Mechanical insertion properties of calcium-phosphate implant coatings

Abstract Objectives: To investigate the influence of protein incorporation on the resistance of biomimetic calcium-phosphate coatings to the shear forces that are generated during implant insertion. Materials and Methods: Thirty-eight standard (5 x 13 mm) Osseotite((R)) implants were coated biomimetically with a layer of calcium phosphate, which either lacked or bore a co-precipitated (incorporated) depot of the model protein bovine serum albumin (BSA). The coated implants were inserted into either artificial bone (n=18) or the explanted mandibles of adult pigs (n=12). The former set-up was established for the measurement of torque and of coating losses during the insertion process. The latter set-up was established for the histological and histomorphometric analysis of the fate of the coatings after implantation. Results: BSA-bearing coatings had higher mean torque values than did those that bore no protein depot. During the insertion process, less material was lost from the former than from the latter type of coating. The histological and histomorphometric analysis revealed fragments of material to be sheared off from both types of coating at vulnerable points, namely, at the tips of the threads. The sheared-off fragments were retained within the peri-implant space. Conclusion: The incorporation of a protein into a biomimetically prepared calcium-phosphate coating increases its resistance to the shear forces that are generated during implant insertion. In a clinical setting, the incorporated protein would be an osteogenic agent, whose osteoinductive potential would not be compromised by the shearing off of coating material, and the osteoconductivity of an exposed implant surface would not be less than that of a coated one. To cite this article: Hägi TT, Enggist L, Michel D, Ferguson SJ, Liu Y, Hunziker EB. Mechanical insertion properties of calcium-phosphate implant coatings. Clin. Oral Impl. Res. xx, 2010; 000-000. doi: 10.1111/j.1600-0501.2010.01916.x.

Clinical and histologic evaluation of granular Beta-tricalcium phosphate for the treatment of human intrabony periodontal defects: a report on five cases

BACKGROUND: The aim of the study is to clinically and histologically evaluate the healing of advanced intrabony defects treated with open flap debridement and the adjunct implantation of granular beta tricalcium phosphate (beta-TCP). METHODS: Five patients, each displaying advanced combined 1- and 2-wall intrabony defects around teeth scheduled for extraction or root resection, were recruited. Approximately 6 months after surgery, the teeth or roots were removed together with a portion of their surrounding soft and hard tissues and processed for histologic evaluation. RESULTS: The mean probing depth (PD) was reduced from 10.8 +/- 2.3 mm presurgically to 4.6 +/- 2.1 mm, whereas a mean clinical attachment level (CAL) gain of 5.0 +/- 0.7 mm was observed. The increase in gingival recession was 1.2 +/- 3.2 mm. The histologic evaluation indicated the formation of new cellular cementum with inserting collagen fibers to a varying extent (mean: 1.9 +/- 0.7 mm; range: 1.2 to 3.03 mm) coronal to the most apical extent of the root instrumentation. The mean new bone formation was 1.0 +/- 0.7 mm (range: 0.0 to 1.9 mm). In most specimens, beta-TCP particles were embedded in the connective tissue, whereas the formation of a mineralized bone-like or cementum-like tissue around the particles was only occasionally observed. CONCLUSION: The present data indicates that treatment of intrabony periodontal defects with this beta-TCP may result in substantial clinical improvements such as PD reduction and CAL gain, but this beta-TCP does not seem to enhance the regeneration of cementum, periodontal ligament, and bone.

