Three-dimensional delayed-detonation models with nucleosynthesis for type ia supernovae

We present results for a suite of 14 three-dimensional, high-resolution hydrodynamical simulations of delayed-detonation models of Type Ia supernova (SN Ia) explosions. This model suite comprises the first set of three-dimensional SN Ia simulations with detailed isotopic yield information. As such, it may serve as a data base for Chandrasekhar-mass delayed-detonation model nucleosynthetic yields and for deriving synthetic observables such as spectra and light curves. We employ aphysically motivated, stochastic model based on turbulent velocity fluctuations and fuel density to calculate in situ the deflagration-to-detonation transition probabilities. To obtain different strengths of the deflagration phase and thereby different degrees of pre-expansion, we have chosen a sequence of initial models with 1, 3, 5, 10, 20, 40, 100, 150, 200, 300 and 1600 (two different realizations) ignition kernels in a hydrostatic white dwarf with a central density of 2.9 × 10 g cm, as well as one high central density (5.5 × 10 g cm) and one low central density (1.0 × 10 g cm) rendition of the 100 ignition kernel configuration. For each simulation, we determined detailed nucleosynthetic yields by postprocessing10 tracer particles with a 384 nuclide reaction network. All delayed-detonation models result in explosions unbinding thewhite dwarf, producing a range of 56Ni masses from 0.32 to 1.11M. As a general trend, the models predict that the stableneutron-rich iron-group isotopes are not found at the lowest velocities, but rather at intermediate velocities (~3000×10 000 km s) in a shell surrounding a Ni-rich core. The models further predict relatively low-velocity oxygen and carbon, with typical minimum velocities around 4000 and 10 000 km s, respectively. © 2012 The Authors. Published by Oxford University Press on behalf of the Royal Astronomical Society.

Prenatal effects of selective serotonin reuptake inhibitor antidepressants, serotonin transporter promoter genotype (SLC6A4), and maternal mood on child behavior at 3 years of age

To investigate whether prenatal selective serotonin reuptake inhibitor (SSRI) antidepressant exposure affects behavior in 3-year-olds of antenatally anxious or depressed mothers and whether risk was moderated by the serotonin transporter promoter (SLC6A4) genotype.

Lacking cytokine production in ES cells and ES-cell-derived vascular cells stimulated by TNF-alpha is rescued by HDAC inhibitor trichostatin A

Inflammation and TNF-alpha signaling play a central role in most of the pathological conditions where cell transplantation could be applied. As shown by initial experiments, embryonic stem (ES) cells and ES-cell derived vascular cells express very low levels of TNF-alpha receptor I (TNFRp55) and thus do not induce cytokine expression in response to TNF-alpha stimulation. Transient transfection analysis of wild-type or deletion variants of the TNFRp55 gene promoter showed a strong activity for a 250-bp fragment in the upstream region of the gene. This activity was abolished by mutations targeting the Sp1/Sp3 or AP1 binding sites. Moreover, treatment with trichostatin A (TSA) led to a pronounced increase in TNFRp55 mRNA and promoter activity. Overexpression of Sp1 or c-fos further enhanced the TSA-induced luciferase activity, and this response was attenuated by Sp3 or c-jun coexpression. Additional experiments revealed that TSA did not affect the Sp1/Sp3 ratio but caused transcriptional activation of the c-fos gene. Thus, we provide the first evidence that ES and ES-cell-derived vascular cells lack cytokine expression in response to TNF-alpha stimulation due to low levels of c-fos and transcriptional activation of Sp1 that can be regulated by inhibition of histone deacetylase activity.

A phase II study of the potent PARP inhibitor, Rucaparib (PF-01367338, AG014699), with temozolomide in patients with metastatic melanoma demonstrating evidence of chemopotentiation

PURPOSE: poly(ADP ribose) polymerase inhibition has been shown to potentiate the cytotoxicity of DNA damaging agents. A phase I study of rucaparib and temozolomide showed that full-dose temozolomide could be given during PARP inhibition. We report the results of a phase II study of intravenous rucaparib 12 mg/m(2) and oral temozolomide 200 mg/m(2) on days 1-5 every 28 days in patients with advanced metastatic melanoma. METHODS: Patients with chemotherapy naïve measurable metastatic melanoma, performance status =2 and good end-organ function were recruited. Treatment was given until progression. A two stage phase II design was used, with response rate the primary endpoint. Population pharmacokinetics and pharmacodynamics were also explored. RESULTS: Forty-six patients were recruited with 37 patients receiving at least 2 cycles and 17 patients at least 6 cycles. Myelosuppression occurred with 25 patients (54 %) requiring a 25 % dose reduction in temozolomide. The response rate was 17.4 %, median time to progression 3.5 months, median overall survival 9.9 months, and 36 % of patients were progression-free at 6 months. CONCLUSIONS: This study showed that temozolomide (150-200 mg/m(2)/day) can safely be given with a PARP inhibitory dose of rucaparib, increasing progression-free survival over historical controls in metastatic melanoma patients.

