Risk factors for linezolid-induced thrombocytopenia in patients without haemato-oncologic diseases.

This study aimed to describe the occurrence and to evaluate the predictive factors of thrombocytopenia caused by parenteral linezolid in hospitalised patients without haemato-oncologic diseases. Using electronic medical records, a retrospective safety evaluation was performed among all hospitalised adult patients who received parenteral linezolid therapy between January 2005 and June 2016. Of all identified 264 patients with an average age of 63.4 (SD 15.8) years, thrombocytopenia occurred at a rate of 29.2% after an average of 11.2 (SD 7.4) days of the initiation of linezolid therapy. Significant predictive factors for thrombocytopenia included the duration of linezolid therapy longer than or equal to 7 days (adjusted odds ratios [ORs] 7.25, 19.51 and 28.80; 95% confidence intervals [CIs] 1.92-27.38, 4.76-79.95 and 6.48-127.92 for 7-13 days, 14-20 days and ≥21 days, respectively; P < 0.01 for all values), baseline platelet count <150 × 103 /mm3 (adjusted OR, 5.08; 95% CI, 2.06-12.55; P < 0.001), creatinine clearance <30 mL/min (adjusted OR, 4.19; 95% CI, 1.59-11.06; P = 0.004) and concurrent low-dose aspirin therapy (adjusted OR, 2.99; 95% CI, 1.26-7.08; P = 0.013). Baseline platelet count less than 150 × 103 /mm3 was an independent predictor of early-onset (≤6 days) thrombocytopenia (adjusted OR, 5.07; 95% CI, 1.46-17.58; P = 0.011). Closer monitoring of platelet count is required in patients who receive parenteral linezolid therapy for 7 days or more, and have low baseline platelet counts or impaired renal function.

MPC1 is essential for PGC-1α-induced mitochondrial respiration and biogenesis.

Mitochondrial pyruvate carrier (MPC), which is essential for mitochondrial pyruvate usage, mediates the transport of cytosolic pyruvate into mitochondria. Low MPC expression is associated with various cancers, and functionally associated with glycolytic metabolism and stemness. However, the mechanism by which MPC expression is regulated is largely unknown. In this study, we showed that MPC1 is down-regulated in human renal cell carcinoma (RCC) due to strong suppression of peroxisome proliferator-activated receptor-gamma co-activator (PGC)-1 alpha (PGC-1α). We also demonstrated that overexpression of PGC-1α stimulates MPC1 transcription, while depletion of PGC-1α by siRNA suppresses MPC expression. We found that PGC-1α interacts with estrogen-related receptor-alpha (ERR-α) and recruits it to the ERR-α response element motif located in the proximal MPC1 promoter, resulting in efficient activation of MPC1 expression. Furthermore, the MPC inhibitor, UK5099, blocked PGC-1α-induced pyruvate-dependent mitochondrial oxygen consumption. Taken together, our results suggest that MPC1 is a novel target gene of PGC-1α. In addition, low expression of PGC-1α in human RCC might contribute to the reduced expression of MPC, resulting in impaired mitochondrial respiratory capacity in RCC by limiting the transport of pyruvate into the mitochondrial matrix.

Green tea extracts for the prevention of metachronous colorectal polyps among patients who underwent endoscopic removal of colorectal adenomas: A randomized clinical trial.

OBJECTIVES: To determine the preventive effect of green tea extract (GTE) supplements on metachronous colorectal adenoma and cancer in the Korean population. MATERIALS AND METHODS: One hundred seventy-six subjects (88 per each group) who had undergone complete removal of colorectal adenomas by endoscopic polypectomy were enrolled. They were randomized into 2 groups: supplementation group (0.9 g GTE per day for 12 months) or control group without GTE supplementation. The 72-h recall method was used to collect data on food items consumed by participants at baseline and the 1-year follow-up during the past 48 h. Follow-up colonoscopy was conducted 12 months later in 143 patients (71 in control group and 72 in the GTE group). RESULTS: Of the 143 patients completed in the study, the incidences of metachronous adenomas at the end-point colonoscopy were 42.3% (30 of 71) in control group and 23.6% (17 of 72) in GTE group (relative risk [RR], 0.56; 95% confidence interval [CI], 0.34-0.92). The number of relapsed adenoma was also decreased in the GTE group than in the control group (0.7 ± 1.1 vs. 0.3 ± 0.6, p = 0.010). However, there were no significant differences between the 2 groups in terms of body mass index, dietary intakes, serum lipid profiles, fasting serum glucose, and serum C-reactive protein levels (all p > 0.05). CONCLUSION: This study of GTE supplement suggests a favorable outcome for the chemoprevention of metachronous colorectal adenomas in Korean patients (ClinicalTrials.gov number, NCT02321969).

