Yttria-stabilized zirconia ceramics is a high-performance material with excellent biocompatibility and mechanical properties, which suggest its suitability for posterior fixed partial dentures. The hypothesis under examination is that the strength and reliability of Y-TZP zirconia ceramics are affected by the inner surface grinding of crowns, and vary with the grinding parameter. Flexural strength, surface roughness, and fracture toughness were determined on samples machined by face and peripheral grinding with varied feed velocities and cutting depths. Results have been compared with those on lapped samples. Analysis of variance and Weibull parameter were used for statistical analysis. It was found that inner surface grinding significantly reduces the strength and reliability of Y-TZP zirconia compared with the lapped control sample. Co-analysis of flexural strength, Weibull parameter, and fracture toughness showed counteracting effects of surface compressive stress and grinding-introduced surface flaws. In conclusion, grinding of Y-TZP needs to be optimized to achieve the CAD/CAM manufacture of all-ceramic restorations with improved strength and reliability.

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Low density lipoprotein (LDL) and fibrinogen apheresis was recently reported to be an effective therapy in sudden hearing loss (SHL). In this study, we investigated whether lipoprotein and/or fibrinogen plasma concentrations, related gene polymorphisms and other cardiovascular risk factors are also risk factors for SHL. Total cholesterol, HDL and LDL cholesterol plasma concentrations, fibrinogen levels, and two functionally relevant fibrinogen polymorphisms were determined in 142 consecutive patients and in 84 age- and sex-matched control subjects of the same ethnic background, using routine laboratory methods and PCR analysis. In addition, we determined the platelet glycoprotein Ia (GPIa) C807T polymorphism, which was recently proposed to be a genetic risk factor for SHL, and we compared the patients' and controls' clinical characteristics. Total and LDL cholesterol concentrations were not different between patients and controls. Fibrinogen plasma levels were significantly increased in SHL patients (260+/-57 vs. 239+/-110 mg/dl, p=0.002). However, fibrinogen was not related to SHL in multivariate analysis, and none of the investigated fibrinogen polymorphisms was associated with SHL. By contrast, T allele carriers of the GPIa 807 polymorphic site had an increased risk to develop SHL (OR 1.81) and were more likely not to recover from SHL, compared to C allele carriers (OR 3.0). Moreover, significantly more SHL patients were current smokers (56.3% vs. 19.3% in the control group, p<0.0001). In conclusion, there is a partial overlap between classical coronary risk factors and risk factors for SHL. Hypercholesterolemia and hypoalphalipoproteinemia (low HDL cholesterol levels) are apparently no major risk factors for SHL, whereas the GPIa C807T polymorphism, elevated fibrinogen levels, and smoking are associated with an increased risk for SHL. Altogether these findings suggest a vascular involvement in the pathogenesis of SHL and may have important implications for the development of therapeutic and preventive strategies.

Abstract-We demonstrate that physiological concentrations of HDL 3 inhibit the thrombin-induced platelet fibrinogen binding and aggregation in a time-and concentration-dependent fashion. The underlying mechanism includes HDL 3 -mediated inhibition of phosphatidylinositol 4,5-bis-phosphate turnover, 1,2-diacylglycerol and inositol 1,4,5-tris-phosphate formation, and intracellular calcium mobilization. The inhibitory effects of HDL 3 on inositol 1,4,5-tris-phosphate formation and intracellular calcium mobilization were abolished after covalent modification of HDL 3 with dimethylsuberimidate. Furthermore, they could be blocked by calphostin C and bis-indolylmaleimide, 2 highly selective and structurally unrelated protein kinase C inhibitors. However, the inhibitory effects of HDL 3 were not blocked by H89, a protein kinase A inhibitor. In addition, HDL 3 failed to induce cAMP formation but stimulated the phosphorylation of the protein kinase C 40-to 47-kD major protein substrate. We observed a close temporal relationship between the HDL 3 -mediated inhibition of thrombininduced inositol 1,4,5-tris-phosphate formation, intracellular calcium mobilization, and fibrinogen binding and the phosphorylation of the protein kinase C 40-to 47-kD major protein substrate. Taken together, these findings indicate that the HDL 3 -mediated inhibition of thrombin-induced fibrinogen binding and aggregation occurs via inhibition of phosphatidylinositol 4,5-bis-phosphate turnover and formation of 1,2-diacylglycerol and inositol 1,4,5-tris-phosphate. Protein kinase C may be involved in this process. (Arterioscler Thromb Vasc Biol. 1998;18:861-869.)Key Words: high-density lipoprotein Ⅲ protein kinase C Ⅲ signal transduction Ⅲ platelet aggregation Ⅲ fibrinogen B oth HDL and platelets are intimately involved in the pathogenesis of atherosclerosis, thrombosis, and coronary heart disease.1-3 Numerous observations demonstrated a direct effect of HDL on platelet functions.4 Platelet hyperreactivity was noted in subjects with hypoalphalipoproteinemia.5 Decreased activation of platelets by strong agonists such as thrombin and collagen has been reported in the presence of physiological concentrations of HDL.6-8 Furthermore, HDL inhibited thromboxane A 2 liberation, and addition of HDL to clotting blood diminished platelet thromboxane A 2 formation capacity. 9,10The mechanism underlying the effects of HDL on platelet function is little understood. HDL 3 , the major HDL subfraction in blood, is known to interact with specific binding sites on platelets that appear to be identical with GP IIb/IIIa. [11][12][13][14] In human platelets, HDL 3 was also shown to activate cellular phospholipases, resulting in the formation of DAG.15-18 The involvement of both phosphatidylcholine-specific phospholipase C and phosphatidylcholine-specific phospholipase D was postulated. 16 -18 Recently, the PKC-dependent enhancement of the Na ϩ /H ϩ antiport in the presence of HDL 3 has been reported. 19Both HDL 3 -induced DAG formation and Na ϩ /H ϩ exchange stimulation w...

