Decomposition of the B2-type matrix

The microstructural stability of aluminide diffusion coatings, prepared by means of a two-stage pack-aluminization treatment on single-crystal nickel-base superalloy substrates, is considered in this article. Edge-on specimens of coated superalloy are studied using transmission electron microscopy (TEM). The effects of coating thickness and post-coating heat treatment (duration, temperature, and atmosphere) on coating microstructure are examined. The article discusses the partial transformation of the matrix of the coating, from a B2-type phase (nominally NiAl) to a L12 phase (nominally Ni3(Al, Ti)), during exposure at temperatures of 850 °C and 950 °C in air and in vacuum for up to 138 hours. Three possible processes that can account for decom- position of the coating matrix are investigated, namely, interdiffusion between the coating and the substrate, oxidation of the coating surface, and aging of the coating. Of these processes, aging of the coating is shown to be the predominant factor in the coating transformation under the conditions considered. © 1992 The Minerals, Metals and Materials Society, and ASM International.

Serum α-tocopherol has a nonlinear inverse association with periodontitis among US adults

Background: Previous experimental models suggest that vitamin E may ameliorate periodontitis. However, epidemiologic studies show inconsistent evidence in supporting this plausible association. Objective: We aimed to investigate the association between serum α-tocopherol (αT) and γ-tocopherol (γT) and periodontitis in a large cross-sectional US population. Methods: This study included 4708 participants in the 1999–2001 NHANES. Serum tocopherols were measured by HPLC and values were adjusted by total cholesterol (TC). Periodontal status was assessed by mean clinical attachment loss (CAL) and probing pocket depth (PPD). Total periodontitis (TPD) was defined as the sum of mild, moderate, and severe periodontitis. All measurements were performed by NHANES. Results: Means ± SDs of serum αT:TC ratio from low to high quartiles were 4.0 ± 0.4, 4.8 ± 0.2, 5.7 ± 0.4, and 9.1 ± 2.7 μmol/mmol. In multivariate regression models, αT:TC quartiles were inversely associated with mean CAL (P-trend = 0.06), mean PPD (P-trend < 0.001), and TPD (P-trend < 0.001) overall. Adjusted mean differences (95% CIs) between the first and fourth quartile of αT:TC were 0.12 mm (0.03, 0.20; P-difference = 0.005) for mean CAL and 0.12 mm (0.06, 0.17; P < 0.001) for mean PPD, whereas corresponding OR for TPD was 1.65 (95% CI: 1.26, 2.16; P-difference = 0.001). In a dose-response analysis, a clear inverse association between αT:TC and mean CAL, mean PPD, and TPD was observed among participants with relatively low αT:TC. No differences were seen in participants with higher αT:TC ratios. Participants with γT:TC ratio in the interquartile range showed a significantly lower mean PPD than those in the highest quartile. Conclusions: A nonlinear inverse association was observed between serum αT and severity of periodontitis, which was restricted to adults with normal but relatively low αT status. These findings warrant further confirmation in longitudinal or intervention settings.

Serum-free process development:improving the yield and consistency of human mesenchymal stromal cell production

Background aims: The cost-effective production of human mesenchymal stromal cells (hMSCs) for off-the-shelf and patient specific therapies will require an increasing focus on improving product yield and driving manufacturing consistency. Methods: Bone marrow-derived hMSCs (BM-hMSCs) from two donors were expanded for 36 days in monolayer with medium supplemented with either fetal bovine serum (FBS) or PRIME-XV serum-free medium (SFM). Cells were assessed throughout culture for proliferation, mean cell diameter, colony-forming potential, osteogenic potential, gene expression and metabolites. Results: Expansion of BM-hMSCs in PRIME-XV SFM resulted in a significantly higher growth rate (P < 0.001) and increased consistency between donors compared with FBS-based culture. FBS-based culture showed an inter-batch production range of 0.9 and 5 days per dose compared with 0.5 and 0.6 days in SFM for each BM-hMSC donor line. The consistency between donors was also improved by the use of PRIME-XV SFM, with a production range of 0.9 days compared with 19.4 days in FBS-based culture. Mean cell diameter has also been demonstrated as a process metric for BM-hMSC growth rate and senescence through a correlation (R² = 0.8705) across all conditions. PRIME-XV SFM has also shown increased consistency in BM-hMSC characteristics such as per cell metabolite utilization, in vitro colony-forming potential and osteogenic potential despite the higher number of population doublings. Conclusions: We have increased the yield and consistency of BM-hMSC expansion between donors, demonstrating a level of control over the product, which has the potential to increase the cost-effectiveness and reduce the risk in these manufacturing processes.