Magnesium phosphate ceramics incorporating a novel indene compound promote osteoblast differentiation in vitro and bone regeneration in vivo.

Incorporating bioactive molecules into synthetic ceramic scaffolds is challenging. In this study, to enhance bone regeneration, a magnesium phosphate (MgP) ceramic scaffold was incorporated with a novel indene compound, KR-34893. KR-34893 induced the deposition of minerals and expression of osteoblast marker genes in primary human bone marrow mesenchymal stem cells (BMSCs) and a mouse osteoblastic MC3T3-E1 cell line. Analysis of the mode of action showed that KR-34893 induced the phosphorylation of MAPK/extracellular signal-regulated kinase and extracellular signal-regulated kinase, and subsequently the expression of bone morphogenetic protein 7, accompanied by SMAD1/5/8 phosphorylation. Accordingly, KR-34893 was incorporated into an MgP scaffold prepared by 3D printing at room temperature, followed by cement reaction. KR-34893-incorporated MgP (KR-MgP) induced the expression of osteoblast differentiation marker genes in vitro. In a rat calvaria defect model, KR-MgP scaffolds enhanced bone regeneration and increased bone volume compared with MgP scaffolds, as assessed by micro-computed tomography and histological analyses. In conclusion, we developed a method for producing osteoinductive MgP scaffolds incorporating a bioactive organic compound, without high temperature sintering. The KR-MgP scaffolds enhanced osteoblast activation in vitro and bone regeneration in vivo.

Proximity of the mandibular molar root apex from the buccal bone surface: a cone-beam computed tomographic study.

OBJECTIVES: The purpose of this study was to evaluate the proximity of the mandibular molar apex to the buccal bone surface in order to provide anatomic information for apical surgery. MATERIALS AND METHODS: Cone-beam computed tomography (CBCT) images of 127 mandibular first molars and 153 mandibular second molars were analyzed from 160 patients' records. The distance was measured from the buccal bone surface to the root apex and the apical 3.0 mm on the cross-sectional view of CBCT. RESULTS: The second molar apex and apical 3 mm were located significantly deeper relative to the buccal bone surface compared with the first molar (p < 0.01). For the mandibular second molars, the distance from the buccal bone surface to the root apex was significantly shorter in patients over 70 years of age (p < 0.05). Furthermore, this distance was significantly shorter when the first molar was missing compared to nonmissing cases (p < 0.05). For the mandibular first molars, the distance to the distal root apex of one distal-rooted tooth was significantly greater than the distance to the disto-buccal root apex (p < 0.01). In mandibular second molar, the distance to the apex of C-shaped roots was significantly greater than the distance to the mesial root apex of non-C-shaped roots (p < 0.01). CONCLUSIONS: For apical surgery in mandibular molars, the distance from the buccal bone surface to the apex and apical 3 mm is significantly affected by the location, patient age, an adjacent missing anterior tooth, and root configuration.

Synthesis, characterization, biocompatibility of hydroxyapatite-natural polymers nanocomposites for dentistry applications.

Hydroxyapatite (HA), the main mineral component of bones and teeth, was synthesized by using the reaction between calcium nitrate tetrahydrate Ca(NO3)2∙4H2O and diammonium hydrogen phosphate (NH4)2HPO4 (DAHP) with a chemical precipitation method. The objective of this study is to utilize novel inorganic-organic nanocomposites for biomedical applications. HA is an inorganic component (75% w) and chitosan, alginate and albumin (Egg white) are organic components of nanocomposites (25% w). Nanocomposites were prepared in deionized water solutions, at room temperature, using a mechanical and magnetic stirrer for 48 h. The microstructure and morphology of sintered n-HAP were tested at different preheating temperature and laser sintering speed with scanning electron microscopy (SEM), X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FT-IR).

Radical prostatectomy versus external beam radiotherapy for localized prostate cancer: Comparison of treatment outcomes.

