White Blood Cell Count and Major Adverse Cardiovascular Events After Percutaneous Coronary Intervention in the Contemporary Era: Insights From the PARIS Study (Patterns of Non-Adherence to Anti-Platelet Regimens in Stented Patients Registry).

Elevated white blood cell (WBC) count is associated with increased major adverse cardiovascular events (MACE) in the setting of acute coronary syndrome. The aim of this study was to evaluate whether similar associations persist in an all-comers population of patients undergoing percutaneous coronary intervention in the contemporary era. In the multicenter, prospective, observational PARIS study (Patterns of Non-Adherence to Anti-Platelet Regimens in Stented Patients Registry), 4222 patients who underwent percutaneous coronary intervention in the United States and Europe between July 1, 2009, and December 2, 2010, were evaluated. The associations between baseline WBC and MACE (composite of cardiac death, stent thrombosis, spontaneous myocardial infarction, or target lesion revascularization) at 24-month follow-up were analyzed using multivariable Cox regression. Patients with higher WBC were more often younger, smokers, and with less comorbid risk factors compared with those with lower WBC. After adjustment for baseline and procedural characteristics, WBC remained independently associated with MACE (hazard ratio [HR] per 10(3) cells/μL increase, 1.05 [95% confidence intervals (CI), 1.02-1.09]; P=0.001), cardiac death (HR, 1.10 [95% CI, 1.05-1.17]; P<0.001), and clinically indicated target revascularization (HR, 1.04 [95% CI, 1.00-1.09]; P=0.03) but not stent thrombosis (HR, 1.07 [95% CI, 0.99-1.16]; P=0.10) or spontaneous myocardial infarction (HR, 1.03 [95% CI, 0.97-1.09]; P=0.29). The association between WBC and MACE was consistent in acute coronary syndrome and non-acute coronary syndrome presentations (interaction P=0.15). Increased WBC is an independent predictor of MACE after percutaneous coronary intervention in a contemporary all-comers cohort. Further studies to delineate the underlying pathophysiologic role of elevated WBC across a spectrum of coronary artery disease presentations are warranted. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00998127

Lattice QCD determination of m_b, f_B and f_Bs with twisted mass Wilson fermions

We present a lattice QCD determination of the b quark mass and of the B and B_s decay constants, performed with N_f=2 twisted mass Wilson fermions, by simulating at four values of the lattice spacing. In order to study the b quark on the lattice, two methods are adopted in the present work, respectively based on suitable ratios with exactly known static limit and on the interpolation between relativistic data, evaluated in the charm mass region, and the static point, obtained by simulating the HQET on the lattice. The two methods provide results in good agreement. For the b quark mass in the MSbar scheme and for the decay constants we obtain m_b(m_b)=4.29(14) GeV, f_B=195(12) MeV, f_Bs=232(10) MeV and f_Bs/f_B=1.19(5). As a byproduct of the analysis we also obtain the results for the f_D and f_Ds decay constants: f_D=212(8) MeV, f_Ds=248(6) MeV and f_Ds/f_D=1.17(5).Comment: 23 pages, 10 figures, 2 tables. Added appendix showing the agreement of the data for the ratios with the HQE prediction. Matching JHEP published versio

In Vitro Photodynamic Therapy with Chlorin e6 Leads to Apoptosis of Human Vascular Smooth Muscle Cells

Percutaneous coronary intervention has become the most common and widely implemented method of heart revascularization. However, the development of restenosis remains the major limitation of this method. Photodynamic therapy (PDT) recently emerged as a new and promising method for the prevention of arterial restenosis. Here the efficacy of chlorin e6 in PDT was investigated in vitro using human vascular smooth muscle cells (TG/HA-VSMCs) as one of the cell types crucial in the development of restenosis. PDT-induced cell death was studied on many levels, including annexin V staining, measurement of the generation reactive oxygen species (ROS) and caspase-3 activity, and assessment of changes in mitochondrial membrane potential and fragmentation of DNA. Photosensitization of TG/HA-VSMCs with a 170 μM of chlorin e6 and subsequent illumination with the light of a 672-nm diode laser (2 J/cm2) resulted in the generation of ROS, a decrease in cell membrane polarization, caspase-3 activation, as well as DNA fragmentation. Interestingly, the latter two apoptotic events could not be observed in photosensitized and illuminated NIH3T3 fibroblasts, suggesting different outcomes of the model of PDT in various types of cells. The results obtained with human VSMCs show that chlorin e6 may be useful in the PDT of aerial restenosis, but its efficacy still needs to be established in an animal model

