Suramin prevents the development of diabetic kidney disease by inhibiting NLRP3 inflammasome activation in KK-Ay mice

Aims/Introduction Nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasomes produce IL-18 upon being activated by various stimuli via the P2 receptors. Previously, we showed that serum and urine IL-18 levels are positively associated with albuminuria in patients with type 2 diabetes, indicating the involvement of inflammasome activation in the pathogenesis of diabetic kidney disease (DKD). In the present study, we investigated whether the administration of suramin, a nonselective antagonist of the P2 receptors, protects diabetic KK.Cg-A(y)/TaJcl (KK-Ay) mice against DKD progression. Materials and Methods Suramin or saline was administered i.p. to KK-Ay and C57BL/6J mice once every 2 weeks for a period of 8 weeks. Mouse mesangial cells (MMCs) were stimulated with ATP in the presence or absence of suramin. Results Suramin treatment significantly suppressed the increase in the urinary albumin-to-creatinine ratio, glomerular hypertrophy, mesangial matrix expansion, and glomerular fibrosis in KK-Ay mice. Suramin also suppressed the upregulation of NLRP3 inflammasome-related genes and proteins in the renal cortex of KK-Ay mice. P2X4 and P2X7 receptors were significantly upregulated in the isolated glomeruli of KK-Ay mice and mainly distributed in the glomerular mesangial cells of KK-Ay mice. Although neither ATP nor suramin affected NLRP3 expression in MMCs, suramin inhibited ATP-induced NLRP3 complex formation and the downstream expression of caspase-1 and IL-18 in MMCs. Conclusions These results suggest that the NLRP3 inflammasome is activated in a diabetic kidney and that inhibition of the NLRP3 inflammasome with suramin protects against the progression of early stage DKD

Measurement of the zygomatic bone and pilot hole technique for safer installation of zygomaticus implants

The zygomaticus implant (Brånemark system, Nobel Biocare, Gotebörg, Sweden) was developed for patients with severe bone resorption of the posterior maxilla, which may eliminate or minimize the need for bone grafting. Although the zygomaticus implant has had a remarkable success rate in a difficult patient population, the method requires an advanced surgical technique and carries increased risk of complications, such as the perforation of the orbital floor or infratemporal fossa. Although it is important to have a detailed understanding of the anatomy of the zygomatic bone when performing the installation, there have been few anatomic studies on the zygomatic bone for installation of zygomaticus implants. In this study, we measured the height and thickness of the zygomatic bone for the installation. The thickness at a 90-degree angle point, where the upper margin of the zygomatic arch and the temporal margin of the frontal process of the zygomatic bone intersect and where the apex of the implant penetrates, according to the original method, was 1.8 ± 0.4 mm, which gradually increased inferiorly and anteriorly. In conclusion, the penetration point of the apex of the zygomaticus implant should be located more inferoanterior to the 90-degree angle point, as the thickness of the 90-degree angle point is thinner than the diameter of the implant. Based on these results, we have proposed a newer and safer installation method for the zygomaticus implant using a drill guide, which can be easily made

Brain MRI with Quantitative Susceptibility Mapping: Relationship to CT Attenuation Values

[Background]: Quantitative susceptibility mapping (QSM) is used to differentiate between calcification and iron deposits. Few studies have examined the relationship between CT attenuation values and magnetic susceptibility in such materials. Purpose: To assess the relationship among metal concentration, CT attenuation values, and magnetic susceptibility in paramagnetic and diamagnetic phantoms, and the relationship between CT attenuation values and susceptibility in brain structures that have paramagnetic or diamagnetic properties. [Materials and Methods]: In this retrospective study, CT and MRI with QSM were performed in gadolinium and calcium phantoms, patients, and healthy volunteers between June 2016 and September 2017. In the phantom study, we evaluated correlations among metal concentration, CT attenuation values, and susceptibility. In the human study, Pearson and Spearman correlations were performed to assess the relationship between CT attenuation values and susceptibility in regions of interest placed in the globus pallidus (GP), putamen, caudate nucleus, substantia nigra, red nucleus, dentate nucleus, choroid plexus, and hemorrhagic and calcified lesions. [Results]: Eighty-four patients (mean age, 64.8 years 6 19.6; 49 women) and 20 healthy volunteers (mean age, 72.0 years 6 7.6; 11 men) were evaluated. In the phantoms, strong linear correlations were identified between gadolinium concentration and CT and MRI QSM values (R2 = 0.95 and 0.99, respectively; P , .001 for both) and between calcium concentration and CT and MRI QSM values (R2 = 0.89 [P = .005] and R2 = 0.98 [P , .001], respectively). In human studies, positive correlations between CT attenuation values and susceptibility were observed in the GP (R2 = 0.52, P , .001) and in hemorrhagic lesions (R2 = 0.38, P , .001), and negative correlations were found in the choroid plexus (R2 = 0.53, P , .001) and in calcified lesions (R2 = 0.38, P = .009). [Conclusion]: CT attenuation values showed a positive correlation with susceptibility in the globus pallidus and hemorrhagic lesions and negative correlation in the choroid plexus and calcified lesions

Dwarf Novae in the Shortest Orbital Period Regime: I. A New Short Period Dwarf Nova, OT J055717+683226