PURPOSE: We retrospectively compared the treatment outcomes of localized prostate cancer between radical prostatectomy (RP) and external beam radiotherapy (EBRT). MATERIALS AND METHODS: We retrospectively analyzed 738 patients with localized prostate cancer who underwent either RP (n = 549) or EBRT (n = 189) with curative intent at our institution between March 2001 and December 2011. Biochemical failure was defined as a prostate-specific antigen (PSA) level of ≥ 0.2 ng/ml in the RP group and the nadir of + ≥ 2 ng/ml in the EBRT group. RESULTS: The median (range) follow-up duration was 48.8 months (0.7-133.2 months) and 48.7 months (1.0-134.8 months) and the median age was 66 years (45-89 years) and 71 years (51-84 years; p < 0.001) in the RP and EBRT groups, respectively. Overall, 21, 42, and 36 % of patients in the RP group, and 15, 27, and 58 % of patients in the EBRT group were classified as low, intermediate, and high risk, respectively (p < 0.001). Androgen-deprivation therapy was more common in the EBRT group (59 vs. 27 %, respectively; p < 0.001). The 8-year biochemical failure-free survival rates were 44 and 72 % (p < 0.001) and the disease-specific survival rates were 98 % and 97 % (p = 0.543) in the RP and EBRT groups, respectively. CONCLUSIONS: Although the EBRT group included more high-risk patients than did the RP group, the outcomes of EBRT were not inferior to those of RP. Our data suggest that EBRT is a viable alternative to RP for treating localized prostate cancer.

Comparative short-term in vitro analysis of mutans streptococci adhesion on esthetic, nickel-titanium, and stainless-steel arch wires.

OBJECTIVE: To test the hypothesis that there are no differences in mutans streptococci (MS) adhesion between esthetic and metallic orthodontic arch wires based on their surface characteristics. MATERIALS AND METHODS: Surface roughness (Ra) and apparent surface free energy (SFE) were measured for six wires-four esthetic, one nickel-titanium (NiTi), and one stainless-steel (SS)-using profilometry and dynamic contact angle analysis, respectively. The amount of MS (Streptococcus mutans and Streptococcus sobrinus) adhering to the wires was quantified using the colony-counting method. The surfaces, coating layers, and MS adhesion were also observed by scanning electron microscopy. Statistical significance was set at P < .05. RESULTS: The Ra values of the esthetic wires were significantly different from one another depending on the coating method (P < .05). The NiTi wire showed the highest SFE, followed by the SS wire and then the four esthetic wires. The NiTi wires produced a significantly higher MS adhesion than did the SS wires (P < .05). The esthetic wires showed significantly lower MS adhesions than did the NiTi wire (P < .05). Pearson correlation analyses found moderate significant positive correlations between the SFE and the S mutans and S sobrinus adhesions (r  =  .636/.427, P < .001/P  =  .001, respectively). CONCLUSIONS: The hypothesis is rejected. This study indicates that some esthetic coatings on NiTi alloy might reduce MS adhesion in vitro in the short term.

Immobilization of a phosphonated analog of matrix phosphoproteins within cross-linked collagen as a templating mechanism for biomimetic mineralization.

Immobilization of phosphoproteins on a collagen matrix is important for the induction of intrafibrillar apatite mineralization. Unlike phosphate esters, polyphosphonic acid has no reactive sites for covalent binding to collagen amine groups. Binding of poly(vinyl phosphonic acid) (PVPA), a biomimetic templating analog of matrix phosphoproteins, to collagen was found to be electrostatic in nature. Thus, an alternative retention mechanism was designed for immobilization of PVPA on collagen by cross-linking the latter with carbodiimide (EDC). This mechanism is based on the principle of size exclusion entrapment of PVPA molecules within the internal water compartments of collagen. By cross-linking collagen with EDC, a zero length cross-linking agent, the sieving property of collagen is increased, enabling the PVPA to be immobilized within the collagen. The absence of covalent cross-linking between PVPA and collagen was confirmed by Fourier transform infrared spectroscopy. Based on these results, a concentration range for immobilized PVPA to template intrafibrillar apatite deposition was established and validated using a single layer reconstituted type I collagen mineralization model. In the presence of a polyacrylic acid-containing mineralization medium optimal intrafibrillar mineralization of the EDC-cross-linked collagen was achieved using 500 and 1000 µg ml⁻¹ PVPA. The mineralized fibrils exhibited a hierarchical order of intrafibrillar mineral infiltration, as manifested by the appearance of electron-dense periodicity within unstained fibrils. Understanding the basic processes in intrafibrillar mineralization of reconstituted collagen creates opportunities for the design of tissue engineering materials for hard tissue repair and regeneration.

