarize those machineries, focusing on the biology of cortical and medullary thymic epithelial cells.

Generation of Peptides That Promote Positive Selection in the Thymus.

To establish an immunocompetent TCR repertoire that is useful yet harmless to the body, a de novo thymocyte repertoire generated through the rearrangement of genes that encode TCR is shaped in the thymus through positive and negative selection. The affinity between TCRs and self-peptides associated with MHC molecules determines the fate of developing thymocytes. Low-affinity TCR engagement with self-peptide-MHC complexes mediates positive selection, a process that primarily occurs in the thymic cortex. Massive efforts exerted by many laboratories have led to the characterization of peptides that can induce positive selection. Moreover, it is now evident that protein degradation machineries unique to cortical thymic epithelial cells play a crucial role in the production of MHC-associated self-peptides for inducing positive selection. This review summarizes current knowledge on positive selection-inducing self-peptides and Ag processing machineries in cortical thymic epithelial cells. Recent studies on the role of positive selection in the functional tuning of T cells are also discussed.