Eosinophils are innate immune leukocytes and play important roles as terminal effector cells owing to their mediators, such as tissue-destructive cationic proteins, cytokines, chemokines, and lipid ...mediators. Historically, they are not only considered an important player in host defense against parasitic, viral, fungal, and bacterial infections but also implicated in the pathogenesis of eosinophil-associated diseases, such as allergic rhinitis, asthma, eosinophilic chronic rhinosinusitis, esophagitis, atopic dermatitis, myopathies, and hypereosinophilic syndrome. Moreover, recent studies have shown that eosinophils have an immune regulatory and homeostatic function. Interestingly, there is emerging evidence that eosinophils are accumulated through adoptive T-helper 2 (Th2) and innate Th2 responses, mechanisms of the classical allergen-specific immunoglobulin E (IgE)-mediated response, and group 2 innate lymphoid cell-derived interleukin-5, respectively. Furthermore, in agreement with current concepts of eosinophil subtypes, it has been shown that resident and phenotypically distinct eosinophils, i.e., resident and recruited inflammatory eosinophils, exist in inflamed sites, and each has different functions. Thus, the classical and novel studies suggest that eosinophils have multiple functions, and their roles may be altered by the environment. In this article, we review multiple biological aspects of eosinophils (novel and classical roles), including their beneficial and detrimental effects, immunoregulation, and homeostatic function.
Intracranial pseudoaneurysms are uncommon and among the most difficult lesions to treat with surgery or endovascular means without parent artery sacrifice. Here, we report on a patient who underwent ...successful treatment using a flow-diverting stent for an iatrogenic intracranial internal carotid artery pseudoaneurysm following a vessel injury after endoscopic pituitary tumor resection via the transsphenoidal approach. A 62-year-old man with a Rathke’s cleft cyst presenting with bitemporal hemianopia and progressive decline of left visual acuity underwent endoscopic transsphenoidal pituitary tumor resection. During dura incision, brisk arterial bleeding was encountered from the right internal carotid artery. Immediate packing was performed, and hemostasis was achieved. Three days after the vessel injury, an angiography revealed a pseudoaneurysm (2.9 × 2.1 mm) at the cavernous segment of the right internal carotid artery, which showed enlargement on follow-up magnetic resonance imaging at six days postoperatively. Pipeline embolization was performed nine days after the vessel injury. Angiography performed one month after Pipeline embolization revealed significant stagnation but not complete occlusion of blood flow inside the pseudoaneurysm cavity. Dual antiplatelet therapy was replaced with single antiplatelet therapy. Follow-up angiograms three months after Pipeline embolization confirmed complete obliteration of the pseudoaneurysm and successful endoluminal reconstruction of the damaged vessel. Despite the possibility of short-term bleeding and the need for dual antiplatelet therapy administration for a certain period, the use of flow-diverting stents is a feasible vessel-sparing option in the management of intracranial internal carotid artery pseudoaneurysms resulting from transsphenoidal surgery injuries if intraoperative hemodynamic stability can be achieved with effective packing.
Background: In Japan, increasing the number of ambulance requests, the case with the use of respiratory assistance devices in prehospital care by paramedics is also increasing1. When patient ...experiences respiratory failure, the first responders frequently select a respiratory assist device (RAD) such as Bag Valve Mask (BVM), Jackson Rees (JR), or BVM with Gas Supply Valve® (BVM+GSV). This is based on both evaluation and experience as there is no study indicating which RAD is the best choice at the pre-hospital emergency site. This study clarified the precautions when using BVM, JR, and BVM+GSV in pre-hospital emergency medical care with healthy volunteers. Methods: Twenty healthy adults were fitted with a RAD while breathing spontaneously, and changes in vital signs and ETCO2 were observed. Results: The level of ETCO2 became elevated after each RAD was attached. The value was significantly higher in the JR group than in the others. Conclusions: The study showed that even in the presence of spontaneous breathing, ETCO2 increased markedly with the application of respiratory assist devices that are used in pre-hospital care for conditions such as hypoxemia and ventilatory disturbance. The increase in ETCO2 was particularly significant in the JR group, suggesting the need for caution when selecting JRs for pre-hospital care. As the number of subjects was only 20 for each RAD, studies with a larger sample size are needed.