Animal-related factors associated with moderate-to-severe diarrhea in children younger than five years in western Kenya: A matched case-control study

Background Diarrheal disease remains among the leading causes of global mortality in children younger than 5 years. Exposure to domestic animals may be a risk factor for diarrheal disease. The objectives of this study were to identify animal-related exposures associated with cases of moderate-to-severe diarrhea (MSD) in children in rural western Kenya, and to identify the major zoonotic enteric pathogens present in domestic animals residing in the homesteads of case and control children. Methodology/Principal findings We characterized animal-related exposures in a subset of case and control children (n = 73 pairs matched on age, sex and location) with reported animal presence at home enrolled in the Global Enteric Multicenter Study in western Kenya, and analysed these for an association with MSD. We identified potentially zoonotic enteric pathogens in pooled fecal specimens collected from domestic animals resident at children’s homesteads. Variables that were associated with decreased risk of MSD were washing hands after animal contact (matched odds ratio [MOR] = 0.2; 95% CI 0.08–0.7), and presence of adult sheep that were not confined in a pen overnight (MOR = 0.1; 0.02–0.5). Variables that were associated with increased risk of MSD were increasing number of sheep owned (MOR = 1.2; 1.0–1.5), frequent observation of fresh rodent excreta (feces/urine) outside the house (MOR = 7.5; 1.5–37.2), and participation of the child in providing water to chickens (MOR = 3.8; 1.2–12.2). Of 691 pooled specimens collected from 2,174 domestic animals, 159 pools (23%) tested positive for one or more potentially zoonotic enteric pathogens (Campylobacter jejuni, C. coli, non-typhoidal Salmonella, diarrheagenic E. coli, Giardia, Cryptosporidium, or rotavirus). We did not find any association between the presence of particular pathogens in household animals, and MSD in children. Conclusions and significance Public health agencies should continue to promote frequent hand washing, including after animal contact, to reduce the risk of MSD. Future studies should address specific causal relations of MSD with sheep and chicken husbandry practices, and with the presence of rodents

PIP5KIβ Selectively Modulates Apical Endocytosis in Polarized Renal Epithelial Cells

Localized synthesis of phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] at clathrin coated pits (CCPs) is crucial for the recruitment of adaptors and other components of the internalization machinery, as well as for regulating actin dynamics during endocytosis. PtdIns(4,5)P2 is synthesized from phosphatidylinositol 4-phosphate by any of three phosphatidylinositol 5-kinase type I (PIP5KI) isoforms (α, β or γ). PIP5KIβ localizes almost exclusively to the apical surface in polarized mouse cortical collecting duct cells, whereas the other isoforms have a less polarized membrane distribution. We therefore investigated the role of PIP5KI isoforms in endocytosis at the apical and basolateral domains. Endocytosis at the apical surface is known to occur more slowly than at the basolateral surface. Apical endocytosis was selectively stimulated by overexpression of PIP5KIβ whereas the other isoforms had no effect on either apical or basolateral internalization. We found no difference in the affinity for PtdIns(4,5)P2-containing liposomes of the PtdIns(4,5)P2 binding domains of epsin and Dab2, consistent with a generic effect of elevated PtdIns(4,5)P2 on apical endocytosis. Additionally, using apical total internal reflection fluorescence imaging and electron microscopy we found that cells overexpressing PIP5KIβ have fewer apical CCPs but more internalized coated structures than control cells, consistent with enhanced maturation of apical CCPs. Together, our results suggest that synthesis of PtdIns(4,5)P2 mediated by PIP5KIβ is rate limiting for apical but not basolateral endocytosis in polarized kidney cells. PtdIns(4,5)P2 may be required to overcome specific structural constraints that limit the efficiency of apical endocytosis. © 2013 Szalinski et al

Person-Related Protective and Vulnerability Factors of Psychopathology Symptoms in Non-Clinical Adolescents

Psychopathology in youths is thought to originate from a dynamic interplay of a variety of protective and vulnerability factors. In this study, a large multi-ethnic sample of non-clinical adolescents (N = 376) completed questionnaires for measuring a wide range of person-related protective and vulnerability factors as well as psychopathology symptoms, in order to explore (a) the relations among various protective and vulnerability factors, and (b) the unique contributions of these protective and vulnerability factors to different types of psychological problems. Results indicated that the overlap among protective and vulnerability factors was quite modest. Further, it was found that factors clustered in theoretically meaningful components reflecting protection, vulnerability, and more specific aspects of coping and social support. Finally, data indicated that each type of psychopathology symptoms was associated with a typical set of protective and vulnerability factors. Although these results should be interpreted with caution because of the cross-sectional nature of the study, they may nevertheless guide future research exploring multifactorial models of psychopathology in youths

