Antibiotic-induced microbiome depletion improves LPS-induced acute lung injury via gut-lung axis.

AIMS: Acute lung injury (ALI) is an acute inflammatory disorder. However, the precise mechanisms underlying the pathology of ALI remain elusive. An increasing evidence suggests the role of the gut-microbiota axis in the pathology of lung injury. This study aimed to investigate whether antibiotic-induced microbiome depletion could affect ALI in mice after lipopolysaccharide (LPS) administration. MAIN METHODS: The effects of antibiotic cocktail (ABX) on ALI in the mice after intratracheally administration of LPS (5 mg/kg) were examined. Furthermore, 16s rRNA analysis and measurement of short-chain fatty acids in feces samples and metabolomics analysis of blood samples were performed. KEY FINDINGS: LPS significantly increased the interleukin-6 (IL-6) levels in the bronchoalveolar lavage fluid (BALF) of water-treated mice. Interestingly, an ABX significantly attenuated the LPS-induced increase in IL-6 in BALF and lung injury scores. Furthermore, ABX and/or LPS treatment markedly altered the α- and ß-diversity of the gut microbiota. There were significant differences in the α- and ß-diversity of the water + LPS group and ABX + LPS group. LEfSe analysis identified Enterococusfaecalis, Clostriumtertium, and Bacteroidescaecimyris as potential microbial markers for ABX + LPS group. Untargeted metabolomics analysis identified several plasma metabolites responsible for discriminating water + LPS group from ABX + LPS group. There were correlations between the relative abundance of the microbiome and plasma metabolites. Integrative network analysis showed correlations between IL-6 levels in BALF and several gut microbes (or plasma metabolites). SIGNIFICANCE: These data suggest that ABX-induced microbiome depletion could protect against LPS-induced ALI via the gut-microbiota-lung axis.

Effects of splenectomy on skin inflammation and psoriasis-like phenotype of imiquimod-treated mice.

Imiquimod (IMQ) is widely used as animal model of psoriasis, a chronic inflammatory skin disorder. Although topical application of IMQ to back skin causes splenomegaly in mice, how the spleen affects the psoriasis-like phenotype of IMQ-treated mice remains unclear. In this study, we analyzed the cellular composition of spleen and measured metabolites in blood of IMQ-treated mice. We also investigated whether splenectomy influences the degree of skin inflammation and pathology in IMQ-treated mice. Flow cytometry showed that the numbers of CD11b+Ly6c+ neutrophils, Ter119+ proerythroblasts, B220+ B cells, F4/80+ macrophages, and CD11c+ dendritic cells in the spleen were significantly higher in IMQ-treated mice compared to control mice. An untargeted metabolomics analysis of blood identified 14 metabolites, including taurine and 2,6-dihydroxybenzoic acid, whose levels distinguished the two groups. The composition of cells in the spleen and blood metabolites positively correlated with the weight of the spleen. However, splenectomy did not affect IMQ-induced psoriasis-like phenotypes compared with sham-operated mice, although splenectomy increased the expression of interleukin-17A mRNA in the skin of IMQ-treated mice. These data suggest that the spleen does not play a direct role in the development of psoriasis-like phenotype on skin of IMQ-treated mice, though IMQ causes splenomegaly.

Mechanisms of action of fluvoxamine for COVID-19: a historical review.

The ongoing coronavirus disease 2019 (COVID-19) pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) accelerates the discovery of prophylactic and therapeutic drugs for persons infected with the virus. Drug repurposing for the COVID-19 pandemic has received particular attention. Increasing clinical data suggest that antidepressant use in early-stage subjects with COVID-19 might be associated with a reduced risk of intubation or death. Among the antidepressants, fluvoxamine is the most attractive drug for mild to moderate subjects with COVID-19. In this article, we review the mechanisms of action (i.e., serotonin transporter, sigma-1 receptor, and acid sphingomyelinase) of fluvoxamine for COVID-19. Furthermore, we discuss a possible link between maternal COVID-19 infection and a risk for neuropsychiatric disorders (i.e., autism spectrum disorder and schizophrenia) in offspring.

A case of pulmonary arterial hypertension with V/Q SPECT/CT that showed localized uptake of 99mTc just below the pleura and a unique distribution.

