Background: Cutaneous wound healing is a complex, dynamic physiological process. Traditional methods of promoting wound healing are not always effective. Consequently, alternative modalities, such as photodynamic therapy (PDT), are needed. We examined the effectiveness and underlying mechanisms of PDT in a murine model of acute wound healing. Methods: Two excisional wounds were produced, one on each side of the midline, in C57bL/6J mice. Methyl 5-aminolevulinate hydrochloride (MAL) was applied to the right-side wound. After 1 to 3 hours of incubation, the wound was irradiated with red light. The left-side wound was not treated with MAL or red light. On Day 14, the wounds were excised and subjected to histological and immunohistochemical analysis. Results: During the first week, no difference was seen between the two sides. However, at week 2, PDT-treated wounds exhibited delayed re-epithelialization. On Day 14, hematoxylin and eosin (HE) staining showed a continuous epithelial lining in untreated wounds. In contrast, PDT-treated wounds partially lacked epithelium in the wound bed. Masson's Trichrome (MTC) staining showed a thicker dermis and more collagen fibers and inflammatory cells in PDT-treated wounds than in untreated wounds. Immunohistochemical analyses showed significantly fewer CD31+ blood vessels and greater collagen III density in PDT-treated wounds than in untreated wounds. However, treated and untreated wounds did not differ in collagen I density. Conclusions: PDT delayed acute wound healing in a murine model of secondary intention wound healing.
Background: Although aberrant proliferation and activation of lung fibroblasts are implicated in the initiation and progression of idiopathic pulmonary fibrosis (IPF), the underlying mechanisms are not well characterized. Numerous microRNAs (miRNAs) have been implicated in this process; however, miRNAs derived from exosomes and the relevance of such miRNAs to fibroblast-to-myofibroblast differentiation are not well understood. In this study, we attempted to identify exosome-derived miRNAs relevant to fibrosis development. Methods: Using miRNA array analysis, we profiled exosome-derived miRNA expression in sera of C57BL/6 mice exhibiting bleomycin-induced pulmonary fibrosis. After validating a selected miRNA by quantitative reverse-transcription polymerase chain reaction, its effect on fibroblast-to-myofibroblast differentiation was investigated in human lung fibroblasts. Furthermore, we determined the role of the selected miRNA in an in vivo model of pulmonary fibrosis. Results: MiRNA array analysis revealed that miR-22 expression was increased by up to 2 fold on day 7 after bleomycin treatment compared with that in vehicle-treated mice. In vitro, miR-22 transfection suppressed TGF-β1-induced α-SMA expression. This was mediated via inhibition of the ERK1/2 pathway. Baseline α-SMA expression was increased upon miR-22 inhibitor transfection. Furthermore, miR-22 negatively regulated connective tissue growth factor expression in the presence of TGF-β1. In vivo, administration of a miR-22 mimic on day 10 after bleomycin challenge ameliorated pulmonary fibrosis lesions accompanied by decreased α-SMA expression in the model mice. Conclusions: Exosomal miR-22 modulates fibroblast-to-myofibroblast differentiation. The present findings warrant further study, which could shed light on miR-22 as a novel therapeutic target in IPF.