Hierarchical and non-hierarchical mineralisation of collagen.

Biomineralisation of collagen involves functional motifs incorporated in extracellular matrix protein molecules to accomplish the objectives of stabilising amorphous calcium phosphate into nanoprecursors and directing the nucleation and growth of apatite within collagen fibrils. Here we report the use of small inorganic polyphosphate molecules to template hierarchical intrafibrillar apatite assembly in reconstituted collagen in the presence of polyacrylic acid to sequester calcium and phosphate into transient amorphous nanophases. The use of polyphosphate without a sequestration analogue resulted only in randomly-oriented extrafibrillar precipitations along the fibrillar surface. Conversely, the use of polyacrylic acid without a templating analogue resulted only in non-hierarchical intrafibrillar mineralisation with continuous apatite strands instead of discrete crystallites. The ability of using simple non-protein molecules to recapitulate different levels of structural hierarchy in mineralised collagen signifies the ultimate simplicity in Nature's biomineralisation design principles and challenges the need for using more complex recombinant matrix proteins in bioengineering applications.

A chemical phosphorylation-inspired design for Type I collagen biomimetic remineralization.

OBJECTIVES: Type I collagen alone cannot initiate tissue mineralization. Sodium trimetaphosphate (STMP) is frequently employed as a chemical phosphorylating reagent in the food industry. This study examined the feasibility of using STMP as a functional analog of matrix phosphoproteins for biomimetic remineralization of resin-bonded dentin. METHODS: Equilibrium adsorption and desorption studies of STMP were performed using demineralized dentin powder (DDP). Interaction between STMP and DDP was examined using Fourier transform-infrared spectroscopy. Based on those results, a bio-inspired mineralization scheme was developed for chemical phosphorylation of acid-etched dentin with STMP, followed by infiltration of the STMP-treated collagen matrix with two etch-and-rinse adhesives. Resin-dentin interfaces were remineralized in a Portland cement-simulated body fluid system, with or without the use of polyacrylic acid (PAA) as a dual biomimetic analog. Remineralized resin-dentin interfaces were examined unstained using transmission electron microscopy. RESULTS: Analysis of saturation binding curves revealed the presence of irreversible phosphate group binding sites on the surface of the DDP. FT-IR provided additional evidence of chemical interaction between STMP and DDP, with increased in the peak intensities of the PO and P-O-C stretching modes. Those peaks returned to their original intensities after alkaline phosphatase treatment. Evidence of intrafibrillar apatite formation could be seen in incompletely resin-infiltrated, STMP-phosphorylated collagen matrices only when PAA was present in the SBF. SIGNIFICANCE: These results reinforce the importance of PAA for sequestration of amorphous calcium phosphate nanoprecursors in the biomimetic remineralization scheme. They also highlight the role of STMP as a templating analog of dentin matrix phosphoproteins for inducing intrafibrillar remineralization of apatite nanocrystals within the collagen matrix of incompletely resin-infiltrated dentin.

Effect of dietary epigallocatechin-3-gallate on cytochrome P450 2E1-dependent alcoholic liver damage: enhancement of fatty acid oxidation.

This study was designed to determine whether dietary epigallocatechin-3-gallate (EGCG), the most abundant catechin polyphenol in green tea, can protect the liver from cytochrome P450 2E1 (CYP2E1)-dependent alcoholic liver damage. Compared with an ethanol group, when EGCG was present in the ethanol diet, the formation of a fatty liver was significantly reduced and the serum aspartate transaminase (AST) and alanine transaminase (ALT) levels were much lower. Ethanol treatment significantly elevated hepatic CYP2E1 expression while simultaneously reducing hepatic phospho-acetyl CoA carboxylase (p-ACC) and carnitine palmitoyl-transferase 1 (CPT-1) levels. While EGCG markedly reversed the effect of ethanol on hepatic p-ACC and CPT-1 levels, it had no effect on the ethanol-induced elevation in CYP2E1 expression. EGCG prevents ethanol-induced hepatotoxicity and inhibits the development of a fatty liver. These effects were associated with improvements in p-ACC and CPT-1 levels. The use of EGCG might be useful in treating patients with an alcoholic fatty liver.

