Prostaglandin E2 Reverses Aberrant Production of an Inflammatory Chemokine by Microglia from Sandhoff Disease Model Mice through the cAMP-PKA Pathway

Background: Sandhoff disease (SD) is a neurodegenerative lysosomal b-hexosaminidase (Hex) deficiency involving excessive accumulation of undegraded substrates, including terminal GlcNAc-oligosaccharides and GM2 ganglioside. Microglia-mediated neuroinflammation contributes to the pathogenesis and progression of SD. Our previous study demonstrated that MIP-1a, a putative pathogenic factor for SD, is up-regulated in microglial cells derived from SD model mice (SD-Mg) through activation of Akt and JNK. Methodology/Principal Findings: In this study, we first demonstrated that prostaglandin E2 (PGE2), which is one of the lipid mediators derived from arachidonic acid and is known to suppress activation of microglia, reduced the aberrant MIP-1a production by SD-Mg to the same level as by WT-Mg. PGE2 also attenuated the activation of Akt and JNK. The inhibition of MIP-1a production and the activation of Akt and JNK occurred through the EP2 and 4/cAMP/PKA signaling pathway in the murine microglia derived from SD model mice. Conclusions/Significance: We propose that PGE2 plays a role as a negative regulator of MIP-1a production in th

Nationwide surveillance of bacterial respiratory pathogens conducted by the surveillance committee of Japanese Society of Chemotherapy, the Japanese Association for Infectious Diseases, and the Japanese Society for Clinical Microbiology in 2010: General view of the pathogens\u27 antibacterial susceptibility

The nationwide surveillance on antimicrobial susceptibility of bacterial respiratory pathogens from patients in Japan, was conducted by Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases and Japanese Society for Clinical Microbiology in 2010.The isolates were collected from clinical specimens obtained from well-diagnosed adult patients with respiratory tract infections during the period from January and April 2010 by three societies. Antimicrobial susceptibility testing was conducted at the central reference laboratory according to the method recommended by Clinical and Laboratory Standard Institutes using maximum 45 antibacterial agents.Susceptibility testing was evaluable with 954 strains (206 Staphylococcus aureus, 189 Streptococcus pneumoniae, 4 Streptococcus pyogenes, 182 Haemophilus influenzae, 74 Moraxella catarrhalis, 139 Klebsiella pneumoniae and 160 Pseudomonas aeruginosa). Ratio of methicillin-resistant S.aureus was as high as 50.5%, and those of penicillin-intermediate and -resistant S.pneumoniae were 1.1% and 0.0%, respectively. Among H.influenzae, 17.6% of them were found to be β-lactamase-non-producing ampicillin (ABPC)-intermediately resistant, 33.5% to be β-lactamase-non-producing ABPC-resistant and 11.0% to be β-lactamase-producing ABPC-resistant strains. Extended spectrum β-lactamase-producing K.pneumoniae and multi-drug resistant P.aeruginosa with metallo β-lactamase were 2.9% and 0.6%, respectively.Continuous national surveillance of antimicrobial susceptibility of respiratory pathogens is crucial in order to monitor changing patterns of susceptibility and to be able to update treatment recommendations on a regular basis

A Case of Cardiac Sarcoidosis ―Significance of Ventricular Tachycardia Originating From the Septum―(心サルコイド症の1例 中隔起源心室頻拍の意義)

雑誌掲載版65歳男.反復する頻拍発作の為入院.心エコー図では心室中隔前方基部が薄く,収縮異常を認めた.電気生理学的検査では心室頻拍があり,右室中隔前方部で著明に分裂した電位が記録され,最初期の電位はHis束近傍にあった.心筋生検により心サルコイド症と診断され