Despite the increase in age-related hearing loss (ARHL) prevalence owing to increased population aging, preventive measures against ARHL have not yet been established. The immune system becomes one ...of the most dysfunctional systems upon aging, and immunosenescence greatly affects homeostasis and promotes systemic aging along with chronic inflammation and oxidative stress. This study aimed to determine whether immuno-rejuvenation procedures can prevent ARHL and have clinical applications as well as to analyze the communication mechanisms between the systemic immune system and the cochlea using a murine model. Lymphocytes from young mice inhibited the progression of ARHL. The method of cryopreserving these lymphocytes and inoculating them at the onset of ARHL suggests their clinical application. Mice that were administered this treatment not only maintained auditory threshold but also avoided spinal ganglion degeneration, cellular immune aging, and nitric oxide production, which causes age-related tissue damage. These findings coincide with our previous strategies against immunosenescence and neuronal aging. Therefore, the manipulation of systemic immune function may contribute not only to the prevention of ARHL but also to the development of novel anti-aging clinical measures, paving the way to healthy longevity with preserved organ function.
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•Age-related hearing loss (ARHL) does not have established preventive measures.•Inoculation of cryopreserved lymphocytes from young mice led to immune regeneration.•This immune manipulation inhibited ARHL progression in aged mice.•Cochlear atrophy and oxidative stress were also suppressed in the hosts.•Autologous lymphocyte inoculation may have clinical application in ARHL prevention.
Esophageal squamous cell carcinoma (ESCC) is the most common subtype of esophageal cancer worldwide. The most commonly mutated gene in ESCC is TP53. Using a combinatorial genetic and carcinogenic ...approach, we generate a novel mouse model of ESCC expressing either mutant or null p53 and show that mutant p53 exhibits enhanced tumorigenic properties and displays a distinct genomic profile. Through RNA‐seq analysis, we identify several endocytic recycling genes, including Rab Coupling Protein (Rab11‐FIP1), which are significantly downregulated in mutant p53 tumor cells. In 3‐dimensional (3D) organoid models, genetic knockdown of Rab11‐FIP1 results in increased organoid size. Loss of Rab11‐FIP1 increases tumor cell invasion in part through mutant p53 but also in an independent manner. Furthermore, loss of Rab11‐FIP1 in human ESCC cell lines decreases E‐cadherin expression and increases mesenchymal lineage‐specific markers, suggesting induction of epithelial–mesenchymal transition (EMT). Rab11‐FIP1 regulates EMT through direct inhibition of Zeb1, a key EMT transcriptional factor. Our novel findings reveal that Rab11‐FIP1 regulates organoid formation, tumor cell invasion, and EMT.
Synopsis
Loss of the Rab coupling protein Rab11‐FIP1 fosters disruption of epithelial stratification, tumor cell invasion and EMT in esophageal squamous cell carcinoma.
Rab11‐FIP1 is significantly downregulated in esophageal cancer.
Rab11‐FIP1 depletion promotes epithelial cell disorganization and tumor cell invasion.
Rab11‐FIP1 regulates EMT through direct inhibition of Zeb1.
Loss of the Rab coupling protein Rab11‐FIP1 fosters disruption of epithelial stratification, tumor cell invasion and EMT in esophageal squamous cell carcinoma.
Loss of the Rab coupling protein Rab11‐FIP1 fosters disruption of epithelial stratification, tumor cell invasion and EMT in esophageal squamous cell carcinoma.