Serum α-tocopherol has a nonlinear inverse association with periodontitis among US adults

Previous experimental models suggest that vitamin E may ameliorate periodontitis. However, epidemiologic studies show inconsistent evidence in supporting this plausible association. We aimed to investigate the association between serum α-tocopherol (αT) and γ-tocopherol (γT) and periodontitis in a large cross-sectional US population. This study included 4708 participants in the 1999–2001 NHANES. Serum tocopherols were measured by HPLC and values were adjusted by total cholesterol (TC). Periodontal status was assessed by mean clinical attachment loss (CAL) and probing pocket depth (PPD). Total periodontitis (TPD) was defined as the sum of mild, moderate, and severe periodontitis. All measurements were performed by NHANES. Means ± SDs of serum αT:TC ratio from low to high quartiles were 4.0 ± 0.4, 4.8 ± 0.2, 5.7 ± 0.4, and 9.1 ± 2.7 μmol/mmol. In multivariate regression models, αT:TC quartiles were inversely associated with mean CAL (P-trend = 0.06), mean PPD (P-trend < 0.001), and TPD (P-trend < 0.001) overall. Adjusted mean differences (95% CIs) between the first and fourth quartile of αT:TC were 0.12 mm (0.03, 0.20; P-difference = 0.005) for mean CAL and 0.12 mm (0.06, 0.17; P < 0.001) for mean PPD, whereas corresponding OR for TPD was 1.65 (95% CI: 1.26, 2.16; P-difference = 0.001). In a dose-response analysis, a clear inverse association between αT:TC and mean CAL, mean PPD, and TPD was observed among participants with relatively low αT:TC. No differences were seen in participants with higher αT:TC ratios. Participants with γT:TC ratio in the interquartile range showed a significantly lower mean PPD than those in the highest quartile. A nonlinear inverse association was observed between serum αT and severity of periodontitis, which was restricted to adults with normal but relatively low αT status. These findings warrant further confirmation in longitudinal or intervention settings.

A posztmodern marketing elvei és gyakorlata a turizmus piacán - Mátrix és turizmus (Theories and practice of the post-modern marketing on tourism market – Matrix and tourism)

Jelen tanulmány a posztmodern kor fogyasztási tendenciáit és a posztmodern marketing sajátos fejlődését elemzi, elsősorban a turizmus példáján. A szerzők a hazai és a nemzetközi szakirodalom, illetve saját kutatásaik és megfigyeléseik alapján ütköztetik az ismert és elfogadott elveket, elméleteket a gyakorlattal, és felhívják a figyelmet a marketingtevékenység alkalmazkodásának hazai problémáira. A Vezetéstudomány című folyóirat 2008/9. számában rendkívül érdekes tanulmány jelent meg Mitev Ariel Zoltán és Horváth Dóra tollából „A posztmodern marketing rózsaszirmai” címmel. A tanulmány előremutató, érdekfeszítő és minden tekintetben konstruktív, újszerű. Jelen tanulmány szerzőire is nagy hatást gyakorolt a cikk, nagyrészt felsorolt erényei miatt, de egyes esetekben kiegészítést kívánva. Mindenképpen inspirálta a továbblépést, az újabb adalékok megfogalmazását, amire ezúton e tanulmány szerzői kísérletet tettek. A cikk egyben szerves gondolati folytatása a szerzőpáros korábbi közös publikációinak, elsősorban a Marketing & Menedzsment folyóiratban megjelent cikknek. _______ In this article the author will analyze consumption tendencies of post-modern age, mainly using tourism marketing examples. Their analysis has been based on results of their own researches and researches published in Hungarian and international marketing literature. In this article they try to confront different theories of post-modern marketing and they will analyze problems of applicability of these theories in Hungarian marketing problem solving. An extremely interesting article was published in Vezetéstudomány (2008/9), written by Zoltán Mitev Ariel and Dóra Horváth, and this article, by its interesting, innovative and constructive aspect has largely influenced authors of present article to continue the path proposed in the abovementioned article. The article, in the same time, is an organic continuation of the earlier common publications of the authors, e.g. the recent article in Marketing & Menedzsment journal.

