Clinical and angiographic results with the beStent: the Registry for Optimal beStent Evaluation (ROSE) trial

BACKGROUND: Although safety and efficacy of the beStent (Medtronic Inc., Santa Rosa, CA, USA) have been described, the long-term angiographic and clinical outcomes have yet to be investigated. The ROSE (Registry for Optimal beStent Evaluation) trial was designed to assess the procedural safety of single 15 mm beStent implantation, and the six-month angiographic and 12-month clinical outcomes of patients treated with this novel coronary stent. METHODS: Patients with angina and a single de novo lesion in a native coronary artery of >/=2.75 mm diameter were included in this multicenter, prospective, observational trial. Clinical follow-up was obtained at one, six and 12 months. Angiography was performed before and after the stent implantation and at six months. The primary end-point included major adverse cardiac events (death, myocardial infarction and target lesion revascularization), major bleeding complications, and thrombotic occlusions at one-month follow-up. Secondary end-points were major cardiac-event-free survival at six- and 12-month follow-up and angiographic restenosis at six months. A total of 120 patients (80% male, mean age 58.6 +/- 10.6 years) with stable (48%) or unstable (44%) angina pectoris were allocated. The target vessel reference diameter pre-procedure was 2.85 +/- 0.52 mm. RESULTS: Minimal lumen diameter pre/post and at follow-up was 0.97 +/- 0.28 mm, 2.53 +/- 0.40 mm and 1.86 +/- 0.63 mm, respectively. Restenosis rate according to the >50% diameter stenosis criterion at six-month follow-up was 21.5%. At 12 months, the event-free survival rate was 75% (no deaths, two Q-wave and seven non-Q-wave infarctions, five bypass surgery interventions and 16 target lesion revascularizations), whilst 87% of the patients were free of angina pectoris. CONCLUSION: Despite the relatively high percentage of small vessels, the outcome of the ROSE trial is comparable to those observed in previous stent trials, indicating that the coronary beStent is safe and effective as a primary device for the treatment of native coronary artery lesions in patients with (un)stable angina pectoris.     

Functional implications of the microbial community structure of undefined mesophilic starter cultures

This review describes the recent advances made in the studies of the microbial community of complex and undefined cheese starter cultures. We report on work related to the composition of the cultures at the level of genetic lineages, on the presence and activity of bacteriophages and on the population dynamics during cheese making and during starter culture propagation. Furthermore, the link between starter composition and starter functionality will be discussed. Finally, recent advances in predictive metabolic modelling of the multi-strain cultures will be discussed in the context of microbe-microbe interactions.     

The cytotoxic,neurotoxic, apoptotic and antiproliferative activities of extracts of some marine algae on the MCF-7 cell line

We investigated the cytotoxic, neurotoxic, apoptotic and antiproliferative effects of extracts from Petalonia fascia, Jania longifurca and Halimeda tuna on the MCF-7 breast cancer cell line. J. longifurca extracts were more toxic than those of P. fascia and H. tuna. The algal extracts showed significant toxic effects at different dilutions. The toxic effects were due to increased oxidative stress and resulted in apoptosis. Algal toxicity may exert negative effects through the food chain or by direct interaction. Algal toxicity also has potential for cancer therapy. The toxic effects that we observed may be especially important for therapy for breast tumors.     

Antagonist-mediated down-regulation of toll-like receptors increases the prevalence of human papillomavirus infection in systemic lupus erythematosus