Pulmonary hypertension (PH) is a life-threatening disorder, which originates from various aetiologies. Ventilation-perfusion (V/Q) scanning is commonly used to evaluate the differential diagnosis of PH. Meanwhile, previous studies have shown that single-photon emission computed tomography (SPECT)/CT imaging can provide a more detailed analysis for the assessment of pulmonary blood flow. However, there is insufficient evidence supporting the merits of V/Q SPECT/CT image data in detecting pulmonary vascular disease. Here, we report a case of pulmonary arterial hypertension with localized accumulation and peculiar distribution just below the pleura on V/Q SPECT/CT. Our finding is unique, and it suggests that V/Q SPECT/CT image data might be useful to detect blood flow not only in cases of pulmonary embolism, but also in the more commonly encountered PH.

(R)-Ketamine ameliorates lethal inflammatory responses and multi-organ injury in mice induced by cecum ligation and puncture.

AIMS: Sepsis is a life-threatening organ dysfunction syndrome arising from infection-induced uncontrolled systemic inflammatory responses. Patients surviving severe sepsis also exhibit increased mortality due to enhanced vulnerability to infections. In this study, we examined whether (R)-ketamine could prevent against lethal sepsis-induced systemic inflammation and inflammatory organ injury. MAIN METHODS: Septic model was induced by cecal ligation and puncture (CLP) surgery on adult mice. (R)-ketamine (10 or 15 mg/kg) was administrated intraperitoneally (i.p.) 24 h before and/or immediately after CLP. KEY FINDINGS: Combined prophylactic and therapeutic use of (R)-ketamine (10 mg/kg), as well as either prophylactic or therapeutic use of (R)-ketamine at a single dose of 15 mg/kg did not reduce 14-day mortality after CLP. However, combined prophylactic and therapeutic use of (R)-ketamine (15 mg/kg) significantly increased 14-day survival rate, attenuated sepsis-induced marked drop in the rectal temperature and increase in the plasma levels of inflammatory cytokines [i.e., interleukin (IL)-6, IL-17A, tumor necrosis factor (TNF)-α, IL-1ß, and IL-10] 12 h after CLP. Furthermore, (R)-ketamine alleviated sepsis-induced increase in the organ injury markers such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), myocardial kinase (CK-MB), and creatinine 24 h after CLP. Moreover, the increased lung wet/dry weight ratio, pulmonary morphological injury and the pulmonary levels of inflammatory cytokines were also attenuated by (R)-ketamine. SIGNIFICANCE: Combined prophylactic and therapeutic use of (R)-ketamine could attenuate systemic inflammation and inflammatory multi-organ injury in mice after CLP-induced lethal sepsis. Therefore, (R)-ketamine would be a potential prophylactic and therapeutic drug for patients prone to sepsis.

Abnormal composition of microbiota in the gut and skin of imiquimod-treated mice.

Psoriasis is a chronic, inflammatory skin disease. Although the precise etiology of psoriasis remains unclear, gut-microbiota axis might play a role in the pathogenesis of the disease. Here we investigated whether the composition of microbiota in the intestine and skin is altered in the imiquimod (IMQ)-treated mouse model of psoriasis. Topical application of IMQ to back skin caused significant changes in the composition of microbiota in the intestine and skin of IMQ-treated mice compared to control mice. The LEfSe algorithm identified the species Staphylococcus lentus as potential skin microbial marker for IMQ group. Furthermore, there were correlations for several microbes between the intestine and skin, suggesting a role of skin-gut-microbiota in IMQ-treated mice. Levels of succinic acid and lactic acid in feces from IMQ-treated mice were significantly higher than control mice. Moreover, the predictive functional analysis of the microbiota in the intestine and skin showed that IMQ caused alterations in several KEGG pathways. In conclusion, the current data indicated that topical application with IMQ to skin alters the composition of the microbiota in the gut and skin of host. It is likely that skin-gut microbiota axis plays a role in pathogenesis of psoriasis.