Eosinophilic chronic rhinosinusitis (ECRS) is a refractory airway disease accompanied by eosinophilic inflammation, the mechanisms of which are unknown. We recently found that CCL4/MIP-1β-a specific ...ligand for CCR5 receptors-was implicated in eosinophil recruitment into the inflammatory site and was substantially released from activated eosinophils. Moreover, it was found in nasal polyps from patients with ECRS, primarily in epithelial cells. In the present study, the role of epithelial cell-derived CCL4 in eosinophil activation was investigated. First, CCL4 expression in nasal polyps from patients with ECRS as well as its role of CCL4 in eosinophilic airway inflammation were investigated in an in vivo model. Furthermore, the role of CCL4 in CD69 expression-a marker of activated eosinophils-as well as the signaling pathways involved in CCL4-mediated eosinophil activation were investigated. Notably, CCL4 expression, but not CCL5, CCL11, or CCL26, was found to be significantly increased in nasal polyps from patients with ECRS associated with eosinophil infiltration as well as in BEAS-2B cells co-incubated with eosinophils. In an OVA-induced allergic mouse model, CCL4 increased eosinophil accumulation in the nasal mucosa and the bronchoalveolar lavage (BALF). Moreover, we found that CD69 expression was upregulated in CCL4-stimulated eosinophils; similarly, phosphorylation of several kinases, including platelet-derived growth factor receptor (PDGFR)β, SRC kinase family (Lck, Src, and Yes), and extracellular signal-regulated kinase (ERK), was upregulated. Further, CCR5, PDGFRβ, and/or Src kinase inhibition partially restored CCL4-induced CD69 upregulation. Thus, CCL4, which is derived from airway epithelial cells, plays a role in the accumulation and activation of eosinophils at inflammatory sites. These findings may provide a novel therapeutic target for eosinophilic airway inflammation, such as ECRS.
Multinodular and vacuolating neuronal tumors (MVNT) have been recently referred to as a distinctive neuronal tumor entity based on histopathological findings. They are characterized by multiple tumor ...nodules, vacuolar alteration and widespread immunolabeling for human neuronal protein HuC/HuD. Only 13 cases have been reported in the literature to date and little is known about the histopathology of these tumors. Herein, we report a case of MVNT with additional confirmation of immunohistochemical features. A 22‐year‐old woman presented with a continuous headache. MRI showed a subcortical white matter lesion with multiple satellite nodules in the frontal lobe appearing as T2/fluid‐attenuated inversion recovery (FLAIR) hyperintensities. Histological examination of the resected lesion revealed well‐defined multiple nodules composed of predominant vacuolating tumor cells. The tumor cells exhibited consistent immunolabeling for doublecortin, as well as HuC/HuD, both representative neuronal biomarkers associated with earlier stages of neuronal development. Immunopositivity for oligodendrocyte transcription factor 2 (Olig2) and S100 was also detected in tumor cells. Additionally, significant overexpression of alpha‐internexin was observed in the background neuropil limited to tumor nodules. Neuronal nuclear antigen (NeuN), synaptophysin and neurofilament, markers for mature neurons, were either negative or weakly positive. The expression profile of neuronal biomarkers can be distinguished from that of classic neuronal tumors and is the immunohistochemical hallmark of MVNT. In summary, we identified the characteristic tumoral expression of HuC/HuD and doublecortin and the presence of abundant neuropil localized in MVNT tumor nodules, which exhibited widespread alpha‐internexin expression. These results supported the presumption that MVNT is a distinct histopathological entity.
Background: Because choking quickly leads to cardiopulmonary arrest, it is crucial that bystanders remove foreign bodies effectively. Although oral instructions in video calls by dispatchers have ...improved the quality of cardiopulmonary resuscitation, it is unclear whether video calls improve the quality of first aid for choking infants. Therefore, this simulation study aimed to determine whether video calls with dispatchers improve the quality of first aid for infants with foreign body airway obstruction (FBAO). Methods: Seventy first-year college students randomly assigned in pairs to communicate by video or audio calls participated in simulated emergency calls for infants with FBAO. Both groups began with oral instruction in voice calls until the transition was made to video calls in the video group. The primary outcome was quality of first aid performance, which was categorized as excellent, acceptable, or poor on the basis of existing guidelines. Results: There were 17 simulations in the video-call groups and 16 in the voice-call groups. After initial oral instruction, the proportion of rescuers that received an evaluation of excellent or acceptable did not differ significantly between the groups (video, 41% vs. voice, 50%; P=0.61); however, evaluations for seven rescuers improved after transitioning to video calls. Ultimately, the proportion receiving a poor evaluation was significantly lower in the video-call group than in the voice-call group (50% vs. 82%, P=0.049). Conclusion: Oral instruction communicated by video calls improved the quality of first aid for infants with FBAO.