IntroductionPrevalence of an abnormal Papanicolaou smear was significantly increased in lupus patients in cross-sectional studies, associated with a higher prevalence of high-risk human papillomavirus (HPV) infection. The nucleic acid-specific Toll-like receptors (TLRs) locate at the endolysosomal compartments and trigger the induction of cytokines for the innate immune response. This study evaluated whether abnormal host innate immune response in lupus patients may enhance HPV persistence.MethodsProtein levels of TLRs 3, 7, 8 and 9 in cervical epithelial cells of lupus patients and controls with or without HPV infection were assessed using flow cytometry. Characteristics associated with the differential expression of TLRs in systemic lupus erythematosus (SLE) were elucidated. The effect and interferon-stimulated genes (ISGs) (ISG15 and Mx-1) gene expressions were then measured in oncogenic HeLa (HPV18), CaSki (HPV) and C33A (HPV negative) cell lines using flow cytometry and quantitative real-time PCR. Ex vivo productions of cytokines and interferon-gamma (IFN-γ) upon TLR ligands stimulations were subsequently measured using cytometric bead array and ELISA.ResultsFor subjects with HPV infection, levels of TLR3 and TLR7 were significantly lower in lupus patients compared with controls. Significantly decreased TLRs 7, 8 and 9 levels were observed in HPV-negative SLE compared to healthy controls. For SLE with and without HPV infection, TLR7 and 9 levels were significantly lower in infected SLE than those in HPV-negative patients. Independent explanatory variables associated with down-regulation of TLR7 level included HPV infection and a higher cumulative dose of prednisolone; while a higher cumulative dose of hydroxychloroquine and HPV infection were associated with down-regulation of TLR9 level. In cervical cell lines, TLRs 3, 7, 8, 9 protein levels and antiviral ISG15 and Mx-1 gene expressions were inhibited in two oncogenic HPV types. Functional data showed that the induction of pro-inflammatory cytokines by TLR ligands (R837, ssRNA and ODN2395) was greatly impaired in CaSki and HeLa than C33A cells.ConclusionsIn conclusion, prednisolone and TLR antagonist (hydroxychloroquine) may down-regulate protein levels of TLR7 and TLR9 in lupus patients, thereby decreasing the innate immune response against HPV infection. Upon infection, HPV further down-regulate TLR7 and 9 levels for viral persistence. Furthermore, reduction of nucleic acid-sensing TLRs 7, 8 and 9 in carcinogenic HPVs ensures that the expression of inducible pro-inflammatory cytokines is minimized to prevent the expression of antiviral ISGs (ISG15 and Mx-1) on a biologically relevant antiviral response.     

Low production of reactive oxygen species in granulocytes is associated with organ damage in systemic lupus erythematosus

Introduction

Polymorphonuclear leukocytes (PMN) are main effector cells in the acute immune response. While the specific role of PMN in systemic lupus erythematosus (SLE) and autoimmunity is still unclear, their importance in chronic inflammation is gaining more attention. Here we investigate aspects of function, bone marrow release and activation of PMN in patients with SLE.

Methods

The following PMN functions and subsets were evaluated using flow cytometry; (a) production of reactive oxygen species (ROS) after ex vivo stimulation with phorbol 12-myristate 13-acetate (PMA) or Escherichia coli (E. coli); (b) capacity to phagocytose antibody-coated necrotic cell material; (c) PMN recently released from bone marrow, defined as percentage of CD10⁻D16^low in peripheral blood, and (d) PMN activation markers; CD11b, CD62L and C5aR.

Results

SLE patients (n = 92) showed lower ROS production compared with healthy controls (n = 38) after activation ex vivo. The ROS production was not associated with corticosteroid dose or other immunotherapies. PMA induced ROS production was significantly reduced in patients with severe disease. In contrast, neither ROS levels after E. coli activation, nor the capacity to phagocytose were associated with disease severity. This suggests that decreased ROS production after PMA activation is a sign of changed PMN behaviour rather than generally impaired functions. The CD10⁻CD16^low phenotype constitute 2% of PMN in peripheral blood of SLE patients compared with 6.4% in controls, indicating a decreased release of PMN from the bone marrow in SLE. A decreased expression of C5aR on PMN was observed in SLE patients, pointing towards in vivo activation.

Conclusions

Our results indicate that PMN from SLE patients have altered function, are partly activated and are released abnormally from bone marrow. The association between low ROS formation in PMN and disease severity is consistent with findings in other autoimmune diseases and might be considered as a risk factor.     

The planetary biology of cytochrome P450 aromatases

Background  

Joining a model for the molecular evolution of a protein family to the paleontological and geological records (geobiology), and then to the chemical structures of substrates, products, and protein folds, is emerging as a broad strategy for generating hypotheses concerning function in a post-genomic world. This strategy expands systems biology to a planetary context, necessary for a notion of fitness to underlie (as it must) any discussion of function within a biomolecular system.     

A method to optimize selection on multiple identified quantitative trait loci

A mathematical approach was developed to model and optimize selection on multiple known quantitative trait loci (QTL) and polygenic estimated breeding values in order to maximize a weighted sum of responses to selection over multiple generations. The model allows for linkage between QTL with multiple alleles and arbitrary genetic effects, including dominance, epistasis, and gametic imprinting. Gametic phase disequilibrium between the QTL and between the QTL and polygenes is modeled but polygenic variance is assumed constant. Breeding programs with discrete generations, differential selection of males and females and random mating of selected parents are modeled. Polygenic EBV obtained from best linear unbiased prediction models can be accommodated. The problem was formulated as a multiple-stage optimal control problem and an iterative approach was developed for its solution. The method can be used to develop and evaluate optimal strategies for selection on multiple QTL for a wide range of situations and genetic models.