The stellar and sub-stellar IMF of simple and composite populations

The current knowledge on the stellar IMF is documented. It appears to become top-heavy when the star-formation rate density surpasses about 0.1Msun/(yr pc^3) on a pc scale and it may become increasingly bottom-heavy with increasing metallicity and in increasingly massive early-type galaxies. It declines quite steeply below about 0.07Msun with brown dwarfs (BDs) and very low mass stars having their own IMF. The most massive star of mass mmax formed in an embedded cluster with stellar mass Mecl correlates strongly with Mecl being a result of gravitation-driven but resource-limited growth and fragmentation induced starvation. There is no convincing evidence whatsoever that massive stars do form in isolation. Various methods of discretising a stellar population are introduced: optimal sampling leads to a mass distribution that perfectly represents the exact form of the desired IMF and the mmax-to-Mecl relation, while random sampling results in statistical variations of the shape of the IMF. The observed mmax-to-Mecl correlation and the small spread of IMF power-law indices together suggest that optimally sampling the IMF may be the more realistic description of star formation than random sampling from a universal IMF with a constant upper mass limit. Composite populations on galaxy scales, which are formed from many pc scale star formation events, need to be described by the integrated galactic IMF. This IGIMF varies systematically from top-light to top-heavy in dependence of galaxy type and star formation rate, with dramatic implications for theories of galaxy formation and evolution.Comment: 167 pages, 37 figures, 3 tables, published in Stellar Systems and Galactic Structure, Vol.5, Springer. This revised version is consistent with the published version and includes additional references and minor additions to the text as well as a recomputed Table 1. ISBN 978-90-481-8817-

Gameplay as a source of intrinsic motivation in a randomized controlled trial of auditory training

Background: Previous studies of frequency discrimination training (FDT) for tinnitus used repetitive task-based training programmes relying on extrinsic factors to motivate participation. Studies reported limited improvement in tinnitus symptoms. Purpose: To evaluate FDT exploiting intrinsic motivations by integrating training with computer-gameplay. Methods: Sixty participants were randomly assigned to train on a conventional taskbased training, or one of two interactive game-based training platforms over six weeks. Outcomes included assessment of motivation, tinnitus handicap, and performance on tests of attention. Results: Participants reported greater intrinsic motivation to train on the interactive game-based platforms, yet compliance of all three groups was similar (~70%) and changes in self-reported tinnitus severity were not significant. There was no difference between groups in terms of change in tinnitus severity or performance on measures of attention. Conclusion: FDT can be integrated within an intrinsically motivating game. Whilst this may improve participant experience, in this instance it did not translate to additional compliance or therapeutic benefit

Overexpression of E2F-5 correlates with a pathological basal phenotype and a worse clinical outcome

The purpose of the present study is to identify genes that contribute to cell proliferation or differentiation of breast cancers independent of signalling through the oestrogen receptor (ER) or human epidermal growth factor receptor 2 (HER2). An oligonucleotide microarray assayed 40 tumour samples from ER(+)/HER2(−), ER(+)/HER2(+), ER(−)/HER2(+), and ER(−)/HER2(−) breast cancer tissues. Quantitative reverse transcriptase PCR detected overexpression of a cell cycle-related transcription factor, E2F-5, in ER-negative breast cancers, and fluorescence in situ hybridisation detected gene amplification of E2F-5 in 5 out of 57 (8.8%) breast cancer samples. No point mutations were found in the DNA-binding or DNA-dimerisation domain of E2F-5. Immunohistochemically, E2F-5-positive cancers correlated with a higher Ki-67 labelling index (59.5%, P=0.001) and higher histological grades (P=0.049). E2F-5-positive cancers were found more frequently in ER(−)/progesterone receptor (PgR)(−)/HER2(−) cancer samples (51.9%, P=0.0049) and in breast cancer samples exhibiting a basal phenotype (56.0%, P=0.0012). Disease-free survival in node-negative patients with E2F-5-positive cancers was shorter than for patients with E2F-5-negative cancers. In conclusion, we identify, for the first time, a population of breast cancer cells that overexpress the cell cycle-related transcription factor, E2F-5. This E2F-5-positive breast cancer subtype was associated with an ER(−)/PgR(−)/HER2(−) status, a basal phenotype, and a worse clinical outcome