ELOVL6 deficiency aggravates allergic airway inflammation through the ceramide-S1P pathway in mice.

BACKGROUND: Elongation of very-long-chain fatty acids protein 6 (ELOVL6), an enzyme regulating elongation of saturated and monounsaturated fatty acids with C12 to C16 to those with C18, has been recently indicated to affect various immune and inflammatory responses; however, the precise process by which ELOVL6-related lipid dysregulation affects allergic airway inflammation is unclear. OBJECTIVES: This study sought to evaluate the biological roles of ELOVL6 in allergic airway responses and investigate whether regulating lipid composition in the airways could be an alternative treatment for asthma. METHODS: Expressions of ELOVL6 and other isoforms were examined in the airways of patients who are severely asthmatic and in mouse models of asthma. Wild-type and ELOVL6-deficient (Elovl6-/-) mice were analyzed for ovalbumin-induced, and also for house dust mite-induced, allergic airway inflammation by cell biological and biochemical approaches. RESULTS: ELOVL6 expression was downregulated in the bronchial epithelium of patients who are severely asthmatic compared with controls. In asthmatic mice, ELOVL6 deficiency led to enhanced airway inflammation in which lymphocyte egress from lymph nodes was increased, and both type 2 and non-type 2 immune responses were upregulated. Lipidomic profiling revealed that the levels of palmitic acid, ceramides, and sphingosine-1-phosphate were higher in the lungs of ovalbumin-immunized Elovl6-/- mice compared with those of wild-type mice, while the aggravated airway inflammation was ameliorated by treatment with fumonisin B1 or DL-threo-dihydrosphingosine, inhibitors of ceramide synthase and sphingosine kinase, respectively. CONCLUSIONS: This study illustrates a crucial role for ELOVL6 in controlling allergic airway inflammation via regulation of fatty acid composition and ceramide-sphingosine-1-phosphate biosynthesis and indicates that ELOVL6 may be a novel therapeutic target for asthma.

Transcriptome genetic differences between responders and non-responders before bronchial thermoplasty.

BACKGROUND: Bronchial thermoplasty (BT) is an endoscopic therapy used for the treatment of refractory asthma. Some predictive factors, for example the number of activations and severity of disease at baseline, have been used to determine the effectiveness of BT in treating patients with asthma. The aim of the present study was to comprehensively analyze RNA samples from the airway bronchial tissues of patients with severe asthma treated by BT, and to characterize each patient as a BT responder or non-responder. METHODS: Eight patients with severe asthma scheduled to undergo BT and bronchus biopsies were recruited before the procedures were conducted. Extracted RNA samples from bronchial tissues were sequenced and differential gene expression analysis was carried out.Results/discussion: Subjects with Asthma Quality of Life Questionnaire score changes ≥0.5 for a period of 12 months were considered BT responders. Non-responders had score changes <0.5 for 12 months. Histopathology findings were similar to those reported previously, and no significant differences in the expression of α-smooth muscle actin and protein gene product 9.5 were observed between responders and non-responders. Transcriptome analysis at baseline identified 67 genes that were differentially expressed between responders and non-responders, including SLPI, MMP3, and MUC19, which were upregulated in responders. Although the differentially expressed gene products may have conflicting effects, genes in the airway epithelium and extracellular matrix of patients with severe asthma may determine the BT response. Our results identified possible transcriptomic changes that could be used to identify BT responders.

Lung Pathology of Mutually Exclusive Co-infection with SARS-CoV-2 and Streptococcus pneumoniae.

Postmortem lung pathology of a patient in Japan with severe acute respiratory syndrome coronavirus 2 infection showed diffuse alveolar damage as well as bronchopneumonia caused by Streptococcus pneumoniae infection. The distribution of each pathogen and the accompanying histopathology suggested the infections progressed in a mutually exclusive manner within the lung, resulting in fatal respiratory failure.

Valsalva retinopathy induced by handstand: a case report.