Cis-4-methylsphingosine is a sphingosine-1-phosphate receptor modulator

Sphingosine-1-phosphate (S1P) acts as high affinity agonist at specific G-protein-coupled receptors, S1P(1-5), that play important roles e.g. in the cardiovascular and immune systems. A S1P receptor modulating drug, FTY720 (fingolimod), has been effective in phase III clinical trials for multiple sclerosis. FTY720 is a sphingosine analogue and prodrug of FTY720-phosphate, which activates all S1P receptors except S1P(2) and disrupts lymphocyte trafficking by internalizing the S1P(1) receptor. Cis-4-methylsphingosine (cis-4M-Sph) is another synthetic sphingosine analogue that is readily taken up by cells and phosphorylated to cis-4-methylsphingosine-1-phosphate (cis-4M-S1P). Therefore, we analysed whether cis-4M-Sph interacted with S1P receptors through its metabolite cis-4M-S1P in a manner similar to FTY720. Indeed, cis-4M-Sph caused an internalization of S1P receptors, but differed from FTY720 as it acted on S1P(2) and S1P(3) and only weakly on S1P(1), while FTY720 internalized S1P(1) and S1P(3) but not S1P(2). Consequently, pre-incubation with cis-4M-Sph specifically desensitized S1P-induced [Ca(2+)](i) increases, which are mediated by S1P(2) and S1P(3), in a time- and concentration-dependent manner. This effect was not shared by sphingosine or FTY720, indicating that metabolic stability and targeting of S1P(2) receptors were important. The desensitization of S1P-induced [Ca(2+)](i) increases was dependent on the expression of SphKs, predominantly of SphK2, and thus mediated by cis-4M-S1P. In agreement, cis-4M-S1P was detected in the supernatants of cells exposed to cis-4M-Sph. It is concluded that cis-4M-Sph, through its metabolite cis-4M-S1P, acts as a S1P receptor modulator and causes S1P receptor internalization and desensitization. The data furthermore help to define requirements for sphingosine kinase substrates as S1P receptor modulating prodrugs.

Glucocorticoids protect renal mesangial cells from apoptosis by increasing cellular sphingosine-1-phosphate

Neutral ceramidase (NCDase) and sphingosine kinases (SphKs) are key enzymes regulating cellular sphingosine-1-phosphate (S1P) levels. In this study we found that stress factor-induced apoptosis of rat renal mesangial cells was significantly reduced by dexamethasone treatment. Concomitantly, dexamethasone increased cellular S1P levels, suggesting an activation of sphingolipid-metabolizing enzymes. The cell-protective effect of glucocorticoids was reversed by a SphK inhibitor, was completely absent in SphK1-deficient cells, and was associated with upregulated mRNA and protein expression of NCDase and SphK1. Additionally, in vivo experiments in mice showed that dexamethasone also upregulated SphK1 mRNA and activity, and NCDase protein expression in the kidney. Fragments (2285, 1724, and 1126 bp) of the rat NCDase promoter linked to a luciferase reporter were transfected into rat kidney fibroblasts and mesangial cells. There was enhanced NCDase promoter activity upon glucocorticoids treatment that was abolished by the glucocorticoid receptor antagonist RU-486. Single and double mutations of the two putative glucocorticoid response element sites within the promoter reduced the dexamethasone effect, suggesting that both glucocorticoid response elements are functionally active and required for induction. Our study shows that glucocorticoids exert a protective effect on stress-induced mesangial cell apoptosis in vitro and in vivo by upregulating NCDase and SphK1 expression and activity, resulting in enhanced levels of the protective lipid second messenger S1P.

Peroxisome proliferator-activated receptor {gamma} coactivator 1{alpha} (PGC-1{alpha}) promotes skeletal muscle lipid refueling in vivo by activating de novo lipogenesis and the pentose phosphate pathway

Exercise induces a pleiotropic adaptive response in skeletal muscle, largely through peroxisome proliferator-activated receptor coactivator 1 (PGC-1 ). PGC-1 enhances lipid oxidation and thereby provides energy for sustained muscle contraction. Its potential implication in promoting muscle refueling remains unresolved, however. Here, we investigated a possible role of elevated PGC-1 levels in skeletal muscle lipogenesis in vivo and the molecular mechanisms that underlie PGC-1 -mediated de novo lipogenesis. To this end, we studied transgenic mice with physiological overexpression of PGC-1 and human muscle biopsies pre- and post-exercise. We demonstrate that PGC-1 enhances lipogenesis in skeletal muscle through liver X receptor -dependent activation of the fatty acid synthase (FAS) promoter and by increasing FAS activity. Using chromatin immunoprecipitation, we establish a direct interaction between PGC-1 and the liver X receptor-responsive element in the FAS promoter. Moreover, we show for the first time that increased glucose uptake and activation of the pentose phosphate pathway provide substrates for RNA synthesis and cofactors for de novo lipogenesis. Similarly, we observed increased lipogenesis and lipid levels in human muscle biopsies that were obtained post-exercise. Our findings suggest that PGC-1 coordinates lipogenesis, intramyocellular lipid accumulation, and substrate oxidation in exercised skeletal muscle in vivo.