Dextran sulfate sodium-induced inflammation and colitis in mice are ameliorated by (R)-ketamine, but not (S)-ketamine: A role of TrkB signaling.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease that causes long-lasting inflammation and colitis in the gastrointestinal tract. Depression is a common symptom in patients with UC. (R)-ketamine is a new safer antidepressant than (R,S)-ketamine and (S)-ketamine. Here, we examined the effects of two ketamine enantiomers on the dextran sulfate sodium (DSS)-induced colitis model of UC. Ingestion of 3% DSS in drinking water for 14 days increased the scores of Disease Activity Index (DAI) in mice. Repeated administration of (R)-ketamine (10 mg/kg/day, 14 days or last 7 days), but not (S)-ketamine (10 mg/kg/day, 14 days or last 7 days), significantly ameliorated the increased DAI score and increased blood levels of interleukin-6 (IL-6) in DSS-treated mice. In addition, (R)-ketamine, but not (S)-ketamine, attenuated the reduced colonic length in DSS-treated mice. Furthermore, DSS-induced increased DAI score and blood IL-6 levels were significantly ameliorated after subsequent repeated administration of (R)-ketamine (10 mg/kg/day for last 7 days), but not 5-aminosalicyclic acid (50 mg/kg/day for last 7 days). Moreover, the pretreatment with a tropomyosin-receptor-kinase B (TrkB) antagonist ANA-12 (0.5 mg/kg) significantly blocked the beneficial effects of (R)-ketamine in DSS-induced UC model. The study shows that (R)-ketamine can produce beneficial effects in DSS-induced colitis model through TrkB stimulation. Therefore, (R)-ketamine may be a novel therapeutic drug for inflammatory bowel diseases such as UC.

Successful transcatheter arterial embolization in an asymptomatic patient with primary racemose hemangioma of the bronchial artery.

An asymptomatic 70-year-old woman presented with a nodular lesion overlapping the pulmonary artery at the right hilar region on a chest X-ray. Bronchial arteriography revealed an aneurysmal dilation of the long segment of the right bronchial artery and a shunt from the right bronchial artery to the right lower pulmonary artery. She was diagnosed with primary racemose hemangioma of the bronchial artery (RHBA). Considering the risk of hemoptysis, we performed a bronchial arterial embolization (BAE) using coils and N-butyl-2-cyanoacrylate. She had no complication after the BAE and no recurrences of hemoptysis at the 36-month follow-up. RHBA should be considered in case of aneurysmal dilation in the long segment of the bronchial artery, and BAE should be considered as a treatment strategy despite the absence of symptoms.

Pulmonary Nocardiosis: A Clinical Analysis of 30 Cases.

Objective Pulmonary nocardiosis frequently develops as an opportunistic infection in patients with malignant tumor and is treated with steroids. This study was performed to clarify the clinical features of pulmonary nocardiosis in Japan. Methods The patients definitively diagnosed with pulmonary nocardiosis at our hospital between January 1995 and December 2015 were retrospectively investigated. Results Nineteen men and 11 women (30 in total) were diagnosed with pulmonary nocardiosis. Almost all patients were complicated by a non-pulmonary underlying disease, such as malignant tumor or collagen vascular disease, or pulmonary disease, such as chronic obstructive pulmonary disease or interstitial pneumonia, and 13 patients (43.3%) were treated with steroids or immunosuppressors. Gram staining was performed in 29 patients, and a characteristic Gram-positive rod was detected in 28 patients (96.6%). Thirty-one strains of Nocardia were isolated and identified. Seven strains of Nocardia farcinica were isolated as the most frequent species, followed by Nocardia nova isolated from 6 patients. Seventeen patients died, giving a crude morality rate of 56.7% and a 1-year survival rate of 55.4%. The 1-year survival rates in the groups with and without immunosuppressant agents were 41.7% and 59.7%, respectively, showing that the outcome of those receiving immunosuppressants tended to be poorer than those not receiving them. Conclusion Pulmonary nocardiosis developed as an opportunistic infection in most cases. The outcome was relatively poor, with a 1-year survival rate of 55.4%, and it was particularly poor in patients treated with immunosuppressant agents. Pulmonary nocardiosis should always be considered in patients presenting with an opportunistic respiratory infection, and an early diagnosis requires sample collection and Gram staining.