BACKGROUND: Valsalva retinopathy is known to occur as a sudden preretinal or sub-internal limiting membrane hemorrhage induced by a rapid rise in venous pressure following increased intrathoracic or intraabdominal pressure. Here we report a case of Valsalva retinopathy that was probably induced by straining that occurred due to following a handstand. CASE PRESENTATION: A 15-year-old boy became aware of decreased visual acuity in his left eye immediately after doing a handstand for approximately 10 s during physical education class, and subsequently visited a local clinic on the same day. Upon examination, a vitreous hemorrhage (VH) in the posterior pole of the fundus was found in his left eye, and he was subsequently referred to our department 7 days later. Upon examination, the VH around the optic nerve head of the left eye appeared to be resolved, and an oval-shaped sub-internal limiting membrane (sub-ILM) hemorrhage was found in the superonasal side of the optic nerve head. No abnormalities were observed in the macular area. Four months later, the sub-ILM hemorrhage was found to have spontaneously resolved. Subsequent fluorescein angiography examinations revealed no abnormal findings at the lesion site. CONCLUSIONS: In this patient, we hypothesize that the Valsalva retinopathy was induced by straining that occurred due to a handstand, and that the resultant sub-ILM hemorrhage progressed to VH.

Transcription Elongation Factor P-TEFb Is Involved in IL-17F Signaling in Airway Smooth Muscle Cells.

BACKGROUND: IL-17F is involved in the pathogenesis of several inflammatory diseases, including asthma and COPD. However, the effects of steroids on the function of IL-17F signaling mechanisms are largely unknown. One of the transcription elongation factors, positive transcription elongation factor b (P-TEFb) composed of cyclin T1 and cyclin-dependent kinase 9 (CDK9), is known as a novel checkpoint regulator of gene expression via bromodomain-containing protein 4 (Brd4). METHODS: Human airway smooth muscle cells were stimulated with IL-17F and the expression of IL-8 was evaluated by real-time PCR and ELISA. Next, the phosphorylation of CDK9 was determined by Western blotting. The CDK9 inhibitor and short interfering RNAs (siRNAs) targeting Brd4, cyclin T1, and CDK9 were used to identify the effect on IL-17F-induced IL-8 expression. Finally, the effect of steroids and its signaling were evaluated. RESULTS: IL-17F markedly induced the transcription of the IL-8 gene and the expression of the protein. Pretreatment of CDK9 inhibitor and transfection of siRNAs targeting CDK9 markedly abrogated IL-17F-induced IL-8 production. Transfection of siRNAs targeting Brd4 and cyclin T1 diminished IL-17F-induced phosphorylation of CDK9 and IL-8 production. Moreover, budesonide decreased CDK9 phosphorylation and markedly inhibited IL-17F-induced IL-8 production. CONCLUSIONS: This is the first report that P-TEFb is involved in IL-17F-induced IL-8 expression and that steroids diminish it via the inhibition of CDK9 phosphorylation. IL-17F and P-TEFb might be novel therapeutic targets for airway inflammatory diseases.

Protective effects of simultaneous splenectomy on small-for-size liver graft injury in rat liver transplantation.

Splenectomy is an effective technique in living donor liver transplantation (LDLT) with small-for-size (SFS) liver grafts for overcoming SFS liver graft injury. However, the protective mechanism of splenectomy is still unclear. The aim of this study was to investigate how splenectomy could attenuate SFS graft injury through the measurement of biochemical factors, particularly the expression of endothelin (ET)-1, which is a key molecule of microcirculatory disorders by mediating sinusoidal vasoconstriction. We performed rat orthotopic liver transplantation using SFS liver grafts with or without splenectomy. We investigated intragraft expression of ET-1 mRNA and hepatic protein levels of ET-1. In addition, portal pressure, hepatic injury and morphological changes, and survival rate were evaluated. In result, intragraft ET-1 mRNA expression after SFS liver transplantation was significantly downregulated by splenectomy, and hepatic expression of ET-1 in SFS grafts was rarely observed. Splenectomy inhibited the increase in portal pressure, ameliorated SFS liver graft injury and improved the graft survival rate after SFS liver transplantation. In conclusion, splenectomy improved the SFS liver injury and decreased the expression of ET-1 by attenuating portal hypertension on SFS liver transplantation. Downregulation of intragraft ET-1 expression plays important roles in the protective mechanism of splenectomy in SFS liver transplantation.