Measurement of carotenoid levels in human serum and a catalog of the lutein conformation populations from semi-empirical calculations

Lutein is a principal constituent of the human macular pigment. This study is composed of two projects. The first studies the conformational geometries of lutein and its potential adaptability in biological systems. The second is a study of the response of human subjects to lutein supplements. Using semi-empirical parametric method 3 (PM3) and density functional theory with the B3LYP/6-31G* basis set, the relative energies of s- cis conformers of lutein were determined. All 512 s-cis conformers were calculated with PM3. A smaller, representative group was also studied using density functional theory. PM3 results were correlated systematically to B3LYP values and this enables the results to be calibrated. The relative energies of the conformers range from 1-30 kcal/mole, and many are dynamically accessible at normal temperatures. Four commercial formulations containing lutein were studied. The serum and macular pigment (MP) responses of human subjects to these lutein supplements with doses of 9 or 20 mg/day were measured, relative to a placebo, over a six month period. In each instance, lutein levels in serum increased and correlated with MP increases. The results demonstrate that responses are significantly dependent upon formulation and that components other than lutein have an important influence serum response.

The relationship among serum levels of manganese superoxide dismutase and mitochondrial DNA 8-hydroxy-2'- deoxyguanosine, and dietary antioxidants intake in type 2 diabetes

Oxidative stress plays a key role in the development of Type 2 Diabetes (T2D). This cross-sectional study examined the relationship among serum levels of manganese superoxide dismutase (MnSOD), 8-hydroxy-2’-deoxyguanosine (8OHdG), dietary antioxidant intakes and glycemic control in African Americans (n=209) and Haitian Americans (n=234) with and without T2D. ^ African Americans had higher BMI (32.8 vs. 29.3 kg/m2), higher energy intake (2148 vs. 1770 kcal), and were more educated as compared to Haitian Americans; all variables were significant at p < .001. Serum levels of 8OHdG and MnSOD for African Americans (1691.0 ± 225.1 pg/ml, 2538.0 ± 1091.8 pg/ml; respectively) were significantly higher than for Haitian Americans (1626.2 ± 222.9, 2015.8 ± 656.3 pg/ml; respectively). 8OHdG was negatively correlated with MnSOD ( r = -.167, p < .001) in T2D. Having T2D was negatively correlated with MnSOD (r = -.337; p < .01) and positively correlated with 8OHdG (r = .500; p < .01). African Americans and Haitian Americans with T2D had fasting plasma glucose (FPG) levels of 143.0 ± 61.0 mg/dl and 157.6 ± 65.5 mg/dl, and A1C of 7.5 ± 1.8 % and 8.4 ± 2.4 %, respectively. African Americans and Haitian Americans without T2D had FPG levels of 95.8 ± 13.2 mg/dl and 98.7 ± 16.9 mg/dl, and A1C of 5.9 ± 0.4% and 6.0 ± 0.5%, respectively. Dietary intakes of vitamin C and vitamin D were negatively correlated with FPG (r = -.21; r = -.19, p < .05) respectively. Carotenoids negatively correlated with A1C (r = -.19, p < .05). Lower levels of MnSOD were associated with lower levels of zinc, r = .10, p < .05, and higher levels of carotenoids r = -.10, p < .05. Higher levels of 8OHdG were associated with lower levels of Vitamin D, r = -.14, p < .01, and carotenoids, r = -.09, p < .05. ^ The results demonstrate greater oxidative mtDNA damage in persons with T2D compared to those without T2D and in African Americans compared with Haitian Americans. The inverse relationship between dietary intake of antioxidants and oxidative stress implies a potential to reduce oxidative stress with diet. ^

Bovine serum albumin as the dominant form of dietary protein reduces subcutaneous fat mass, plasma leptin and plasma corticosterone in high fat-fed C57/BL6J mice

Acknowledgements The authors thank Harriett Schellekens from the University College Cork and Paula O’Connor from Teagasc Moorepark Food Research Centre for their assistance in procuring laboratory space and equipment. The present study was funded by Teagasc. B. L. M. was funded by the Walsh Fellowship Program. J. R. S. was supported by a 1000-talents professorship from the Chinese government. The funding bodies had no input on the design of the study or in the interpretation of the data.