We report the observation of a new dwarf nova, OT J055717+683226, during its first-ever recorded superoutburst in December 2006. Our observation shows that this object is an SU UMa-type dwarf nova having a very short superhump period of 76.67+/- 0.03 min (0.05324+/-0.00002 d). The next superoutburst was observed in March 2008. The recurrence time of superoutbursts (supercycle) is, hence, estimated to be ~480 d. The supercycle is much shorter than those of WZ Sge-type dwarf novae having supercycles of >~ 10 yr, which are a major population of dwarf novae in the shortest orbital period regime (<~85 min). Using a hierarchical cluster analysis, we identified seven groups of dwarf novae in the shortest orbital period regime. We identified a small group of objects that have short supercycles, small outburst amplitudes, and large superhump period excesses, compared with those of WZ Sge stars. OT J055717+683226 probably belongs to this group.Comment: 14 pages, 11 figures, accepted for publication in PAS

Grading Meningioma : A Comparative Study of Thallium-SPECT and FDG-PET

The purpose was to compare capability of fluorine-18 fluorodeoxyglucose (FDG)-PET and thallium-201 (Tl)-SPECT for grading meningioma. This retrospective study was conducted as a case-control study under approval by the institutional review board. In the hospital information system, 67 patients (22 men and 45 women) who had both FDG-PET and Tl-SPECT preoperative examinations were found with histopathologic diagnosis of meningioma. The maximum FDG uptake values of the tumors were measured, and they were standardized to the whole body (SUVmax) and normalized as gray matter ratio (SUVRmax). Mean and maximum Tl uptake ratios (TURmean and TURmax, respectively) of the tumors were measured and normalized as ratios to those of the contralateral normal brain. Receiver-operating characteristic curve analyses of the 4 indexes were conducted for differentiation between low- and high-grade meningiomas, and areas under the curves (AUCs) were compared. Correlation coefficients were calculated between these indexes and Ki-67. Fifty-six meningiomas were classified as grade I (low grade), and 11 were grade II or III (high grade). In all 4 indexes, a significant difference was observed between low- and high-grade meningiomas (P<0.05). AUCs were 0.817 (SUVmax), 0.781 (SUVRmax), 0.810 (TURmean), and 0.831 (TURmax), and no significant difference was observed among the indexes. Their sensitivity and specificity were 72.7% to 90.9% and 71.4% to 87.5%, respectively. Correlation of the 4 indexes to Ki-67 was statistically significant, but coefficients were relatively low (0.273-0.355). Tl-SPECT, which can be used at hospitals without a cyclotron or an FDG distribution network, has high diagnostic capability of meningioma grades comparable to FDG-PET

A randomized, quadruple crossover single-blind study on immediate action of chewed and unchewed low-dose acetylsalicylic acid tablets in healthy volunteers

金沢大学附属病院薬剤部In the initial treatment of acute myocardial infarction, it is important to administer oral low-dose acetylsalicylic acid (ASA) within 10 min of arrival at the hospital. However, ASA is supplied as an enteric-coated tablet or buffered tablet to prevent gastric irritation. Although current guidelines recommended that patients should chew their initial dose of ASA, there is little evidence as to whether this is efficacious. Therefore, we aimed to make a direct comparison of the pharmacokinetics and pharmacodynamics of ASA after ingestion of intact and chewed nonenteric-coated buffered ASA tablet (NBA) and enteric-coated ASA tablet (ECA) in a quadruple crossover study in healthy volunteers. Chewing ECA accelerated tmax of ASA absorption, which became equivalent to that after ingestion of intact or chewed NBA. A significant decrease in serum thromboxane B2 was observed 20 min after ingestion of chewed ECA, or intact or chewed NBA, and inhibition of platelet aggregation was also observed within 20 min. Thus, chewing of the ECA appears to result in a similar timing of ASA action to that in the case of chewed or unchewed NBA. © 2011 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci Copyright © 2011 Wiley-Liss, Inc.発行後1年より全文公開

Role of cyclooxygenase-2-mediated prostaglandin E2-prostaglandin E receptor 4 signaling in cardiac reprogramming

Direct cardiac reprogramming from fibroblasts can be a promising approach for disease modeling, drug screening, and cardiac regeneration in pediatric and adult patients. However, postnatal and adult fibroblasts are less efficient for reprogramming compared with embryonic fibroblasts, and barriers to cardiac reprogramming associated with aging remain undetermined. In this study, we screened 8400 chemical compounds and found that diclofenac sodium (diclofenac), a non-steroidal anti-inflammatory drug, greatly enhanced cardiac reprogramming in combination with Gata4, Mef2c, and Tbx5 (GMT) or GMT plus Hand2. Intriguingly, diclofenac promoted cardiac reprogramming in mouse postnatal and adult tail-tip fibroblasts (TTFs), but not in mouse embryonic fibroblasts (MEFs). Mechanistically, diclofenac enhanced cardiac reprogramming by inhibiting cyclooxygenase-2, prostaglandin E2/prostaglandin E receptor 4, cyclic AMP/protein kinase A, and interleukin 1β signaling and by silencing inflammatory and fibroblast programs, which were activated in postnatal and adult TTFs. Thus, anti-inflammation represents a new target for cardiac reprogramming associated with aging