Increase of nitrosative stress in patients with eosinophilic pneumonia

<p>Abstract</p> <p>Background</p> <p>Exhaled nitric oxide (NO) production is increased in asthma and reflects the degree of airway inflammation. The alveolar NO concentration (Calv) in interstitial pneumonia is reported to be increased. However, it remains unknown whether NO production is increased and nitrosative stress occurs in eosinophilic pneumonia (EP). We hypothesized that nitrosative stress markers including Calv, inducible type of NO synthase (iNOS), and 3-nitrotyrosine (3-NT), are upregulated in EP.</p> <p>Methods</p> <p>Exhaled NO including fractional exhaled NO (FE_NO) and Calv was measured in ten healthy subjects, 13 patients with idiopathic pulmonary fibrosis (IPF), and 13 patients with EP. iNOS expression and 3-NT formation were assessed by immunocytochemistory in BALf cells. The exhaled NO, lung function, and systemic inflammatory markers of the EP patients were investigated after corticosteroid treatment for 4 weeks.</p> <p>Results</p> <p>The Calv levels in the EP group (14.4 ± 2.0 ppb) were significantly higher than those in the healthy subjects (5.1 ± 0.6 ppb, p < 0.01) and the IPF groups (6.3 ± 0.6 ppb, p < 0.01) as well as the FE_NOand the corrected Calv levels (all p < 0.01). More iNOS and 3-NT positive cells were observed in the EP group compared to the healthy subject and IPF patient. The Calv levels had significant positive correlations with both iNOS (r = 0.858, p < 0.05) and 3-NT positive cells (r = 0.924, p < 0.01). Corticosteroid treatment significantly reduced both the FE_NO(p < 0.05) and the Calv levels (p < 0.01). The magnitude of reduction in the Calv levels had a significant positive correlation with the peripheral blood eosinophil counts (r = 0.802, p < 0.05).</p> <p>Conclusions</p> <p>These results suggested that excessive nitrosative stress occurred in EP and that Calv could be a marker of the disease activity.</p

Benzothiazolylphenol–Substituted Ketoester is a Useful Fluorescent Probe for Detection of the Mitochondrion in Sea Urchin Sperm

One of the ketoesters derived from benzothiazolylphenol-substituted dioxetane,benzothiazolylphenol-substituted ketoester (TPKE), demonstrates fluorescence in a 0.1 MNaOH 1). In this study, the fluorescent staining of a living cell with TPKE was demonstratedby fluorescence microscopy. When sperm from two species of sea urchins—Pseudocentrotusdepressus and Anthocidaris crassispina—were used as biological materials, TPKE showed afluorescent signal in the midpiece that was composed of a single mitochondrion. The ratioof fluorescent signal intensity to background noise (S/N) was high in the sperm stained with1.0–5.0 μg/ml TPKE in normal artificial seawater (pH 8.0). The S/N ratio decreased inacidic seawater (pH 6.0); acidic conditions repress respiratory activity in sea urchin sperm.Moreover, in the presence of the respiratory chain inhibitor antimycin A and the uncouplercarbonyl cyanide p--trifluoromethoxyphenyl-hydrazone, the sperm showed faint or nofluorescence in normal artificial seawater (pH 8.0). Sea urchin sperm stained with TPKEafter fixation showed faint or no fluorescence. These results suggest that TPKE is apotential fluorescent probe of living sea urchin sperm mitochondria with high respiratoryactivities

The Impact of Tofogliflozin on Physiological and Hormonal Function, Serum Electrolytes, and Cardiac Diastolic Function in Elderly Japanese Patients with Type 2 Diabetes Mellitus

The sodium glucose transporter 2 (SGLT2) inhibitor tofogliflozin is a glucose-lowering drug that causes the excretion of surplus glucose by inhibiting SGLT2. Because of tofogliflozin’s osmotic diuresis mechanism, patients’ serum electrolytes, body fluid levels, and cardiac function must be monitored. We retrospectively analyzed the cases of 64 elderly Japanese patients with type 2 diabetes mellitus (T2DM) who received tofogliflozin for 3 months. Their HbA1c, serum electrolytes (sodium, potassium, chloride), hematocrit, brain natriuretic peptide (cardiac volume load marker) and renin and aldosterone (RAA; an index of regulatory hormones involved in body fluid retention) were continuously monitored during the investigation period. Renal function and cardiac function (by echocardiography) were assessed throughout the period. HbA1c significantly decreased (β1=−0.341, p<0.0001, linear regression analysis [LRA]). Most of the hormonal, electrolyte, and physiological parameters were maintained throughout the study period. In these circumstances, E/e’ tended to decrease (β1=−0.382, p=0.13, LRA). Compared to the baseline, E/e’ was significantly decreased at 1 and 3 months (p<0.01, p<0.05). In the higher E/e’ group (E/e’≥10, n=34), E/e’ decreased significantly (β1=−0.63, p<0.05, LRA). ΔE/e’ was correlated with body-weight change during treatment (r=0.64, p<0.01). The 3-month tofogliflozin treatment improved glycemic control and diastolic function represented by E/e’ in T2DM patients, without affecting serum electrolytes, renal function, or RAA. No negative impacts on the patients were observed. Three-month tofogliflozin treatment lowered glucose and improved cardiac diastolic function