(-)-Catechin suppresses expression of Kruppel-like factor 7 and increases expression and secretion of adiponectin protein in 3T3-L1 cells.

Adiponectin is an adipocyte-specific secretory hormone that can increase insulin sensitivity and promote adipocyte differentiation. Administration of adiponectin to obese or diabetic mice reduces plasma glucose and free fatty acid levels. Green tea polyphenols possess many pharmacological activities such as antioxidant, anti-inflammatory, antiobesity, and antidiabetic activities. To investigate whether green tea polyphenols have an effect on the regulation of adiponectin, we measured expression and secretion levels of adiponectin protein after treatment of each green tea polyphenols in 3T3-L1 adipocytes. We found that (-)-catechin enhanced the expression and secretion of adiponectin protein in a dose- and time-dependent manner. Furthermore, treatment of (-)-catechin increased insulin-dependent glucose uptake in differentiated adipocytes and augmented the expression of adipogenic marker genes, including PPARgamma, CEBPalpha, FAS, and SCD-1, when (-)-catechin was treated during adipocyte differentiation. In search of the molecular mechanism responsible for inducible effect of (-)-catechin on adiponectin expression, we found that (-)-catechin markedly suppresses the expression of Kruppel-like factor 7 (KLF7) protein, which has recently been reported to inhibit the expression of adiponectin and other adipogenesis related genes, including leptin, PPARgamma, C/EBPalpha, and aP2 in adipocytes. KLF7 is a transcription factor in adipocyte and plays an important role in the pathogenesis of type 2 diabetes. Taken together, these data suggest that the upregulation of adiponectin protein by (-)-catechin may involve, at least in part, suppression of KLF7 in 3T3-L1 cells.

Protective effects of green tea polyphenol extracts against ethanol-induced gastric mucosal damages in rats: stress-responsive transcription factors and MAP kinases as potential targets.

There are multiple lines of compelling evidence from epidemiologic and laboratory studies supporting that frequent consumption of green tea is inversely associated with the risk of chronic human diseases including cancer. The chemopreventive and chemoprotective effects of green tea have been largely attributed to antioxidative and anti-inflammatory activities of its polyphenolic constituents, such as epigallocatechin gallate. The present study was designed to evaluate the efficacy of green tea polyphenols in protecting against alcohol-induced gastric damage and to elucidate the underlying mechanisms. Intragastric administration of ethanol to male Sprague-Dawley rats caused significant gastric mucosal damage, which was accompanied by elevated expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) as well as transient activation of redox-sensitive transcription factors, such as NF-kappaB and AP-1, and mitogen-activated protein kinases (MAPKs). Oral administration of the green tea polyphenolic extract (GTE) significantly ameliorated mucosal damages induced by ethanol and also attenuated the ethanol-induced expression of COX-2 and iNOS. Inactivation of MAPKs, especially p38 and ERKl/2, by GTE might be responsible for inhibition of ethanol-induced expression of COX-2 and iNOS.

Inhibition of phorbol ester-induced COX-2 expression by epigallocatechin gallate in mouse skin and cultured human mammary epithelial cells.

Green tea polyphenols are reported to possess substantial antiinflammatory and chemopreventive properties. However, the molecular mechanism of chemopreventive activity of green tea polyphenols is not fully understood. An abnormally elevated level of cyclooxygenase-2 (COX-2) is implicated in the pathogenesis of carcinogenesis. In the present study, we found that pretreatment of the green tea extract enriched with catechin and epigallocatechin gallate (EGCG) by gavage inhibited COX-2 expression induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) in mouse skin. Similarly, EGCG downregulated COX-2 in TPA-stimulated human mammary epithelial cells (MCF-10A) in culture. To further elucidate the underlying mechanism of COX-2 inhibition by green tea extract and EGCG, we examined their effects on the activation of extracellular signal-regulated protein kinase (ERK) and p38 mitogen-activated protein kinase (MAPK), which are upstream enzymes known to regulate COX-2 expression in many cell types. Pretreatment with EGCG as well as green tea extract caused a decrease in the activation of ERK. In addition, EGCG inhibited the catalytic activity of ERK and p38 MAPK, suggesting that these signal-transducing enzymes could be potential targets for previously reported antitumor promoting activity of EGCG.