Delivery and Scavenging of Nucleic Acids by Polycationic Polymers

Electrostatic interaction is a strong force that attracts positively and negatively charged molecules to each other. Such an interaction is formed between positively charged polycationic polymers and negatively charged nucleic acids. In this dissertation, the electrostatic attraction between polycationic polymers and nucleic acids is exploited for applications in oral gene delivery and nucleic acid scavenging. An enhanced nanoparticle for oral gene delivery of a human Factor IX (hFIX) plasmid is developed using the polycationic polysaccharide, chitosan (Ch), in combination with protamine sulfate (PS) to treat hemophilia B. For nucleic acid scavenging purposes, the development of an effective nucleic acid scavenging nanofiber platform is described for dampening hyper-inflammation and reducing the formation of biofilms.

Non-viral gene therapy may be an attractive alternative to chronic protein replacement therapy. Orally administered non-viral gene vectors have been investigated for more than one decade with little progress made beyond the initial studies. Oral administration has many benefits over intravenous injection including patient compliance and overall cost; however, effective oral gene delivery systems remain elusive. To date, only chitosan carriers have demonstrated successful oral gene delivery due to chitosan’s stability via the oral route. In this study, we increase the transfection efficiency of the chitosan gene carrier by adding protamine sulfate to the nanoparticle formulation. The addition of protamine sulfate to the chitosan nanoparticles results in up to 42x higher in vitro transfection efficiency than chitosan nanoparticles without protamine sulfate. Therapeutic levels of hFIX protein are detected after oral delivery of Ch/PS/phFIX nanoparticles in 5/12 mice in vivo, ranging from 3 -132 ng/mL, as compared to levels below 4 ng/mL in 1/12 mice given Ch/phFIX nanoparticles. These results indicate the protamine sulfate enhances the transfection efficiency of chitosan and should be considered as an effective ternary component for applications in oral gene delivery.

Dying cells release nucleic acids (NA) and NA-complexes that activate the inflammatory pathways of immune cells. Sustained activation of these pathways contributes to chronic inflammation related to autoimmune diseases including systemic lupus erythematosus, rheumatoid arthritis, and inflammatory bowel disease. Studies have shown that certain soluble, cationic polymers can scavenge extracellular nucleic acids and inhibit RNA-and DNA-mediated activation of Toll-like receptors (TLRs) and inflammation. In this study, the cationic polymers are incorporated onto insoluble nanofibers, enabling local scavenging of negatively charged pro-inflammatory species such as damage-associated molecular pattern (DAMP) molecules in the extracellular space, reducing cytotoxicity related to unwanted internalization of soluble cationic polymers. In vitro data show that electrospun nanofibers grafted with cationic polymers, termed nucleic acid scavenging nanofibers (NASFs), can scavenge nucleic acid-based agonists of TLR 3 and TLR 9 directly from serum and prevent the production of NF-ĸB, an immune system activating transcription factor while also demonstrating low cytotoxicity. NASFs formed from poly (styrene-alt-maleic anhydride) conjugated with 1.8 kDa branched polyethylenimine (bPEI) resulted in randomly aligned fibers with diameters of 486±9 nm. NASFs effectively eliminate the immune stimulating response of NA based agonists CpG (TLR 9) and poly (I:C) (TLR 3) while not affecting the activation caused by the non-nucleic acid TLR agonist pam3CSK4. Results in a more biologically relevant context of doxorubicin-induced cell death in RAW cells demonstrates that NASFs block ~25-40% of NF-ĸβ response in Ramos-Blue cells treated with RAW extracellular debris, ie DAMPs, following doxorubicin treatment. Together, these data demonstrate that the formation of cationic NASFs by a simple, replicable, modular technique is effective and that such NASFs are capable of modulating localized inflammatory responses.