EGFR mutation and ALK fusion-positive non-small cell lung cancer: a multicenter prospective cohort study in Nagano Prefecture, Japan

Introduction. We prospectively examined current clinical practices in patients with inoperable epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) fusion-positive (EGFR+ and ALK+, respectively) non-small cell lung cancer (NSCLC) in Nagano Prefecture, Japan.  Material and methods. The study population consisted of newly diagnosed patients with inoperable EGFR+ and ALK+ NSCLC in 14 hospitals in Nagano between May 2016 and March 2019. Both initial and subsequent treatment decisions were made at the discretion of the attending physician.  Results. A total of 281 patients with EGFR+ NSCLC (mean age, 74 years, 59.1% female) and 26 patients with ALK+ NSCLC (mean age, 66 years, 53.8% female) were included in the study. The study population consisted of 148/107/29/20/3 cases with performance status 0/1/2/3/4 and 6/2/31/194/75 cases with clinical stage I/II/III/IV/recurrence, respectively. First-line therapy with tyrosine kinase inhibitors was performed in 259 (92.2%) and 22 (84.6%) patients with EGFR+ and ALK+ NSCLC, respectively. The median overall survival rate was 41.2 months (95% CI 36.8–45.6 months) with EGFR+. It was not reached with ALK+ .  Conclusions. This observational analysis represents a valuable resource for evaluating the outcomes of treatment in patients with NSCLC

Morphological features and mixing states of soot-containing particles in the marine boundary layer over the Indian and Southern oceans

Mixing states of soot-containing aerosol particles constitute important information for the simulation of climatic effects of black carbon in the atmosphere. To elucidate the mixing states and morphological features of soot-containing particles over remote oceans, we conducted on-board observations over the southern Indian Ocean and the Southern Ocean during the TR/V Umitaka-maru UM-08-09 cruise, which started from Benoa, Indonesia, on 1 December 2008 via Cape Town, South Africa, and which terminated in Fremantle, Australia, on 6 February 2009. The light absorption coefficients of size-segregated particles ( &lt;  0.5 and  &lt;  1.0 µm diameter) and aerosol number concentrations (0.1–0.5 µm diameter) were measured to assist direct aerosol sampling. Size-segregated aerosol particles were collected for chemical analysis using ion chromatography. For transmission electron microscopy (TEM) analyses using water-dialysis methods, dried submicrometer aerosol particles were collected using a cascade impactor. We analyzed 13 TEM samples. Results of water-dialysis analysis demonstrate that most particles were water-soluble. However, for all TEM samples, particles were rarely found (2.1 % of particles on a TEM sample at a maximum) containing insoluble residuals with the characteristic soot shape. For samples collected over the Indian and Southern oceans at latitudes less than 62° S, some (20–35 %) soot-containing particles were found as bare soot. For samples collected near the Antarctic coast (65–68° S, 38–68° E), all soot-containing particles were mixed with water-soluble materials. Furthermore, 56 % of soot-containing particles had a satellite structure formed by the impact of droplets such as sulfuric acid. Chemical analysis of submicrometer particles near the Antarctic coast revealed high concentrations of non-sea-salt (nss) SO42− and CH3SO3−, suggesting that aged soot-containing particles were transformed by soluble materials derived from dimethyl sulfide (DMS) oxidation. The obtained information of soot at various remote ocean areas is expected to be useful to understand long-range transport processes and to improve simulations of global soot concentration.</p

Neurodegenerative processes accelerated by protein malnutrition and decelerated by essential amino acids in a tauopathy mouse model

Protein malnutrition is epidemiologically suggested as a potential risk factor for senile dementia, although molecular mechanisms linking dietary proteins and amino acids to neurodegeneration remain unknown. Here, we show that a low-protein diet resulted in down-regulated expression of synaptic components and a modest acceleration of brain atrophy in mice modeling neurodegenerative tauopathies. Notably, these abnormal phenotypes were robustly rescued by the administration of seven selected essential amino acids. The up-regulation of inflammation-associated gene expression and progressive brain atrophy in the tauopathy model were profoundly suppressed by treatment with these essential amino acids without modifications of tau depositions. Moreover, the levels of kynurenine, an initiator of a pathway inducing neuroinflammatory gliosis and neurotoxicity in the brain, were lowered by treatment through inhibition of kynurenine uptake in the brain. Our findings highlight the importance of specific amino acids as systemic mediators of brain homeostasis against neurodegenerative processes