Inhibition of enamel demineralization by buffering effect of S‐PRG filler‐containing dental sealant

The buffering capacity and inhibitory effects on enamel demineralization of two commercially available dental sealants were evaluated in this study. The effects of filler particles were also examined. Disks of enamel and cured sealant materials of BeautiSealant (silica or S‐PRG filler) or Teethmate F‐1 were incubated in lactic acid solutions (pH 4.0) for 1–6 d. The pH changes and amounts of ions released in the solutions were assessed, and enamel surfaces were observed using a scanning electron microscope. The pH of the solution with BeautiSealant (S‐PRG filler) was neutralized from pH 4.0 to pH 6.1 (after incubation for 1 d) and from pH 4.0 to pH 6.7 (after incubation for 6 d). In addition, no release of calcium ions was detected and the enamel surface was morphologically intact in scanning electron microscopy images. However, the pH of the solution with Teethmate F‐1 remained below pH 4.0 during incubation from days 1 to 6. Calcium release was increased in solutions up to and after 6 d of incubation. Scanning electron microscopy images showed that the structures of hydroxyapatite rods were exposed at the specimen surfaces as a result of demineralization. Ions released from S‐PRG filler‐containing dental sealant rapidly buffered the lactic acid solution and inhibited enamel demineralization.     

In vitro degradation of resin–dentin bonds with one-bottle self-etching adhesives

The purpose of this study was to evaluate the durability of one-bottle self-etching adhesive during long-term water-storage testing. Resin–dentin bonded specimens were prepared using four commercially available one-bottle self-etching adhesives. The specimens were sectioned perpendicular to the adhesive interface to produce beam-shaped specimens that were stored in water for 24 h (control group) and 100, 200, and 300 d (experimental groups). After each storage period, the beams were subjected to a microtensile bond test. After the bond test, fractured surfaces were examined using a scanning electron microscope. In addition, interfacial observations of the silver tracer were performed using the secondary and back-scatter modes of the scanning electron microscope. The bond strength of all tested adhesives decreased significantly after 100 or more days in water. The interfacial observations showed an oxygen-inhibition zone as electron lucent in the adhesive–composite border in control specimens, displaying silver impregnation with breakage after aging. The deterioration of the oxygen-inhibition zone in the adhesive–resin composite junction resulted in a decrease in bond strength after 100 d in water for one-bottle self-etching adhesives.     

Chromosomal and microsatellite instability in sporadic gastric cancer

BACKGROUND: Gastric cancer can progress through two pathways of genomic instability: chromosomal (CIN) and microsatellite instability (MSI). It is hypothesized that these two pathways are not always independent and that some tumors show overlap between these two mechanisms. METHODS: A total of 98 sporadic gastric cancers were classified based on their MSI status, using microsatellite assay with BAT26. Evidence for CIN was investigated by identifying loss of heterozygosity (LOH) events on chromosome arms, 5q, 10p, 17p, 17q, and 18q, which are regions harboring tumor suppressor genes that are significant in gastric cancer development. RESULTS: Twelve tumors (12%) showed high-frequency MSI (MSI-H). Overall, 43 of the tumors (44%) had at least one LOH event, with most frequent chromosomal losses observed on 10p and 18q (30%, respectively), followed by 5q (21%), 17p (14%), and 17q (12%). Interestingly, overlap was observed between CIN and MSI pathways. Of 43 cancers with LOH events, four (9%) were also MSI-H. It was also found that 48% of cancers without MSI-H had no LOH events identified, comprising a subgroup of tumors that were not representative of either of these two pathways of genomic instability. CONCLUSION: These results suggest that molecular mechanisms of genomic instability are not necessarily independent and may not be fully defined by either the MSI or CIN pathways in sporadic gastric cancers.     

An Exploratory Study of Dapagliflozin for the Attenuation of Albuminuria in Patients with Heart Failure and Type 2 Diabetes Mellitus (DAPPER)

Background and Aims

Sodium-dependent glucose transporter-2 (SGLT-2) inhibitors, which are anti-diabetic drugs, reportedly decrease the incidence of cardiovascular events in high-risk patients with cardiovascular diseases, and thus chronic heart failure (CHF). SGLT-2 inhibitors also decrease albuminuria in patients with type 2 diabetes mellitus (T2D). Since albuminuria is a biomarker of not only chronic kidney disease but also cardiovascular events, we hypothesized that, among T2D patients with CHF, SGLT-2 inhibitors will decrease the extent of albuminuria and also improve CHF concomitantly.

Methods

DAPPER (UMIN000025102) is a multicenter, randomized, open-labeled, parallel-group, standard treatment-controlled study, which is designed to evaluate whether dapagliflozin, one of the SGLT-2 inhibitors, decreases albuminuria in T2D patients with CHF and exerts cardioprotective effects on the failing heart. The patients are randomized to either of the dapagliflozin (5 or 10 mg, once daily orally) or control group (administration of anti-diabetic drugs administered other than SGLT 2 inhibitors). The estimated number of patients that need to be enrolled is 446 in total (223 in each group). The primary objective is the changes in the urinary albumin-to-creatinine ratio from the baseline after 2-year treatment. The key secondary objectives are (1) the safety of dapagliflozin and (2) the cardiovascular and renal efficacies of dapagliflozin.

Conclusion and Perspectives

DAPPER study investigates whether dapagliflozin decreases albuminuria and exerts beneficial effects on the failing heart in T2D patients. (UMIN000025102).