Purpose: Intravenous immunoglobulin (IVIG) therapy has been used to treat sepsis, but its mechanisms of action remain unclear. Sepsis causes multiple organ failure, such as acute lung injury (ALI), which involves apoptosis of alveolar epithelial cells. In this study, we hypothesized that IVIG suppresses apoptosis in alveolar epithelial cells and evaluated mortality, cytokine levels, histological changes in the lung, and alveolar epithelial cell apoptosis after IVIG administration, in mice with experimentally induced sepsis. Methods: Mice received an injection of vehicle (saline) or immunoglobulin (100 mg/kg or 400 mg/kg) into the tail vein, after which they underwent cecal ligation and puncture. A sham-operated group was used as the normal control. Survival was assessed in all groups after 72 hours. Plasma levels of TNF-α and IL-6, histopathological changes and wet-to-dry ratio in lung, and alveolar epithelial cell apoptosis were evaluated in all groups at 4 hours after surgery. Results: In the vehicle group, histopathological injury of the lung was severe, and apoptosis of alveolar epithelial cells was significant. Survival and plasma cytokine levels were better in the IVIG treatment groups than in the vehicle group. IVIG 400 mg/kg suppressed apoptosis of alveolar epithelial cells and reduced ALI. Conclusion: IVIG suppressed inflammatory cytokine levels and improved survival. Lung histopathology and alveolar epithelial cell apoptosis were improved by IVIG treatment, in a dose-dependent manner. Suppressing apoptosis in alveolar epithelial cells appears to be a mechanism by which IVIG improves survival.
Background: We compared our early experience of visual outcomes, operation time, and complications for two techniques of intrascleral intraocular lens (IOL) fixation: T-fixation and flanged IOL fixation. Methods: Data from patients who underwent scleral fixation of an IOL between October 2017 and December 2018 were analyzed retrospectively. Intraoperative time for fixation steps, corneal endothelial cell density (ECD) rate reduction, and intraoperative/postoperative complications were compared between T-fixation (Group T, n = 4) and flanged IOL fixation (Group F, n = 6). Results: Mean patient age was 73.7 ± 13.0 years. Intraoperative time was significantly longer for Group T (27.5 ± 9.7 min) than for Group F (13.0 ± 3.8 min; P=0.03, Mann-Whitney U-test). Intraoperative complications included iris damage from the 30-G needle in 2 eyes in Group F. Postoperative complications included iris capture by the IOL in 1 eye in Group F. No incidents of postoperative retinal detachment or IOL dislocation were identified. The ECD reduction rate did not significantly differ between groups. Conclusions: Both techniques yielded favorable surgical outcomes. Flanged IOL fixation might be superior because of its shorter intraoperative time but could initially be technically difficult because of the need to perform angled sclerotomy with a 30-G needle to avoid iris injury.
Background: Because the cause of liver dysfunction after allogeneic hematopoietic stem cell transplantation (HSCT) is difficult to identify in the early stages, treatment may be delayed. Therefore, early factors associated with unfavorable outcomes of liver dysfunction must be identified. The objective of this study was to identify unfavorable prognostic factors for liver dysfunction during the early period after transplantation. Methods: We defined liver dysfunction as elevated liver or biliary enzyme levels (corresponding to Grade 2 in the Common Terminology Criteria for Adverse Events version 4.0) within 30 days of transplantation and retrospectively investigated data from 82 patients who had undergone allogeneic HSCT at our center. Results: Elevated liver or biliary enzyme levels were observed in almost half of the patients studied (n=40, 48.7%). Elevated total bilirubin (T-Bil) level was the most frequently observed unfavorable prognostic factor and had the greatest effect on overall survival (OS), progression-free survival (PFS), and non-relapse mortality (NRM) (probability of unfavorable outcome in patients without and with elevated T-Bil level: OS, 58.9% vs. 15.4%, p < 0.001; PFS, 46.4% vs. 15.4%, p < 0.001; NRM, 10.7% vs. 53.8%, p < 0.001). Moreover, the probability of an unfavorable outcome increased in relation to the degree of T-Bil elevation and absence of improvement over time in T-Bil level. Conclusion: Elevated T-Bil level was an important marker of outcomes for liver dysfunction after allogeneic HSCT.
Mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) is a clinicoradiological syndrome characterized by transient mild encephalopathy and magnetic resonance imaging (MRI) findings of a reversible lesion in the splenium of the corpus callosum (SCC). Patients with MERS generally present with central nervous system symptoms such as consciousness disturbance, headache, and seizure; adult-onset MERS with cerebellar ataxia is rare. A 53-year-old man was admitted to our hospital with fever of 1 week's duration, headache, neck stiffness, and gait disturbance. Neurological examination revealed bilateral intention tremor (predominantly affecting the right hand) and gait ataxia. Diffusion-weighted brain MRI showed a focal hyperintense lesion in the SCC. Cerebrospinal fluid analysis revealed elevated levels of mononuclear cells and proteins. Brain imaging with 123I-iofetamine single-photon emission computed tomography showed reduced cerebral blood flow in the left thalamus and right cerebellum. Several diseases, including cerebellar stroke and acute cerebellitis, develop as comorbidities in patients with acute cerebellar ataxia. This case suggests that MERS should be suspected in adults with cerebellar ataxia.
Screening esophagogastroduodenoscopy of a 65-year-old man revealed a 4.7-cm polypoid in the gastric high body. Clinical and laboratory findings, including serum gastrin level (460 pg/mL) and biopsy findings, were consistent with a diagnosis of type I neuroendocrine tumor (NET). Histologically, the mass consisted of dilated tortuous glands at the surface and grade 1 NET in deeper tissue. Some hyperplastic glands exhibited a transition to adenocarcinoma, which invaded the NET, simulating a "tumor in tumor" appearance. Next-generation sequencing revealed that the adenocarcinoma component harbored a TP53 mutation, whereas the NET component showed no pathogenic mutation. To our knowledge, this unusual collision of adenocarcinoma and NET within a single gastric hyperplastic polyp has not been previously described. This case suggests that large gastric hyperplastic polyps should be carefully examined because of the possibility of underlying NET and malignant transformation of surface epithelium.
Background: Aneurysmal subarachnoid hemorrhage is a rare but important cause of maternal death during pregnancy. Case Description: A 34-year-old primigravida (31 weeks of pregnancy) with acute headache but no neurological deficits or neck stiffness was prescribed medication and returned home. Four weeks later she presented with severe headache and consciousness disturbance. She was admitted to our hospital, where she fell into a deep coma. Brain CT and three-dimensional CT angiography showed subarachnoid hemorrhage and a 5-mm right internal carotid-posterior communicating artery aneurysm. Fetal heart rate was 60 beats per minute. Emergent cesarean section and surgical clipping were performed. Intraoperative examination revealed that the aneurysm originated at the right posterior communicating artery. There were no postoperative neurological focal deficits. On postoperative day 13 she developed delayed cerebral ischemia of the right temporo-parieto-occipital lobe. She was discharged home 36 days after surgery with left hemianopsia. The infant was free of complications and was discharged at age 17 days. Conclusions: A pregnant woman with severe headache should undergo brain CT or magnetic resonance imaging to rule out subarachnoid hemorrhage.
Hemophagocytic lymphohistiocytosis (HLH) associated with Epstein-Barr virus (EBV) infection can be self-limiting, severe/aggressive, or fatal. We report a case of EBV-HLH with persistent fever, severe pancytopenia, hypertriglyceridemia, and hypofibrinogenemia in a 4-year-old boy. Levels of plasma cytokines and chemokines were measured with a Bio-Plex system at 1, 2, 3, 4, 5, and 8 days after hospital admission. Administration of steroid and high-dose intravenous immunoglobulin (1 g/kg) did not alleviate fever or reduce cytokine production; however, after administration of etoposide (an antineoplastic agent), fever decreased immediately, the patient's general condition improved, and levels of IL-6, IL-10, IL-8, MCP-1, IFN-γ, and TNF-α declined after etoposide administration. In particular, IFN-γ production sharply declined, from 1,104.1 pg/mL to 101.5 pg/mL, and IL-6 level decreased from 229.8 pg/mL to 11.0 pg/mL, on the day after initial etoposide administration. There was no later recurrence of symptoms during treatment with dexamethasone, etoposide, and cyclosporine A. This case suggests that early etoposide administration is critical for treatment success and indicates that etoposide promptly inhibits cytokine production.