An understandable way to clinically apply the NASF is as a wound bandage. Chronic wounds are a serious clinical problem that is attributed to an extended period of inflammation as well as the presence of biofilms. An NASF bandage can potentially have two benefits in the treatment of chronic wounds by reducing the inflammation and preventing biofilm formation. NASF can prevent biofilm formation by reducing the NA present in the wound bed, therefore removing large components of what the bacteria use to develop their biofilm matrix, the extracellular polymeric substance, without which the biofilm cannot develop. The NASF described above is used to show the effect of the nucleic acid scavenging technology on in vitro and in vivo biofilm formation of P. aeruginosa, S. aureus, and S. epidermidis biofilms. The in vitro studies demonstrated that the NASFs were able to significantly reduce the biofilm formation in all three bacterial strains. In vivo studies of the NASF on mouse wounds infected with biofilm show that the NASF retain their functionality and are able to scavenge DNA, RNA, and protein from the wound bed. The NASF remove DNA that are maintaining the inflammatory state of the open wound and contributing to the extracellular polymeric substance (EPS), such as mtDNA, and also removing proteins that are required for bacteria/biofilm formation and maintenance such as chaperonin, ribosomal proteins, succinyl CoA-ligase, and polymerases. However, the NASF are not successful at decreasing the wound healing time because their repeated application and removal disrupts the wound bed and removes proteins required for wound healing such as fibronectin, vibronectin, keratin, and plasminogen. Further optimization of NASF treatment duration and potential combination treatments should be tested to reduce the unwanted side effects of increased wound healing time.

Seasonal changes in Vitamin D-effective UVB availability in Europe and associations with population serum 25-Hydroxyvitamin D

Low vitamin D status is common in Europe. The major source of vitamin D in humans is ultraviolet B (UVB)-induced dermal synthesis of cholecalciferol, whereas food sources are believed to play a lesser role. Our objectives were to assess UVB availability (Jm−2) across several European locations ranging from 35° N to 69° N, and compare these UVB data with representative population serum 25-hydroxyvitamin D (25(OH)D) data from Ireland (51–54° N), Iceland (64° N) and Norway (69° N), as exemplars. Vitamin D-effective UVB availability was modelled for nine European countries/regions using a validated UV irradiance model. Standardized serum 25(OH)D data was accessed from the EC-funded ODIN project. The results showed that UVB availability decreased with increasing latitude (from 35° N to 69° N), while all locations exhibited significant seasonal variation in UVB. The UVB data suggested that the duration of vitamin D winters ranged from none (at 35° N) to eight months (at 69° N). The large seasonal fluctuations in serum 25(OH)D in Irish adults was much dampened in Norwegian and Icelandic adults, despite considerably lower UVB availability at these northern latitudes but with much higher vitamin D intakes. In conclusion, increasing the vitamin D intake can ameliorate the impact of low UVB availability on serum 25(OH)D status in Europe.

The relationship among serum levels of manganese superoxide dismutase and mtDNA 8-hydroxy-2'-deoxyguanosine, and dietary antioxidants intake in Type 2 Diabetes

