Evaluation of Exhaled Nitric Oxide in Thoracic Surgery Patients under One Lung Ventilation Using a Newly Designed Online Exhaled Nitric Oxide Measuring System

Measurement of exhaled nitric oxide (NO) has been gaining much interest lately. However, an ideal measuring system is not yet available in the clinical setting. The aims of the present study were to construct an exhaled NO measuring system and to investigate the effects of one lung ventilation (OLV) on exhaled NO output in patients who underwent thoracic surgery. At first, the NO measuring system was constructed with an NO analyzer, a respiratory flowmeter and a data processing computer system in which the algorithm was indwelled for correcting the distorted NO output wave form. Then, accuracy of this system was tested by using a simulator. This simulator was reworked in order to simulate NO production from the lung under both spontaneous respiration and mechanical ventilation. The data of peak NO concentration (pNO) and NO output (VNO) obtained with the NO monitoring system were significantly correlated with "alveolar" NO concentration (aNO) and exhaled NO volume from the simulator. Then, exhaled NO was measured in 12 thoracic surgery patients who underwent OLV using this system. pNO and VNO were significantly decreased by about half during OLV, and returned to baseline 25 min after releasing OLV. These data suggest that the newly designed online exhaled NO measuring system accurately detected aNO and exhaled NO volume in a breath-by-breath manner, and OLV for about 3 h did not influence the NO output from the lung after releasing OLV in thoracic surgery patients

Polaprezinc Protects Mice against Endotoxin Shock

Polaprezinc (PZ), a chelate compound consisting of zinc and l-carnosine (Car), is an anti-ulcer drug developed in Japan. In the present study, we investigated whether PZ suppresses mortality, pulmonary inflammation, and plasma nitric oxide (NO) and tumor necrosis factor (TNF)-α levels in endotoxin shock mice after peritoneal injection of lipopolysaccharide (LPS), and how PZ protects against LPS-induced endotoxin shock. PZ pretreatment inhibited the decrease in the survival rate of mice after LPS injection. PZ inhibited the increases in plasma NO as well as TNF-α after LPS. Compatibly, PZ suppressed LPS-induced inducible NO synthase mRNA transcription in the mouse lungs. PZ also improved LPS-induced lung injury. However, PZ did not enhance the induction of heat shock protein (HSP) 70 in the mouse lungs after LPS. Pretreatment of RAW264 cells with PZ suppressed the production of NO and TNF-α after LPS addition. This inhibition likely resulted from the inhibitory effect of PZ on LPS-mediated nuclear factor-κB (NF-κB) activation. Zinc sulfate, but not Car, suppressed NO production after LPS. These results indicate that PZ, in particular its zinc subcomponent, inhibits LPS-induced endotoxin shock via the inhibition of NF-κB activation and subsequent induction of proinflammatory products such as NO and TNF-α, but not HSP induction

Geranylgeranylacetone Ameliorates Inflammatory Response to Lipopolysaccharide (LPS) in Murine Macrophages: Inhibition of LPS Binding to The Cell Surface

We investigated whether pretreatment with geranylgeranylacetone (GGA), a potent heat shock protein (HSP) inducer, could inhibit proinflammatory cytokine liberation and nitric oxide (NO) production in lipopolysaccharide (LPS)-treated murine macrophages. The levels of NO and tumor necrosis factor-α (TNF-α) released from murine macrophage RAW 264 cells were increased dose- and time-dependently following treatment with LPS (1 µg/ml). GGA (80 µM) treatment 2 h before LPS addition significantly suppressed TNF-α and NO productions at 12 h and 24 h after LPS, respectively, indicating that GGA inhibits activation of macrophages. However, replacement by fresh culture medium before LPS treatment abolished the inhibitory effect of GGA on NO production in LPS-treated cells. Furthermore, GGA inhibited both HSP70 and inducible NO synthase expressions induced by LPS treatment despite an HSP inducer. When it was examined whether GGA interacts with LPS and/or affects expression of Toll-like receptor 4 (TLR4) and CD14 on the cell surface, GGA inhibited the binding of LPS to the cell surface, while GGA did not affect TLR4 and CD14 expressions. These results indicate that GGA suppresses the binding of LPS to the cell surface of macrophages, resulting in inhibiting signal transduction downstream of TLR4

Immunological Microenvironment Predicts the Survival of the Patients with Hepatocellular Carcinoma Treated with Anti-PD-1 Antibody