Nationwide survey on resource availability for implementing current sepsis guidelines in Mongolia

To assess if secondary and tertiary hospitals in Mongolia have the resources needed to implement the 2008 Surviving Sepsis Campaign (SSC) guidelines.

Effects of Food Availability on Yolk Androgen Deposition in the Black-Legged Kittiwake (Rissa tridactyla), a Seabird with Facultative Brood Reduction

In birds with facultative brood reduction, survival of the junior chick is thought to be regulated primarily by food availability. In black-legged kittiwakes (Rissa tridactyla) where parents and chicks are provided with unlimited access to supplemental food during the breeding season, brood reduction still occurs and varies interannually. Survival of the junior chick is therefore affected by factors in addition to the amount of food directly available to them. Maternally deposited yolk androgens affect competitive dynamics within a brood, and may be one of the mechanisms by which mothers mediate brood reduction in response to a suite of environmental and physiological cues. The goal of this study was to determine whether food supplementation during the pre-lay period affected patterns of yolk androgen deposition in free-living kittiwakes in two years (2003 and 2004) that varied in natural food availability. Chick survival was measured concurrently in other nests where eggs were not collected. In both years, supplemental feeding increased female investment in eggs by increasing egg mass. First-laid ("A") eggs were heavier but contained less testosterone and androstenedione than second-laid ("B") eggs across years and treatments. Yolk testosterone was higher in 2003 (the year with higher B chick survival) across treatments. The difference in yolk testosterone levels between eggs within a clutch varied among years and treatments such that it was relatively small when B chick experienced the lowest and the highest survival probabilities, and increased with intermediate B chick survival probabilities. The magnitude of testosterone asymmetry in a clutch may allow females to optimize fitness by either predisposing a brood for reduction or facilitating survival of younger chicks.

CD69 modulates sphingosine-1-phosphate-induced migration of skin dendritic cells

In this study, we have investigated the role of CD69, an early inducible leukocyte activation receptor, in murine dendritic cell (DC) differentiation, maturation, and migration. Skin DCs and DC subsets present in mouse lymphoid organs express CD69 in response to maturation stimuli. Using a contact sensitization model, we show that skin DCs migrated more efficiently to draining lymph nodes (LNs) in the absence of CD69. This was confirmed by subcutaneous transfer of CD69-/- DCs, which presented an increased migration to peripheral LNs. Two-photon microscopy analysis showed that once DCs reached the LNs, CD69 deficiency did not alter DC interstitial motility in the LNs. Chemotaxis to sphingosine-1-phosphate (S1P) was enhanced in CD69-/- DCs compared with wild-type DCs. Accordingly, we detected a higher expression of S1P receptor type-1 (S1P(1)) by CD69-/- DCs, whereas S1P(3) expression levels were similar in wild-type and CD69-/- DCs. Moreover, in vivo treatment with S1P analogs SEW2871 and FTY720 during skin sensitization reduced skin DC migration to peripheral LNs. These results suggest that CD69 regulates S1P-induced skin DC migration by modulating S1P(1) function. Together, our findings increase our knowledge on DC trafficking patterns in the skin, enabling the development of new directed therapies using DCs for antigen (Ag) delivery.

Four-year results following treatment of intrabony periodontal defects with an enamel matrix derivative alone or combined with a biphasic calcium phosphate

The aim of this study was to evaluate the 4-year clinical outcomes following regenerative surgery in intrabony defects with either EMD + BCP or EMD. Twenty-four patients with advanced chronic periodontitis, displaying one-, two-, or three-walled intrabony defect with a probing depth of at least 6 mm, were randomly treated with either EMD + BCP (test) or EMD alone (control). The following clinical parameters were evaluated at baseline, at 1 year and at 4 years after regenerative surgery: plaque index, gingival index, bleeding on probing, probing depth, gingival recession, and clinical attachment level (CAL). The primary outcome variable was CAL. No differences in any of the investigated parameters were observed at baseline between the two groups. The test group demonstrated a mean CAL change from from 10.8 ± 1.6 mm to 7.4 ± 1.6 mm (p < 0.001) and to 7.6 ± 1.7 mm (p < 0.001) at 1 and 4 years, respectively. In the control group, mean CAL changed from 10.4 ± 1.3 at baseline to 6.9 ± 1.0 mm (p < 0.001) at 1 year and 7.2 ± 1.2 mm (p < 0.001) at 4 years. At 4 years, two defects in the test group and three defects in the control group have lost 1 mm of the CAL gained at 1 year. Compared to baseline, at 4 years, a CAL gain of ≥3 mm was measured in 67% of the defects (i.e., in 8 out of 12) in the test group and in 75% of the defects (i.e., in 9 out of 12) in the control group. There were no statistically significant differences in any of the investigated parameters at 1 and at 4 years between the two groups. Within their limits, the present results indicate that: (a) the clinical improvements obtained with both treatments can be maintained over a period of 4 years, and (b) in two- and three-walled intrabony defects, the addition of BCP did not additionally improve the outcomes obtained with EMD alone. In two- and three-walled intrabony defects, the combination of EMD + BCP did not show any advantage over the use of EMD alone.

