Type A behavior and risk of all-cause mortality, CAD, and CAD-related mortality, in a type 1 diabetes population: 22 years of follow-up in the Pittsburgh Epidemiology of Diabetes Complications Study

Objective To determine whether type A behavior predicts all cause mortality and incident coronary artery disease (CAD) in a type 1 diabetes population. Research Design and Methods Twenty-two year follow-up data from the Pittsburgh Epidemiology of Diabetes Complications (EDC) study of childhood onset type 1 diabetes were analyzed for the 506 participants who completed the Bortner Rating Scale (measuring type A myocardial infarction as determined by hospital records/ Q waves on ECG, CAD death behavior) and Beck’s Depression Inventory (BDI) at baseline (1986-1988). CAD comprised (determined by a mortality classification committee), angiographic stenosis, ischemic ECG and angina. Results There were 128 deaths (25.3%) during follow-up. Univariate analysis showed an inverse relationship between Bortner scores and all cause mortality (p=0.01) which remained significant after allowing for age, sex, duration, HbA1c, education, smoking, BMI, and physical activity (p=0.03). However, the addition of BDI scores attenuated the relationship (p=0.11) with a significant interaction (p=0.03) such that any protective effect against mortality was limited among individuals with lower BDI scores (bottom 3 quintiles) (p=0.07), while no effect was seen in those with higher BDI (p=0.97). Bortner scores showed only a borderline association with incident CAD (p=0.09). Conclusions Those with higher type A behavior have lower all-cause mortality in our type 1 diabetes population, an effect that interacts with depressive symptomatology such that it is only operative in those with low BDI scores. Further research should focus on understanding this interaction

Purification and characterization of the bacteriophage T7 gene 2.5 protein : a single-stranded DNA-binding protein

Bacteriophage T7 gene 2.5 protein has been purified to homogeneity from cells overexpressing its gene. Native gene 2.5 protein consists of a dimer of two identical subunits of molecular weight 25,562. Gene 2.5 protein binds specifically to single-stranded DNA with a stoichiometry of approximately 7 nucleotides bound per monomer of gene 2.5 protein; binding appears to be noncooperative. Electron microscopic analysis shows that gene 2.5 protein is able to disrupt the secondary structure of single-stranded DNA. The single-stranded DNA is extended into a chain of gene 2.5 protein dimers bound along the DNA. In fluorescence quenching and nitrocellulose filter binding assays, the binding constants of gene 2.5 protein to single-stranded DNA are 1.2 x 10(6) M-1 and 3.8 x 10(6) M-1, respectively. Escherichia coli single-stranded DNA-binding protein and phage T4 gene 32 protein bind to single-stranded DNA more tightly by a factor of 25. Fluorescence spectroscopy suggests that tyrosine residue(s), but not tryptophan residues, on gene 2.5 protein interacts with single-stranded DNA

Interplay between distribution of live cells and growth dynamics of solid tumours

Experiments show that simple diffusion of nutrients and waste molecules is not sufficient to explain the typical multilayered structure of solid tumours, where an outer rim of proliferating cells surrounds a layer of quiescent but viable cells and a central necrotic region. These experiments challenge models of tumour growth based exclusively on diffusion. Here we propose a model of tumour growth that incorporates the volume dynamics and the distribution of cells within the viable cell rim. The model is suggested by in silico experiments and is validated using in vitro data. The results correlate with in vivo data as well, and the model can be used to support experimental and clinical oncology

Genetics of Type A Behavior in Two European Countries: Evidence for Sibling Interaction

Young male twins in The Netherlands and England completed the Jenkins Activity Survey (Dutch and English versions, respectively), a measure of Type A behavior. Separate model fitting analysis revealed a similar pattern of variance estimates and associated goodness of fit across the two countries. The data were then analyzed concurrently, with a scalar parameter included to account for differences in variance due to the disparity of the measurement scales. A model including additive genetic and individual environmental effects gave a good explanation to the data. The heritability estimate was 0.28. Models of social interaction and dominance explained the data even better, the former being preferred. The twins' parents were included in the analysis to examine population variation for Type A behavior intergenerationally. There was evidence for individual environmental experiences having a greater influence on Type A behavior in the older generation. © 1991 Plenum Publishing Corporation

