Fracture resistance of different partial-coverage ceramic molar restorations: An in vitro investigation

BACKGROUND: The authors conducted a study to evaluate the influence of preparation design on reliability and fracture resistance of press-ceramic posterior partial-coverage restorations (PCRs) under fatigue. They compared the results for PCRs fabricated of a new press ceramic (IPS e.max Press-VP 1989/4, Ivoclar-Vivadent, Schaan, Liechtenstein) with results for ceramic inlays and unprepared molars. METHODS: The authors randomly divided 96 human upper molars into six equal groups. Control group NP specimens remained unprepared. Control group IN specimens received a mesio-occlusal-distal (MOD) inlay preparation. The test groups received PCR preparation designs based on group IN's inlay design, with additional cuspal reduction that increased from group to group. The authors fabricated 16 ceramic inlays and 64 PCRs of IPS e.max Press and luted them adhesively. All specimens underwent masticatory fatigue loading (1.2 million cycles, 1.6 hertz, 98 newtons), 5,300 thermal cycles and observation for fracture patterns. Afterward, the authors loaded all surviving specimens until fracture. RESULTS: No fractures occurred during the exposure to the masticatory simulation. After undergoing loading in a universal testing machine, the groups showed no significant differences in fracture strength values (P = .6026). Thus, the different preparation designs of the PCRs demonstrated no significant influence on the restorations' fracture resistance. The median failure loads ranged from 1,567 to 1,960 newtons. CONCLUSION: All-ceramic PCRs for molars made of IPS e.max Press were shown to be fracture-resistant, results comparable with those of natural unprepared teeth. CLINICAL IMPLICATIONS: When a posterior ceramic PCR is indicated, the clinician should perform a defect-oriented preparation that preserves tooth structure. Further clinical investigations are recommended to verify the authors' in vitro results.     

MRS2500 [2-iodo-N6-methyl-(N)-methanocarba-2'-deoxyadenosine-3',5'-bisphosphate], a potent, selective, and stable antagonist of the platelet P2Y1 receptor with strong antithrombotic activity in mice

The platelet P2Y(1) ADP receptor is an attractive target for new antiplatelet drugs. However, because of the lack of strong and stable antagonists, only a few studies have suggested that pharmacological inhibition of the P2Y(1) receptor could efficiently inhibit experimental thrombosis in vivo. Our aim was to determine whether the newly described potent and selective P2Y(1) receptor antagonist MRS2500 [2-iodo-N(6)-methyl-(N)-methanocarba-2'-deoxyadenosine-3',5'-bisphosphate] could inhibit platelet function ex vivo and experimental thrombosis in mice in vivo. MRS2500 was injected intravenously into mice, and its effect on ex vivo platelet aggregation and in several models of thrombosis in vivo was determined. MRS2500 displayed high potency and stable and selective P2Y(1) receptor inhibition ex vivo. Although MRS2500 injection resulted in only moderate prolongation of the bleeding time, it provided strong protection in systemic thromboembolism induced by infusion of a mixture of collagen and adrenaline. MRS2500 also potently inhibited localized arterial thrombosis in a model of laser-induced vessel wall injury with two degrees of severity. Moreover, combination of MRS2500 with clopidogrel, the irreversible inhibitor of the platelet P2Y(12) receptor for ADP, led to increased antithrombotic efficacy compared with each alone. These results add further evidence for a role of the P2Y(1) receptor in thrombosis and validate the concept that targeting the P2Y(1) receptor could be a relevant alternative or complement to current antiplatelet strategies.     

The role of prostaglandin E receptor-dependent signaling via cAMP in Mdr1b gene activation in primary rat hepatocyte cultures

Multidrug resistance (mdr) proteins of the mdr1 type function as multispecific xenobiotic transporters in hepatocytes. In the liver, mdr1 overexpression occurs during regeneration, cirrhosis, and hepatocarcinogenesis and may contribute to primary chemotherapy resistance. Cultured rat hepatocytes exhibit a time-dependent "intrinsic" increase in functional mdr1b expression, which depends on cyclooxygenase-catalyzed prostaglandin E(2) release. In the present study, the prostaglandin E (EP) receptor agonist misoprostol (1-10 microg/ml) further enhanced intrinsic mdr1b mRNA expression in primary rat hepatocytes. On the other hand, [1alpha(z),2beta,5alpha]-(+)-7-[5-[1,1'-(biphenyl)-4-yl]methoxy]-2-(4-morpholinyl)-3-oxocyclopentyl]-4-heptenoic acid (AH23848B) (30 microM), an antagonist of the cAMP-coupled EP4 receptor, and the protein kinase A (PKA) inhibitor, N-(2-[bromocinnamylamino]ethyl)-5-isoquinolinesulfonamide (H89) (10 nM), repressed intrinsic mdr1b mRNA up-regulation, whereas the stable cAMP analog 8-bromo-cAMP (10 microM) and the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) (100 microM) further enhanced intrinsic mdr1b expression. Primary rat hepatocytes, transiently transfected with reporter gene constructs controlled by mdr1b 5'-gene-flanking regions [-1074 to +154 base pairs (bp) or -250 to +154 bp], demonstrated pronounced mdr1b promoter activity, already without the addition of exogenous modulators. Nevertheless, activity was further stimulated by misoprostol, 8-bromo-cAMP, or IBMX. Cotransfection with expression vectors for PKI, an inhibitor protein of cAMP-dependent PKA, or KCREB, a dominant-negative mutant of the cAMP-responsive element-binding protein (CREB), decreased high-intrinsic mdr1b promoter activity. KCREB also counteracted misoprostol-induced mdr1b promoter activation. In conclusion, these data provide evidence for a pivotal role of EP receptor-stimulated, cAMP-dependent activation of PKA and CREB or CREB-related proteins in mdr1b gene activation in primary rat hepatocytes. Thus, these data might offer potential new target structures for the reversal of primary drug resistance, for example, of liver tumors.     

Seasonal variations in onset of Wegener's granulomatosis: increased in summer?

OBJECTIVE: Investigators have reported significant seasonal variations of onset of Wegener's granulomatosis (WG), but those data were not confirmed by others. We reexamined the hypothesis of a seasonal pattern of onset of WG. METHODS: We conducted telephone interviews with 59 patients with newly diagnosed WG fulfilling the American College of Rheumatology criteria. Patients were identified having been enrolled from 2001 to 2004 by French hospitals in 2 multicenter therapeutic trials. The interviews investigated precisely how and when their disease had appeared to establish an index date, defined as the year and month of the first symptom(s) attributable to WG. Once telephone interviews had been completed, index dates were also retrieved from medical records. RESULTS: Among the 59 patients interviewed, 14 (24%) were unable to specify an exact month of WG onset. Based on the remaining 45 "informative" patients, the month of onset distribution varied significantly (p = 0.03, exact goodness-of-fit chi-square test), notably with a higher onset rate in August (p = 0.001). Seasonal distributions also differed significantly (p = 0.01), with an increased rate of summer onset (June-August) (p = 0.001). Index dates extracted from medical files showed that onset was also more frequent in summer (p = 0.01). CONCLUSION: Our results confirm the seasonality in onset of WG, but unlike previous reports indicating an increase in winter, instead suggest that this vasculitis preferentially appears in summer. These findings might support an allergic mechanism in the pathogenesis of WG.