Effects of dietary supplementation with synthetic vitamin D-3 and 25-hydroxycholecalciferol on blood calcium and phosphate levels and performance in laying hens

We investigated the effects of different dietary vitamin D regimen on selected blood parameters in laying hens. Supplementation with vitamin D-3 only was compared with a combination of vitamin D-3 and its metabolite 25-hydroxy-cholecalciferol (25(OH)D-3). Blood concentrations of total calcium, phosphate and 25 (OH)D-3 were determined. Four thousand one-day-old LSL chicks were split in two treatment groups and distributed to eight pens. The control group was given a commercial animal diet containing 2800 IU synthetic vitamin D-3 in the starter feed and 2000 IU synthetic vitamin D-3 in the pullet feed. The experimental group was fed the same commercial diet in which half the synthetic vitamin D-3 content had been substituted with 25(OH)D-3 (Hy center dot D (R)). At 18 weeks of age, pullets were transferred to the layer house. At the ages of 11, 18 and 34 weeks, between 120 and 160 blood samples were collected from both the control and the experimental groups, respectively. The experimental group had higher levels of 25 (OH)D-3 than the control group at all three ages. Serum calcium levels did not differ between the treatment groups at any age. With the onset of laying, calcium levels rose significantly. Whereas blood serum concentration at 18 weeks was 3 mmol/L in both treatment groups, it increased to 8.32 mmol/L in the control group and to 8.66 mmol/L in the experimental group at week 34. At weeks 11 and 34, phosphate was significantly lower in the experimental group. In conclusion, HyD (R) significantly affected serum phosphate and 25(OH)D-3 levels. No effects of (25(OH)D-3 supplementation on performance, shell quality and fractures of keelbones were found.

Phase I trial of combretastatin A4 phosphate (CA4P) in combination with bevacizumab in patients with advanced cancer

The vascular disrupting agent (VDA) combretastatin A4 phosphate (CA4P) induces significant tumor necrosis as a single agent. Preclinical models have shown that the addition of an anti-VEGF antibody to a VDA attenuates the revascularization of the surviving tumor rim and thus significantly increases antitumor activity.

Impact of the availability of an influenza virus rapid antigen test on diagnostic decision making in a pediatric emergency department

OBJECTIVES: Fever is one of the most commonly seen symptoms in the pediatric emergency department. The objective of this study was to observe how the rapid testing for influenza virus impacts on the management of children with fever. METHODS: We performed a review of our pediatric emergency department records during the 2008/2009 annual influenza season. The BinaxNow Influenza A+B test was performed on patients with the following criteria: age 1.0 to 16.0 years, fever greater than 38.5 °C, fever of less than 96 hours' duration after the onset of clinical illness, clinical signs compatible with acute influenza, and nontoxic appearance. Additional laboratory tests were performed at the treating physician's discretion. RESULTS: The influenza rapid antigen test was performed in 192 children. One hundred nine (57%) were influenza positive, with the largest fraction (101 patients) positive for influenza A. The age distribution did not differ between children with negative and positive test results (mean, 5.3 vs. 5.1 years, not statistically significant). A larger number of diagnostic tests were performed in the group of influenza-negative patients. Twice as many complete blood counts, C-reactive protein determinations, lumbar punctures, and urinalyses were ordered in the latter group. CONCLUSIONS: Rapid diagnosis of influenza in the pediatric emergency department affects the management of febrile children as the confirmation of influenza virus infection decreases additional diagnostic tests ordered.