Low-molecular-weight cyclin E: the missing link between biology and clinical outcome

Cyclin E, a key mediator of transition during the G(1)/S cellular division phase, is deregulated in a wide variety of human cancers. Our group recently reported that overexpression and generation of low-molecular-weight (LMW) isoforms of cyclin E were associated with poor clinical outcome among breast cancer patients. However, the link between LMW cyclin E biology in mediating a tumorigenic phenotype and clinical outcome is unknown. To address this gap in knowledge, we assessed the role of LMW isoforms in breast cancer cells; we found that these forms of cyclin E induced genomic instability and resistance to p21, p27, and antiestrogens in breast cancer. These findings suggest that high levels of LMW isoforms of cyclin E not only can predict failure to endocrine therapy but also are true prognostic indicators because of their influence on cell proliferation and genetic instability

Parallel cyclin E and cyclin A expression in neoplastic lesions of the uterine cervix

Cyclin E levels are high during late G1 and early S-phase in normal cells. The cyclin E expression over the cell cycle in tumours is not fully known. The impact on patient outcome by high cyclin E levels during other parts of the cell cycle than late G1- and early S-phase is unknown. We set out to study the expression of cyclin E over the cell cycle in cervical carcinomas. Using immunofluorescence staining of cyclin A, digital microscopy, and digital image analysis, we determined which cells in a tissue section that were in S- or G2-phase. M-phase cells were detected by morphology. By simultaneously staining for cyclin E, we investigated the variation in cyclin E levels over the cell cycle in cervical carcinoma lesions. In a case–control study, in which each deceased patient was matched with a patient still alive and well after >5 years of follow-up, we found that the deceased patients had a considerably higher fraction of cyclin A-positive cells staining for cyclin E than the survivors (n=36). We conclude that parallel cyclin E and cyclin A expression is an indicator for poor outcome in cervical carcinomas. In addition, we investigated the expression pattern of cyclin E and cyclin A in consecutive biopsy samples from cervical carcinomas at different stages, as well as in human papillomavirus positive or negative adenocarcinomas in order to further study the cyclin E and cyclin A expression pattern in neoplastic lesions of the uterine cervix

WACCM-D Whole Atmosphere Community Climate Model with D-region ion chemistry

Energetic particle precipitation (EPP) and ion chemistry affect the neutral composition of the polar middle atmosphere. For example, production of odd nitrogen and odd hydrogen during strong events can decrease ozone by tens of percent. However, the standard ion chemistry parameterization used in atmospheric models neglects the effects on some important species, such as nitric acid. We present WACCM-D, a variant of the Whole Atmosphere Community Climate Model, which includes a set of lower ionosphere (D-region) chemistry: 307 reactions of 20 positive ions and 21 negative ions. We consider realistic ionization scenarios and compare the WACCM-D results to those from the Sodankylä Ion and Neutral Chemistry (SIC), a state-of-the-art 1-D model of the D-region chemistry. We show that WACCM-D produces well the main characteristics of the D-region ionosphere, as well as the overall proportion of important ion groups, in agreement with SIC. Comparison of ion concentrations shows that the WACCM-D bias is typically within ±10% or less below 70 km. At 70–90 km, when strong altitude gradients in ionization rates and/or ion concentrations exist, the bias can be larger for some groups but is still within tens of percent. Based on the good agreement overall and the fact that part of the differences are caused by different model setups, WACCM-D provides a state-of-the-art global representation of D-region ion chemistry and is therefore expected to improve EPP modeling considerably. These improvements are demonstrated in a companion paper by Andersson et al

Effects of controlled diesel exhaust exposure on apoptosis and proliferation markers in bronchial epithelium – an in vivo bronchoscopy study on asthmatics, rhinitics and healthy subjects