Left hepatic trisectionectomy for hepatolithiasis with occluded left and right anterior branches of the portal vein: report of a case.

A 64-year-old male was admitted to a local hospital with epigastric pain. Diagnostic imaging revealed hepatolithiasis in the atrophic left lobe. However, endoscopic intervention was impossible because of the presence of many large stones. He was referred to our hospital for surgical treatment. Enhanced multidetector-row computed tomography revealed that the right posterior portal vein (PV) was branched from the portal trunk as a first-order branch, and the bile duct of segment 3 ran caudally to the umbilical portion of the left PV. Furthermore, the umbilical portion of the left PV, which was located between the dilated bile ducts of segment 2 and segment 3, and also the right anterior PV, was occluded with thrombus. Based on these findings, he underwent left hepatic trisectionectomy. Although the indications for left hepatic trisectionectomy for hepatolithiasis are limited, it is therefore extremely important to determine the most appropriate surgical procedure based on the anatomy and findings of hepatic hilus in individual cases.

[A case of main-duct IPMN with multicentric invasive carcinoma].

Intraductal papillary mucinous neoplasm (IPMN) of the pancreas often contains multifocal lesions, and total pancreatectomy is sometimes needed for curative resection. We report here our experience with a case of IPMN with multiple invasive carcinoma foci that was successfully treated with total pancreatectomy. A 66-year-old man had jaundice, and a computed tomography (CT) scan revealed a hypovascular mass in the pancreas head in conjunction with calcification and dilation of the entire main pancreatic duct. He was diagnosed with pancreas head cancer and chronic pancreatitis, and a pancreaticoduodenectomy was planned. Intraoperative pathological examination revealed papillary growth of high grade dysplasia in the main and branch duct epithelium and perineural invasion of the atypical glands. After 2 additional resections, we performed a total pancreatectomy. Pathological findings showed that the pancreas head tumor was an invasive carcinoma derived from main-duct IPMN of the pancreas. It was a mucinous carcinoma with calcification. Moreover, we found other multiple, discontinuous invasive foci in the body and tail of the pancreas which were undetectable by preoperative imaging. This case was highly suggestive for preoperative diagnosis for pancreas tumor and developmental pattern of main-duct IPMN.

Pathophysiology of pulmonary nontuberculous mycobacterial (NTM) disease.

In recent years, the incidence and prevalence of pulmonary nontuberculous mycobacterial (NTM) disease have increased worldwide. Although the reasons for this increase are unclear, dealing with this disease is essential. Pulmonary NTM disease is a chronic pulmonary infection caused by NTM bacteria, which are ubiquitous in various environments. In Japan, Mycobacterium avium-intracellulare complex (MAC) accounts for approximately 90% of the causative organisms of pulmonary NTM disease, which is also called pulmonary MAC disease or pulmonary MAI disease. It is important to elucidate the pathophysiology of this disease, which occurs frequently in postmenopausal women despite the absence of obvious immunodeficiency. The pathophysiology of this disease has not been fully elucidated; however, it can largely be divided into bacterial (environmental) and host-side problems. The host factors can be further divided into immune and airway problems. The authors suggest that the triangular relationship between bacteria, immunity, and the airway is important in the pathophysiology of this disease. The latest findings on the pathophysiology of pulmonary NTM disease are reviewed.

Risk factors for clinical progression in patients with pulmonary Mycobacterium avium complex disease without culture-positive sputum: a single-center, retrospective study.