Introduction: Although immune checkpoint inhibitors (ICIs) have been considered as promising agents for the treatment of advanced hepatocellular carcinoma (HCC), previous clinical trials revealed that the response to anti-programmed cell death protein 1 (anti-PD-1) monotherapy was as low as 20%. Identifying subgroups that respond well to ICIs is clinically important. Here, we studied the prognostic factors for anti-PD-1 antibody treatment based on the molecular and immunological features of HCC. Methods: Patients who were administered anti-PD1 antibody for advanced HCC at Kindai University Hospital were included. Clinicopathological backgrounds and antitumor responses were examined in 34 cases where tumor tissues before treatment were available. Transcriptome analysis was performed using 40 HCC samples obtained from surgical resection, and immune status was compared between 20 HCCs with activating mutations in β-catenin and those without the mutations using transcriptome-based immunogram. Results: Univariate analysis showed that the disease control rate was significantly better in patients with α-fetoprotein < 400 ng/mL, negative for β-catenin/glutamate synthetase (GS) staining, high combined positive score (CPS) of programmed death-ligand 1 (PD-L1), and increased infiltration of CD8+ cells in tumor tissues. Among them, negative staining of β-catenin/GS, CPS of PD-L1 ≥ 1, and high degree of CD8+ tumor-infiltrating lymphocytes (TILs) were significantly associated with longer survival in both progression-free survival (PFS) and overall survival (OS). The combination of these factors well stratified the survival of the patients on anti-PD-1 antibody in both PFS and OS (p < 0.0001 and p = 0.0048 for PFS and OS, respectively). In addition, the immunogram revealed that tumor-carrying mutations in β-catenin showed downregulation of immune-related genes, especially in those related to priming and activation by dendritic cells, interferon-γ response, inhibitory molecules, and regulatory T cells. Discussion/Conclusion: The combined score including Wnt/β-catenin activation, CPS of PD-L1, and degree of CD8+ TILs in HCC is informative for predicting the response to ICI in HCC cases. Constitutive activation of β-catenin can induce an immune cold phenotype with downregulation of immune-related genes, and immunohistochemistry-based evaluation is beneficial for identifying the subgroup that shows a good response to ICI

Critical role of cholinergic transmission from the laterodorsal tegmental nucleus to the ventral tegmental area in cocaine-induced place preference

Conditioned place preference (CPP) is widely used to investigate the rewarding properties of cocaine. Various brain regions and neurotransmitters are involved in developing cocaine CPP. However, the contribution of cholinergic transmission in the ventral tegmental area (VTA) to cocaine CPP remains largely unexplored. Here, we examined the role of cholinergic input arising from the laterodorsal tegmental nucleus (LDT) to the VTA in the acquisition and expression of cocaine CPP in rats. Intra-LDT injection of carbachol, which hyperpolarizes LDT neurons, and of NMDA and AMPA receptor antagonists before cocaine conditioning blocked and attenuated cocaine CPP, respectively, indicating the necessity of LDT activity for acquiring the CPP. Additionally, intra-VTA injection of scopolamine or mecamylamine before cocaine conditioning also attenuated cocaine CPP, demonstrating the contribution of cholinergic transmission via muscarinic and nicotinic acetylcholine receptors in CPP acquisition. Furthermore, intra-VTA injection of scopolamine or mecamylamine immediately before the test attenuated cocaine CPP, indicating that cholinergic signaling is also associated with the expression of CPP. These results suggest that cholinergic transmission from the LDT to the VTA is critically involved in both acquiring and retrieving cocaine-associated memories in cocaine CPP

Employment-related difficulties and distressed living condition in patients with hepatitis B virus: A qualitative and quantitative study

Abstract Background In Japan, an estimated 400,000 people have the hepatitis B virus (HBV), many of whom were infected as a result of group vaccinations. People with HBV face many challenges, including disease progression, employment-related difficulties, and increased medical expenses. The relationship between HBV victims’ daily life suffering and poverty associated with HBV-related employment changes has not been examined. We aimed to clarify the employment-related hardships experienced by Japanese HBV victims, and the relationships between these hardships and daily life suffering, including poverty, through qualitative and quantitative analyses. Methods The study population comprised 11,046 people infected with HBV via group vaccination who filed lawsuits in Japan’s District Courts by 2014. First, we conducted a qualitative study (2013) using the KJ method, with 107 participants (68 men, mean age 58.9 years; 39 women, mean age 55.3 years). Semi-structured interviews were conducted covering participants’ current condition, treatment, medical expenses, and life difficulties (employment- and family-related problems). In 2014, we conducted a quantitative study. We mailed questionnaires to the entire study population, investigating the topics covered in the interviews (response rate 60.1%). Daily life suffering was determined by responses to the question “What do you think about your everyday life situation?” We performed binomial logistic regression analyses to verify the relationships between daily life suffering and disease, employment, and income status. Results Interview data were integrated into seven islands: intention to work, lack of understanding of HBV in the workplace, inability to buy life insurance, burden due to medical expenses, life failure, dissatisfaction with the system, and wishing for life balance. The quantitative analyses showed significant positive correlations between daily life suffering and liver cancer (odds ratio [OR] 1.47, 95% confidence interval [CI]: 1.00–2.17, p < 0.05), being a part-time/casual employee (OR 1.46, 95% CI: 1.11–1.92 p < 0.01), and an income below the national average (p < 0.01). Conclusion We qualitatively and quantitatively demonstrated that employment-related hardships and daily life suffering are prevalent in people with HBV. Their likelihood of experiencing distress in daily life increases with increasing medical expenses, insecure employment status (e.g., job loss) attributable to HBV, and the resulting poverty