BackgroundEpidemiological evidence demonstrates that exposure to traffic-derived pollution worsens respiratory symptoms in asthmatics, but controlled human exposure studies have failed to provide a mechanism for this effect. Here we investigated whether diesel exhaust (DE) would induce apoptosis or proliferation in the bronchial epithelium in vivo and thus contribute to respiratory symptoms.MethodsModerate (n?=?16) and mild (n?=?16) asthmatics, atopic non-asthmatic controls (rhinitics) (n?=?13) and healthy controls (n?=?21) were exposed to filtered air or DE (100 ?g/m 3 ) for 2 h, on two separate occasions. Bronchial biopsies were taken 18 h post-exposure and immunohistochemically analysed for pro-apoptotic and anti-apoptotic proteins (Bad, Bak, p85 PARP, Fas, Bcl-2) and a marker of proliferation (Ki67). Positive staining was assessed within the epithelium using computerized image analysis.ResultsNo evidence of epithelial apoptosis or proliferation was observed in healthy, allergic or asthmatic airways following DE challenge.ConclusionIn the present study, we investigated whether DE exposure would affect markers of proliferation and apoptosis in the bronchial epithelium of asthmatics, rhinitics and healthy controls, providing a mechanistic basis for the reported increased airway sensitivity in asthmatics to air pollutants. In this first in vivo exposure investigation, we found no evidence of diesel exhaust-induced effects on these processes in the subject groups investigated

Baicalin administration attenuates hyperglycemia-induced malformation of cardiovascular system

In this study, the effects of Baicalin on the hyperglycemia-induced cardiovascular malformation during embryo development were investigated. Using early chick embryos, an optimal concentration of Baicalin (6 μM), was identified which could prevent hyperglycemia-induced cardiovascular malformation of embryos. Hyperglycemia-enhanced cell apoptosis was reduced in embryos and HUVECs in the presence of Baicalin. Hyperglycemia-induced excessive ROS production was inhibited when Baicalin was administered. Analyses of SOD, GSH-Px, MAQE and GABAA suggested Baicalin plays an antioxidant role in chick embryos possibly through suppression of outwardly rectifying Cl(-) in the high-glucose microenvironment. In addition, hyperglycemia-enhanced autophagy fell in the presence of Baicalin, through affecting the ubiquitin of p62 and accelerating autophagy flux. Both Baicalin and Vitamin C could decrease apoptosis, but CQ did not, suggesting autophagy to be a protective function on the cell survival. In mice, Baicalin reduced the elevated blood glucose level caused by streptozotocin (STZ). Taken together, these data suggest that hyperglycemia-induced embryonic cardiovascular malformation can be attenuated by Baicalin administration through suppressing the excessive production of ROS and autophagy. Baicalin could be a potential candidate drug for women suffering from gestational diabetes mellitus

siRNA-Based Targeting of Cyclin E Overexpression Inhibits Breast Cancer Cell Growth and Suppresses Tumor Development in Breast Cancer Mouse Model

Cyclin E is aberrantly expressed in many types of cancer including breast cancer. High levels of the full length as well as the low molecular weight isoforms of cyclin E are associated with poor prognosis of breast cancer patients. Notably, cyclin E overexpression is also correlated with triple-negative basal-like breast cancers, which lack specific therapeutic targets. In this study, we used siRNA to target cyclin E overexpression and assessed its ability to suppress breast cancer growth in nude mice. Our results revealed that cyclin E siRNA could effectively inhibit overexpression of both full length and low molecular weight isoforms of cyclin E. We found that depletion of cyclin E promoted apoptosis of cyclin E-overexpressing cells and blocked their proliferation and transformation phenotypes. Significantly, we further demonstrated that administration of cyclin E siRNA could inhibit breast tumor growth in nude mice. In addition, we found that cyclin E siRNA synergistically enhanced the cell killing effects of doxorubicin in cell culture and this combination greatly suppressed the tumor growth in mice. In conclusion, our results indicate that cyclin E, which is overexpressed in 30% of breast cancer, may serve as a novel and effective therapeutic target. More importantly, our study clearly demonstrates a very promising therapeutic potential of cyclin E siRNA for treating the cyclin E-overexpressing breast cancers, including the very malignant triple-negative breast cancers