Telomere length and cell function can be preserved by the human reverse transcriptase telomerase (hTERT), which synthesizes the new telomeric DNA from a RNA template, but is normally restricted to cells needing a high proliferative capacity, such as stem cells. Consequently, telomerase-based therapies to elongate short telomeres are developed, some of which have successfully reached the stage I in clinical trials. Telomerase is also permissive for tumorigenesis and 90% of all malignant tumors use telomerase to obtain immortality. Thus, reversal of telomerase upregulation in tumor cells is a potential strategy to treat cancer. Natural and small-molecule telomerase inhibitors, immunotherapeutic approaches, oligonucleotide inhibitors, and telomerase-directed gene therapy are useful treatment strategies. Telomerase is more widely expressed than any other tumor marker. The low expression in normal tissues, together with the longer telomeres in normal stem cells versus cancer cells, provides some degree of specificity with low risk of toxicity. However, long term telomerase inhibition may elicit negative effects in highly-proliferative cells which need telomerase for survival, and it may interfere with telomere-independent physiological functions. Moreover, only a few hTERT molecules are required to overcome senescence in cancer cells, and telomerase inhibition requires proliferating cells over a sufficient number of population doublings to induce tumor suppressive senescence. These limitations may explain the moderate success rates in many clinical studies. Despite extensive studies, only one vaccine and one telomerase antagonist are routinely used in clinical work. For complete eradication of all subpopulations of cancer cells a simultaneous targeting of several mechanisms will likely be needed. Possible technical improvements have been proposed including the development of more specific inhibitors, methods to increase the efficacy of vaccination methods, and personalized approaches. Telomerase activation and cell rejuvenation is successfully used in regenerative medicine for tissue engineering and reconstructive surgery. However, there are also a number of pitfalls in the treatment with telomerase activating procedures for the whole organism and for longer periods of time. Extended cell lifespan may accumulate rare genetic and epigenetic aberrations that can contribute to malignant transformation. Therefore, novel vector systems have been developed for a ‘mild’ integration of telomerase into the host genome and loss of the vector in rapidly-proliferating cells. It is currently unclear if this technique can also be used in human beings to treat chronic diseases, such as atherosclerosis.

Abstract-HDL plasma concentrations decline with age in prospective studies. Decline in HDL concentration and function may occur secondary because of hormonal changes, inflammatory processes, and diabetes mellitus. Beyond these effects specific aging processes may be involved. Replicative aging, the telomere-driven loss of divisional capacity, is a species-specific aging mechanism that may decrease HDL concentration and function. Cross-sectionally, by contrast, HDL levels do not change much or even slightly increase with age, suggesting that only people with still high HDL concentrations survive. A selection bias by HDL lowering genetic variation may explain why HDL deficiency is extremely rare among centenarians. Vice versa, HDL may modulate the aging process, not only by its well-known antiatherogenic effects, eg, its ability to remove cellular lipids and by antiatherogenic pleiotropic effects on cell survival, but possibly also by direct interfering with aging signaling or survival factor KLOTHO. Most of the current findings, however, are based on cell culture and selected animal experiments and await further confirmation by appropriate in vivo models. T he influence of age on atherosclerosis is generally explained by the simple passage of time and a higher number and severity of risk factors with increasing age. However, the observation of senescence-like changes in atherosclerotic lesions, 1 the severe atherosclerosis in premature aging syndromes, 2 and the identification of age as by far the most predictive independent risk factor for atherosclerosis effective even in absence of other risk factors 3 suggests that atherogenesis is more directly related to the aging process than previously presumed.Aging is a complex process that (on the cellular level) includes cell cycle arrest, morphology remodeling with functional decline, chromatin silencing with profound gene expression changes, and changes in metabolism. As summarized in Figure 1, different triggers may act together in a cooperative fashion and use overlapping signaling pathways to induce and propagate the aging process. 4 Replicative aging results from the progressive shortening of telomeres (composed of conserved nucleotide sequences, TTAGGG in vertebrates) attributable to incomplete end replication during cell divisions. It may protect against increased cancer risk but may also contribute to atherosclerosis in later life, particularly at "atherosclerosis-prone areas" with high replication rates. 5 Next to age, a low high-density lipoprotein (HDL) cholesterol level is one of the strongest predictors of premature coronary heart disease and stroke. 6 In contrast to high low-density lipoprotein (LDL) cholesterol, low HDL cholesterol remains a powerful risk predictor into old age. HDL may directly influence specific aging processes and, vice versa, aging may influence HDL concentration and function. However, it is important to bear in mind the caveats of the current studies. First, most findings are based on cell culture and animal models and have not be...

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