The purpose of this study was to investigate the involvement of organic anion transporting polypeptide (OATP/Oatp) and P-glycoprotein (P-gp)/multidrug resistance 1 (MDR1/Mdr1) in intestinal ...absorption of pitavastatin. Pitavastatin was found to be a substrate for human OATP1A2, OATP2B1, and MDR1 and rat Oatp1a5, Oatp2b1, and Mdr1a in experiments using transporter-expressing Xenopus oocytes and LLC-PK1 cell systems. Naringin inhibited Oatp1a5- and Mdr1a-mediated transport of pitavastatin with IC 50 values of 18.5 and 541 μM, respectively. The difference in the IC 50 values of naringin for Oatp1a5 and Mdr1a-mediated pitavastatin transport may account for the complex concentrationdependent effect of naringin on the intestinal absorption of pitavastatin. Rat intestinal permeability of pitavastatin measured by the in situ closed-loop perfusion method was indeed significantly reduced by 200 μM naringin, but was significantly increased by 1000 μM naringin. Furthermore, the permeability was significantly increased by elacridar, a potent inhibitor of Mdr1, while the permeability was significantly decreased in the presence of both elacridar and naringin, suggesting that Oatp1a5 and Mdr1a are both involved in intestinal absorption of pitavastatin. Our present results indicate that OATP/Oatp and MDR1/ Mdr1 play roles in the intestinal absorption of pitavastatin as influx and efflux transporters, respectively.
Disturbance in placental epigenetic regulation contributes to the pathogenesis of preeclampsia (PE). Although aberrant placental DNA methylation status in PE has been thoroughly studied, the role of ...histone modifications, including histone methylation, in PE remains unclear. Moreover, no study has ever reported the association between PE and placental histone methylation status by focusing on histone methyltransferases. The present study aimed to investigate the possible involvement of placental epigenetic regulation by histone methylation via histone methyltransferases in the pathophysiology of PE.
Placental mRNA expression of histone methyltransferases was examined using quantitative RT-PCR. Protein expression of histone methyltransferases and histone methylation status in placentas and trophoblast cell lines were assessed by immunoblotting and immunohistochemistry.
Expression profile of histone methyltransferases in the placentas using quantitative RT-PCR revealed that the mRNA expression levels of histone 3 lysine 4 (H3K4) methyltransferases, SETD1A and SMYD3, were significantly increased in placentas from PE patients. Immunoblotting and immunohistochemistry revealed that not only protein expression levels of SETD1A and SMYD3, but also H3K4 methylation status was increased in the trophoblasts from PE placentas. In vitro studies using HTR-8/SV-neo and BeWo cells showed that hypoxia induced the expression levels of SETD1A and SMYD3, and subsequently enhanced H3K4 methylation. Furthermore, the overexpression of SETD1A and SMYD3 in HTR-8/SV-neo cells enhanced H3K4 methylation in response to hypoxia.
Our study results suggest that placental epigenetic alteration by enhanced histone H3K4 methylation through upregulated SETD1A and SMYD3 might play a role in the pathophysiological process of PE associated with hypoxia.
•The expression levels of H3K4 histone methyltransferases SETD1A and SMYD3 were increased in PE placentas.•The methylation status of H3K4 was enhanced in PE placentas.•Hypoxia induced the upregulation of SETD1A and SMYD3 and enhanced H3K4 methylation in human trophoblast cells.•The overexpression of SETD1A and SMYD3 in human trophoblast cells enhanced hypoxia-induced H3K4 methylation.
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