OBJECTIVES: Limited data are available on the progression of pulmonary Mycobacterium avium complex (MAC) disease without culture-positive sputum. The aim of this study was to identify the risk factors associated with clinical progression of pulmonary MAC disease diagnosed by bronchoscopy. METHODS: A single-center, retrospective, observational study was conducted. Pulmonary MAC patients diagnosed by bronchoscopy without culture-positive sputum from January 1, 2013, to December 31, 2017 were analyzed. Clinical progression after diagnosis was defined as having culture-positive sputum at least once or initiation of guideline-based therapy. Then, clinical characteristics were compared between clinically progressed patients and stable patients. RESULTS: Ninety-three pulmonary MAC patients diagnosed by bronchoscopy were included in the analysis. During the 4-year period after diagnosis, 38 patients (40.9%) started treatment, and 35 patients (37.6%) had new culture-positive sputum. Consequently, 52 patients (55.9%) were classified into the progressed group, and 41 patients (44.1%) were classified into the stable group. There were no significant differences between the progressed and the stable groups in age, body mass index, smoking status, comorbidities, symptoms, or species isolated from bronchoscopy. On multivariate analysis, male sex, monocyte to lymphocyte ratio (MLR) ≥ 0.17, and the presence of combined lesions in the middle (lingula) and lower lobes were risk factors for clinical progression. CONCLUSIONS: Some patients with pulmonary MAC disease without culture-positive sputum progress within 4 years. Therefore, pulmonary MAC patients, especially male patients, having higher MLR or lesions in the middle (lingula) and lower lobes might need careful follow-up for a longer time.

[A case of pancreaticoduodenectomy for duodenal carcinoma with a replaced common hepatic artery running through the pancreatic parenchyma].

To perform safe and radical pancreaticoduodenectomy, adequate knowledge of the branching and running course of the common hepatic artery is necessary. Formation of a common trunk by the common hepatic artery and superior mesenteric artery, called the hepatomesenteric trunk, is very rare. When it occurs, the common hepatic artery arising from the hepatomesenteric trunk usually runs behind the pancreas head. In the present case, however, it ran through the pancreatic parenchyma. Therefore, pancreaticoduodenectomy for duodenal carcinoma was performed with preservation of the intrapancreatic common hepatic artery. When pancreaticoduodenectomy is performed in patients with a replaced common hepatic artery running through the pancreatic parenchyma, it is necessary to preoperatively determine whether to preserve or resect the common hepatic artery in the pancreas with consideration of the curability. If resected, whether to reconstruct it must also be determined. If reconstructed, the reconstruction method must be determined, and if not, it is important to perform preoperative coiling of the common hepatic artery and intraoperative measurement of the hepatic blood flow with a Doppler flow meter.

A case of Pneumocystis jirovecii pneumonia in a patient with acquired immune deficiency syndrome who showed eosinophilia and an increased serum TARC/CCL17 level.

Pneumocystis jirovecii pneumonia (PCP) in patients with acquired immune deficiency syndrome (AIDS) shows eosinophilic pneumonia like condition. The detailed mechanisms how AIDS-associated PCP causes eosinophilic pneumonia has not been elucidated, but it has been suggested that beta-D-glucan, a major component of Pneumocystis jirovecii, and T helper type 2 immunity may be involved in the mechanism of eosinophilia in the lung. We experienced the case who developed an eosinophilic pneumonia-like condition in a patient with AIDS-associated PCP, whose clinical course indicated the importance of TARC/CCL17 but not IL-4 and IL-5 as involved in eosinophilia caused by HIV and Pneumocystis jirovecii infection.

A case of secondary pneumothorax due to multiple pulmonary metastases of granulosa cell tumor.