Oxidative stress plays a key role in the development of Type 2 Diabetes (T2D). This cross-sectional study examined the relationship among serum levels of manganese superoxide dismutase (MnSOD), 8-hydroxy-2’-deoxyguanosine (8OHdG), dietary antioxidant intakes and glycemic control in African Americans (n=209) and Haitian Americans (n=234) with and without T2D. African Americans had higher BMI (32.8 vs. 29.3 kg/m2), higher energy intake (2148 vs. 1770 kcal), and were more educated as compared to Haitian Americans; all variables were significant at p < .001. Serum levels of 8OHdG and MnSOD for African Americans (1691.0 ± 225.1 pg/ml, 2538.0 ± 1091.8 pg/ml; respectively) were significantly higher than for Haitian Americans (1626.2 ± 222.9, 2015.8 ± 656.3 pg/ml; respectively). 8OHdG was negatively correlated with MnSOD (r = -.167, p < .001) in T2D. Having T2D was negatively correlated with MnSOD (r = -.337; p < .01) and positively correlated with 8OHdG (r = .500; p < .01). African Americans and Haitian Americans with T2D had fasting plasma glucose (FPG) levels of 143.0 ± 61.0 mg/dl and 157.6 ± 65.5 mg/dl, and A1C of 7.5 ± 1.8 % and 8.4 ± 2.4 %, respectively. African Americans and Haitian Americans without T2D had FPG levels of 95.8 ± 13.2 mg/dl and 98.7 ± 16.9 mg/dl, and A1C of 5.9 ± 0.4% and 6.0 ± 0.5%, respectively. Dietary intakes of vitamin C and vitamin D were negatively correlated with FPG (r = -.21; r = -.19, p < .05) respectively. Carotenoids negatively correlated with A1C (r = -.19, p < .05). Lower levels of MnSOD were associated with lower levels of zinc, r = .10, p < .05, and higher levels of carotenoids r = -.10, p < .05. Higher levels of 8OHdG were associated with lower levels of Vitamin D, r = -.14, p < .01, and carotenoids, r = -.09, p < .05. The results demonstrate greater oxidative mtDNA damage in persons with T2D compared to those without T2D and in African Americans compared with Haitian Americans. The inverse relationship between dietary intake of antioxidants and oxidative stress implies a potential to reduce oxidative stress with diet. African Americans were significantly younger (53.3 vs. 55.6 years), had higher BMI (32.8 vs. 29.3 kg/m2), higher energy intake (2148 vs. 1770 kcal), and were more educated as compared to Haitian Americans; all variables were significant at p < .001. Serum levels of 8OHdG and MnSOD for African Americans (1691.0 ± 225.1 pg/ml, 2538.0 ± 1091.8 pg/ml; respectively) were significantly higher than for Haitian Americans (1626.2 ± 222.9, 2015.8 ± 656.3 pg/ml; respectively). 8OHdG was negatively correlated with MnSOD (r = -.167, p < .001) in T2D. Having T2D was negatively correlated with MnSOD (r = -.337; p < .01) and positively correlated with 8OHdG (r = .500; p < .01). African Americans and Haitian Americans with T2D had fasting plasma glucose (FPG) levels of 143.0 ± 61.0 mg/dl and 157.6 ± 65.5 mg/dl, and A1C of 7.5 ± 1.8 % and 8.4 ± 2.4 %, respectively. African Americans and Haitian Americans without T2D had FPG levels of 95.8 ± 13.2 mg/dl and 98.7 ± 16.9 mg/dl, and A1C of 5.9 ± 0.4% and 6.0 ± 0.5%, respectively. Dietary intakes of vitamin C and vitamin D were negatively correlated with FPG (r = -.21; r = -.19, p < .05) respectively. Carotenoids negatively correlated with A1C (r = -.19, p < .05). Lower levels of MnSOD were associated with lower levels of zinc, r = .10, p < .05, and higher levels of carotenoids r = -.10, p < .05. Higher levels of 8OHdG were associated with lower levels of Vitamin D, r = -.14, p < .01, and carotenoids, r = -.09, p < .05. The results demonstrate greater oxidative mtDNA damage in persons with T2D compared to those without T2D and in African Americans compared with Haitian Americans. The inverse relationship between dietary intake of antioxidants and oxidative stress implies a potential to reduce oxidative stress with diet.

Serum Amyloid P-Component Prevents Cardiac Remodeling in Hypertensive Heart Disease

The potential for serum amyloid P-component (SAP) to prevent cardiac remodeling and identify worsening diastolic dysfunction (DD) was investigated. The anti-fibrotic potential of SAP was tested in an animal model of hypertensive heart disease (spontaneously hypertensive rats treated with SAP [SHR - SAP] × 12 weeks). Biomarker analysis included a prospective study of 60 patients with asymptomatic progressive DD. Compared with vehicle-treated Wistar-Kyoto rats (WKY-V), the vehicle-treated SHRs (SHR-V) exhibited significant increases in left ventricular mass, perivascular collagen, cardiomyocyte size, and macrophage infiltration. SAP administration was associated with significantly lower left ventricular mass (p < 0.01), perivascular collagen (p < 0.01), and cardiomyocyte size (p < 0.01). Macrophage infiltration was significantly attenuated in the SHR-SAP group. Biomarker analysis showed significant decreases in SAP concentration over time in patients with progressive DD (p < 0.05). Our results indicate that SAP prevents cardiac remodeling by inhibiting recruitment of pro-fibrotic macrophages and that depleted SAP levels identify patients with advancing DD suggesting a role for SAP therapy.

Long-term statin therapy in patients with systolic heart failure and normal cholesterol:effects on elevated serum markers of collagen turnover, inflammation, and B-type natriuretic peptide

BACKGROUND: The role of statin therapy in heart failure (HF) is unclear. The amino-terminal propeptide of procollagen type III (PIIINP) predicts outcome in HF, and yet there are conflicting reports of statin therapy effects on PIIINP.