Hemorrhoids as a risk factor for colorectal adenomas on colonoscopy

Background and study aims Colorectal premalignant polyps and hemorrhoids are important findings in colonoscopy; however, the association between them is unclear. Therefore, we investigated the association between the presence and severity of hemorrhoids and the detection of precancerous colorectal polyps on colonoscopy. Patients and methods This retrospective, single-center, cross-sectional study enrolled patients who underwent colonoscopy at Toyoshima Endoscopy Clinic between May 2017 and October 2020. The association between hemorrhoids and other outcomes (patient age, sex, withdrawal time for colonoscopy, expert endoscopist, number of adenomas per colonoscopy, detection rates of adenoma, advanced neoplasia, clinically significant serrated polyp, and sessile serrated lesion) was assessed using a binomial logistic regression model. Results A total of 12,408 patients were enrolled in this study. Hemorrhoids were identified in 1,863 patients. Univariable analysis showed that patients with hemorrhoids were older (61.0 vs. 52.5 years, P < 0.001), had a higher number of adenomas per colonoscopy (1.16 vs. 0.756, P < 0.001) than those without hemorrhoids. Multivariable analyses also demonstrated that hemorrhoids were associated with a higher number of adenomas per colonoscopy (odds ratio [OR]: 1.061; P = 0.002), regardless of patient age, sex, and expert endoscopist. Among patients with hemorrhoids, severe hemorrhoids with a mucosal elevation ≥ 10 mm were associated with a higher number of adenomas per colonoscopy than mild hemorrhoids (OR: 1.112, P = 0.044), regardless of patient age, sex, and expert endoscopist. Conclusions Hemorrhoids, especially severe ones, are associated with a high number of adenomas. Complete colonoscopy should be performed in patients with hemorrhoids

PGE2 reduces MIP-1α production by SD-Mg via putative EP2 and EP4 receptors.

<p><b>A</b>: SD-Mg was treated with the indicated concentrations of PGE2, Butaprost, PGE1-alcohol and Sulprostone for 6 h. The amounts of MIP-1α protein in CM were determined by ELISA. <b>B</b>: SD-Mg was pretreated with the AH6809 and GW627368X at each 20 µM for 30 min, and then treated with 10 nM PGE2 for 6 h. The amounts of MIP-1α protein in CM were determined by ELISA. <b>C</b>, <b>D</b>: Cell viability was determined 6 h after treatment with the drugs. Values represent the means ± SD for three independent experiments. Significance was evaluated by means of Student's <i>t</i>-test. *<i>P</i><0.05 and **<i>P</i><0.01 versus controls.</p

Activation of cAMP/PKA reduces MIP-1α production by SD-Mg through dephosphorylation.

<p><b>A</b>: SD-Mg was treated with cAMP analogs, the 6-Bnz-cAMP (PKA-selective; PKA-cA) and 8-pCPT-2′O-Me-cAMP (Epac-selective; Epac-cA) analogs, at 200 µM alone or in combination for 6 h. The amounts of MIP-1α protein in CM were determined by ELISA. Values represent the means ± SD for three independent experiments. **<i>P</i><0.01 versus untreated controls (<i>t</i>-test). <b>B</b>: Cell viability was determined 6 h after treatment with the cAMP analogs. <b>C</b>, <b>D</b>: SD-Mg was treated with 200 µM PKA-selective cAMP for 30 min. Phosphorylation states of Akt and JNK were analyzed by immunoblotting. The histogram on the bottom panels represents the ratio of phorphorylated protein to total protein measured by densitometry. Values represent the means ± SD for three independent experiments. Significance was evaluated by means of Student's <i>t</i>-test. **<i>P</i><0.01 versus WT-Mg.</p

PGE2 attenuates activation of Akt and JNK in SD-Mg.

<p><b>A</b>, <b>B</b>: Cell lysates were prepared with lysis buffer containing 1% SDS and 1% Triton X-100, and then subjected to immunoblotting using antibodies against Akt, JNK, phosphorylated Akt and JNK. <b>C</b>, <b>D</b>: SD-Mg was treated with 10 nM PGE2 for the indicated time periods. Phosphorylation of Akt and JNK was analyzed by immunoblotting. The histogram on the bottom panels represents the ratio of phorphorylated protein to total protein measured by densitometry. Values represent the means ± SD for three independent experiments. Significance was evaluated by means of Student's <i>t</i>-test. *<i>P</i><0.05 and **<i>P</i><0.01 versus WT-Mg or untreated SD-Mg.</p