Introduction: Ovarian granulosa cell tumor is a relatively rare tumor that accounts for 2-5% of malignant ovarian tumors. This tumor progresses slowly and may recur late in life. Case presentation: A 70-year-old woman was admitted to our hospital with a left secondary pneumothorax due to metastatic lung tumors of granulosa cell tumor. Reports of secondary pneumothorax due to granulosa cell tumor are rare. Thoracoscopic suturing and pleurodesis using talc were effective in the treatment of this pneumothorax. Conclusions: We experienced a rare case of secondary pneumothorax due to multiple pulmonary metastases of granulosa cell tumor. It should be noted that pulmonary metastasis of granulosa cell tumor can lead to secondary pneumothorax.

Recovery from severe metabolic alkalosis with acute kidney injury due to gastric cancer: a case report.

Objective: Most cases of severe metabolic alkalosis have many causes that may result in renal failure and death. Therefore, these should be treated promptly for successful recovery. Patient: A 61-year-old man was hospitalized due to an acute kidney injury (creatinine level of 4.36 mg/dL) after a 3-month history of anorexia and recurrent vomiting. He had been treated for tuberculosis in the past. Results: Blood gas analysis revealed severe metabolic alkalosis with pH=7.66, HCO3=94 mmol/L, and pCO2=82.0 mmHg. Routine biochemical examination revealed severe hypokalemia (K 2.9 mEq/L) that was associated with prolonged QTc interval (0.52 seconds) on the electrocardiogram. Gastrofiberscopic examination also revealed severe stenosis and ulcerated scarring of the gastric pylorus and severe esophagitis. Intravenous hydration and correction of hypokalemia improved renal function and resolved metabolic alkalosis. An investigation that was repeated after 6 days revealed a creatinine level of 1.58 mg/dL, pH=7.47, HCO3=23.4 mmol/L, K=3.6 mEq/L, and QTc of 0.45 seconds. The patient underwent gastrectomy and adenocarcinoma was observed. Conclusion: We described a resolved case of severe metabolic alkalosis and acute kidney injury in a rural medical setting following conservative management.

The Role of NRF2 in Mycobacterial Infection.

The incidence of pulmonary nontuberculous mycobacterial (NTM) infection is increasing worldwide, and its clinical outcomes with current chemotherapies are unsatisfactory. The incidence of tuberculosis (TB) is still high in Africa, and the existence of drug-resistant tuberculosis is also an important issue for treatment. To discover and develop new efficacious anti-mycobacterial treatments, it is important to understand the host-defense mechanisms against mycobacterial infection. Nuclear erythroid 2 p45-related factor-2 (NRF2) is known to be a major regulator of various antioxidant response element (ARE)-driven cytoprotective gene expressions, and its protective role has been demonstrated in infections. However, there are not many papers or reviews regarding the role of NRF2 in mycobacterial infectious disease. Therefore, this review focuses on the role of NRF2 in the pathogenesis of Mycobacterium tuberculosis and Mycobacterium avium infection.

ROS-Nrf2 pathway mediates the development of TGF-ß1-induced epithelial-mesenchymal transition through the activation of Notch signaling.

Epithelial-mesenchymal transition (EMT) is a cellular process by which epithelial cells transform to acquire mesenchymal phenotypes. Accumulating evidence indicate the involvement of EMT in the progression of malignant diseases. Notch signaling mediates TGF-ß1-induced EMT through direct transcriptional activation of Snai1. The molecular mechanism how TGF-ß1 activates Notch signaling, however, remains unknown. In this study, we show a pivotal role for reactive oxygen species (ROS)-Nrf2 pathway in TGF-ß1-induced Notch signaling activation and EMT development. TGF-ß1 induces Nrf2 activation through ROS production. Inhibiting Nrf2 activation either by reducing ROS levels by N-acetylcysteine or by knocking down of Nrf2 by small interfering RNA attenuated both Notch signaling activation and EMT development. TGF-ß1 induced the transcription of Notch4 via Nrf2-dependent promoter activation. In conclusion, our study indicates the ROS-Nrf2 pathway mediates the development of TGF-ß1-induced EMT through the activation of Notch signaling.