OBJECTIVES: This study determined whether there was an increase in serum markers of inflammation, fibrosis (including PIIINP), and B-type natriuretic peptide (BNP) in patients with systolic HF and normal total cholesterol and determined the effects of long-term treatment with atorvastatin on these markers.

METHODS: Fifty-six white patients with systolic HF and normal cholesterol levels (age 72 [13] years; 68% male; body mass index 27.0 [7.3] kg/m(2); ejection fraction 35 [13]%; 46% with history of smoking) were randomly allocated to atorvastatin treatment for 6 months, titrated to 40 mg/d (A group) or not (C group). Age- and/or sex-matched subjects without HF (N group) were also recruited. Biomarkers were measured at baseline (all groups) and 6 months (A and C groups).

RESULTS: Serum markers of collagen turnover, inflammation, and BNP were significantly elevated in HF patients compared with normal participants (all P < 0.05). There were correlations between these markers in HF patients but not in normal subjects. Atorvastatin treatment for 6 months caused a significant reduction in the following biomarkers compared with baseline: BNP, from median (interquartile range) 268 (190-441) pg/mL to 185 (144-344) pg/mL; high-sensitivity C-reactive protein (hs-CRP), from 5.26 (1.95 -9.29) mg/L to 3.70 (2.34-6.81) mg/L; and PIIINP, from 4.65 (1.86) to 4.09 (1.25) pg/mL (all P < 0.05 baseline vs 6 months). Between-group differences were significant for PIIINP only (P = 0.027). There was a positive interaction between atorvastatin effects and baseline hs-CRP and PIIINP (P < 0.01).

CONCLUSIONS: Long-term statin therapy reduced PIIINP in this small, selected HF population with elevated baseline levels. Further evaluation of statin therapy in the management of HF patients with elevated PIIINP is warranted.

Epigenetics within the matrix:a neo-regulator of fibrotic disease

Fibrosis of any tissue is characterized by excessive extracellular matrix accumulation that ultimately destroys tissue architecture and eventually abolishes normal organ function. Although much research has focused on the mechanisms underlying disease pathogenesis, there are still no effective antifibrotic therapies that can reverse, stop or delay the formation of scar tissue in most fibrotic organs. As fibrosis can be described as an aberrant wound healing response, a recent hypothesis suggests that the cells involved in this process gain an altered heritable phenotype that promotes excessive fibrotic tissue accumulation. This article will review the most recent observations in a newly emerging field that links epigenetic modifications to the pathogenesis of fibrosis. Specifically, the roles of DNA methylation and histone modifications in fibrotic disease will be discussed.

An Ex Vivo Model for Studying Hepatic Schistosomiasis and the Effect of Released Protein from Dying Eggs

BACKGROUND: We report the use of an ex vivo precision cut liver slice (PCLS) mouse model for studying hepatic schistosomiasis. In this system, liver tissue is unfixed, unfrozen, and alive for maintenance in culture and subsequent molecular analysis.

METHODS AND FINDINGS: Using thick naive mouse liver tissue and sterile culture conditions, the addition of soluble egg antigen (SEA) derived from Schistosoma japonicum eggs, followed 4, 24 and 48 hrs time points. Tissue was collected for transcriptional analysis and supernatants collected to quantitate liver enzymes, cytokines and chemokines. No significant hepatotoxicity was demonstrated by supernatant liver enzymes due to the presence of SEA. A proinflammatory response was observed both at the transcriptional level and at the protein level by cytokine and chemokine bead assay. Key genes observed elevated transcription in response to the addition of SEA included: IL1-α and IL1-β, IL6, all associated with inflammation. The recruitment of antigen presenting cells was reflected in increases in transcription of CD40, CCL4 and CSF1. Indications of tissue remodeling were seen in elevated gene expression of various Matrix MetalloProteinases (MMP3, 9, 10, 13) and delayed increases in TIMP1. Collagen deposition was significantly reduced in the presence of SEA as shown in COL1A1 expression by qPCR after 24 hrs culture. Cytokine and chemokine analysis of the culture supernatants confirmed the elevation of proteins including IL6, CCL3, CCL4 and CXCL5.

CONCLUSIONS: This ex vivo model system for the synchronised delivery of parasite antigen to liver tissue provides an insight into the early phase of hepatic schistosomiasis, corresponding with the release of soluble proteins from dying schistosome eggs.