     

Toll-like receptor 2 mediates apolipoprotein CIII-induced monocyte activation

Apolipoprotein (apo)CIII predicts risk for coronary heart disease. We recently reported that apoCIII directly activates human monocytes. Recent evidence indicates that toll-like receptor (TLR)2 can contribute to atherogenesis through transduction of inflammatory signals. Here, we tested the hypothesis that apoCIII activates human monocytoid THP-1 cells through TLR2. ApoCIII induced the association of TLR2 with myeloid differentiation factor 88, activated nuclear factor (NF)-kappaB in THP-1 cells, and increased their adhesion to human umbilical vein endothelial cells (HUVECs). Anti-TLR2 blocking antibody, but not anti-TLR4 blocking antibody or isotype-matched IgG, inhibited these processes (P<0.05). ApoCIII bound with high affinity to human recombinant TLR2 protein and showed a significantly higher (P<0.05) and saturable binding to 293 cells overexpressing human TLR2 than to parental 293 cells with no endogenous TLR2. Overexpression of TLR2 in 293 cells augmented apoCIII-induced NF-kappaB activation and beta(1) integrin expression, processes inhibited by anti-apoCIII antibody as well as anti-TLR2 antibody. Exposure of peripheral blood monocytes isolated from C57BL/6 (wild-type) mice to apoCIII activated their NF-kappaB and increased their adhesiveness to HUVECs. In contrast, apoCIII did not activate monocytes from TLR2-deficient mice. Finally, intravenous administration to C57BL/6 mice of apoCIII-rich very-low-density lipoprotein (VLDL), but not of apoCIII-deficient VLDL, activated monocytes and increased their adhesiveness to HUVECs, processes attenuated by anti-TLR2 or anti-apoCIII antibody. ApoCIII-rich VLDL did not activate monocytes from TLR2-deficient mice. In conclusion, apoCIII activated monocytes at least partly through a TLR2-dependent pathway. The present study identifies a novel mechanism for proinflammatory and proatherogenic effects of apoCIII and a role for TLR2 in atherosclerosis induced by atherogenic lipoproteins.     

Can negative cardiac effect of proton pump inhibitor and high-dose H2-blocker have clinical influence on patients with stable angina?

BACKGROUND: Aspirin and anti-platelet drugs are used commonly for patients with coronary heart disease. Proton pump inhibitor (PPI) and high-dose H2-blocker were recommended for preventing NSAIDs-related ulcer. Previously H2-blocker reported to have some negative cardiovascular effects. Additionally, a recent in vitro study showed that PPI reduced cardiac contractility. In this study, we evaluated whether chronic administration of PPI and high-dose H2-blocker affects left ventricular function. METHOD: Fifty-two stable angina patients were enrolled and classified into PPI group ([P]; lansoprazole: 15mg/day, n=28), H2-blocker group ([H]; famotidine: 40mg/day, n=8), and control ([C]; none or mucosal-defense drug, n=16). Eligible patients showed normal cardiac function in initial catheterization without administrated PPI or H2-blocker. They received percutaneous coronary intervention and follow-up catheterization. We compared changes in ejection fraction (EF: %), end diastolic/systolic volume index (EDVI/ESVI: ml/m(2)), and peak positive/negative dp/dt (+/-dp/dt: mmHg/s) in left ventricular angiography series. RESULT: There were no significant differences among three groups regarding patient characteristics, backgrounds of angiographic and intervention, except for fewer smokers in [C]. Other drugs such as beta- and Ca-blocker did not have effects on cardiac function except for aspirin during 255+/-115 days follow-up. Rate of EF changes significantly decreased in [P], and tended to decrease in [H] (C: 3.8+/-9.8%, H: -1.6+/-7.6%, P: -2.1+/-5.9%; p<0.05 for [C] vs. [P]). Those of ESVI changes were significantly greater in [P], and tended to be greater in [H] (C: -4.5+/-16.2%, H: 4.9+/-15.5%, P: 7.3+/-16.2%; p<0.05 for [C] vs. [P]), though, EDVI changes' were similar (C: 2.5+/-8.9%, H: 2.6+/-3.6%, P: 1.6+/-6.1%; p=ns). Rate of +/-dp/dt-changes tended to decrease in [H] (+dp/dt: C: 3.9+/-15.5%, H: -10.0+/-25.2%, P: 0.3+/-19.6%; p=ns, -dp/dt: C: -0.1+/-19.5%, H: -8.5+/-20.4%, P: 5.7+/-27.7%; p=ns). CONCLUSION: In this study, PPI and high-dose H2-blocker have EF-reducing tendency. However, these changes were small and these drugs seemed to exhibit little influence clinically.     

Motility of the Sphincter of Oddi and Pancreatic Main Ductal Pressure in Patients with Alcoholic, Gallstone-Associated, and Idiopathic Chronic Pancreatitis

We endoscopically measured pressures of the pancreatic duct (PP) and the sphincter of Oddi (SO) in patients with alcoholic (ALCP, n = 10), gallstone-associated (GSCP, n = 7), and idiopathic chronic pancreatitis (ICP, n = 21), and in 20 controls. The PP was significantly higher in the patients with ALCP (55.7 +/- 28.9 mm Hg), GSCP (33.6 +/- 16.2 mm Hg), or ICP (44.5 +/- 25.8 mm Hg) than in the controls (16.2 +/- 8.7 mm Hg), but there was no significant difference between ALCP, GSCP, and ICP. There was no significant difference between control subjects and ICP in the motility of SO. In ICP, there was no correlation between the PP and the motility of SO. In ALCP and GSCP, the frequencies of the papillary sphincter waves were significantly higher than in normal subjects, and there were correlations between the PP and the motility of SO. These data suggest that increased pancreatic ductal pressure in GSCP with papillitis or ALCP may be due in part to papillary dysfunction, but not in ICP.