Purification, characterization and molecular cloning of chymotrypsin inhibitor peptides from the venom of Burmese Daboia russelii siamensis

One novel Kunitz BPTI-like peptide designated as BBPTI-1, with chymotrypsin inhibitory activity was identified from the venom of Burmese Daboia russelii siamensis. It was purified by three steps of chromatography including gel filtration, cation exchange and reversed phase. A partial N-terminal sequence of BBPTI-1, HDRPKFCYLPADPGECLAHMRSF was obtained by automated Edman degradation and a Ki value of 4.77. nM determined. Cloning of BBPTI-1 including the open reading frame and 3' untranslated region was achieved from cDNA libraries derived from lyophilized venom using a 3' RACE strategy. In addition a cDNA sequence, designated as BBPTI-5, was also obtained. Alignment of cDNA sequences showed that BBPTI-5 exhibited an identical sequence to BBPTI-1 cDNA except for an eight nucleotide deletion in the open reading frame. Gene variations that represented deletions in the BBPTI-5 cDNA resulted in a novel protease inhibitor analog. Amino acid sequence alignment revealed that deduced peptides derived from cloning of their respective precursor cDNAs from libraries showed high similarity and homology with other Kunitz BPTI proteinase inhibitors. BBPTI-1 and BBPTI-5 consist of 60 and 66 amino acid residues respectively, including six conserved cysteine residues. As these peptides have been reported to have influence on the processes of coagulation, fibrinolysis and inflammation, their potential application in biomedical contexts warrants further investigation. © 2013 Elsevier Inc.

Discovery of a Potent Boronic Acid Derived Inhibitor of the HCV RNA-Dependent RNA Polymerase

A boronic acid moiety was found to be a critical pharmacophore for enhanced in vitro potency against wild type hepatitis C replicons and known clinical polymorphic and resistant HCV mutant replicons. The synthesis, optimization, and structure-activity relationships associated with inhibition of HCV replication in a sub-genomic replication system for a series of non-nucleoside boron-containing HCV RNA-Dependent RNA Polymerase (NS5B) inhibitors are described. A summary of the discovery of GSK5852 (3), a molecule which entered clinical trials in subjects infected with HCV in 2011, is included.

Reduced soluble receptor for advanced glycation end-products (sRAGE) scavenger capacity precedes pre-eclampsia in Type 1 diabetes

Objective Increased advanced glycation end-products (AGEs) and their soluble receptors (sRAGE) have been implicated in the pathogenesis of pre-eclampsia (PE). However, this association has not been elucidated in pregnancies complicated by diabetes. We aimed to investigate the serum levels of these factors in pregnant women with Type 1 diabetes mellitus (T1DM), a condition associated with a four-fold increase in PE. Design Prospective study in women with T1DM at 12.2 ± 1.9, 21.6 ± 1.5 and 31.5 ± 1.7 weeks of gestation [mean ± standard deviation (SD); no overlap] before PE onset. Setting Antenatal clinics. Population Pregnant women with T1DM (n = 118; 26 developed PE) and healthy nondiabetic pregnant controls (n = 21). Methods Maternal serum levels of sRAGE (total circulating pool), N -(carboxymethyl)lysine (CML), hydroimidazolone (methylglyoxal-modified proteins) and total AGEs were measured by immunoassays. Main outcome measures Serum sRAGE and AGEs in pregnant women with T1DM who subsequently developed PE (DM PE+) versus those who remained normotensive (DM PE-). Results In DM PE+ versus DM PE-, sRAGE was significantly lower in the first and second trimesters, prior to the clinical manifestation of PE (P <0.05). Further, reflecting the net sRAGE scavenger capacity, sRAGE:hydroimidazolone was significantly lower in the second trimester (P <0.05) and sRAGE:AGE and sRAGE:CML tended to be lower in the first trimester (P <0.1) in women with T1DM who subsequently developed PE versus those who did not. These conclusions persisted after adjusting for prandial status, glycated haemoglobin (HbA1c), duration of diabetes, parity and mean arterial pressure as covariates. Conclusions In the early stages of pregnancy, lower circulating sRAGE levels, and the ratio of sRAGE to AGEs, may be associated with the subsequent development of PE in women with T1DM. © 2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology © 2012 RCOG.

Cardiomyopathy and Diastolic Dysfunction in the Embryo and Neonate of a Type 1 Diabetic Mouse Model

Objective: The purpose of this study was to examine the effect of maternal type 1 diabetes on the structure and function of the embryonic and neonatal mouse heart.

Methods: Type 1 diabetes was induced in female C57BL6/J mice using streptozotocin. Embryonic (n = 105) and neonatal hearts (n = 46) were examined using high-frequency ultrasound (US) and a cohort of E18.5 (n = 34) and 1-day-old pup hearts (n = 27) underwent histological examination.

Results: Global cardiac hypertrophy in late gestation (E18.5) was evident on US in the diabetic group compared to controls with increased interventricular septal (IVS) thickness (0.44 ± 0.08 mm vs 0.36 ± 0.08 mm, P < .05) and increased left ventricular wall thickness (0.38 ± 0.04 mm vs 0.29 mm ± 0.05, P < .01). Isovolumetric relaxation time was initially prolonged in the diabetic group but resolved by E18.5 to control values. Histological examination at E18.5 demonstrated increased transverse measurements (2.42 ± 0.72 mm/g vs 1.86 ± 0.55 mm/g, P < .05) and increased IVS thickness (0.64 ± 0.20 mm/g vs 0.43 ± 0.15 mm/g, P < .05) in diabetic embryos compared to control embryos.

Conclusion: Maternal hyperglycemia has severe effects on offspring with evidence of cardiac impairment and cardiac hypertrophy in the embryo. These effects persisted in the 1-day old but attenuated in the 1-week old suggesting cardiac remodeling after the hyperglycemic milieu of pregnancy is removed

Apolipoprotein-defined lipoproteins and apolipoproteins:Associations with abnormal albuminuria in type 1 diabetes in the diabetes control and complications trial/epidemiology of diabetes interventions and complications cohort

Dyslipoproteinemia has been associated with nephropathy in diabetes, with stronger correlations in men than in women. We aimed to characterize and compare plasma lipoprotein profiles associated with normal and increased albuminuria in men and women using apolipoprotein-defined lipoprotein subclasses and simple apolipoprotein measures.

Serum Inflammatory Markers and Preeclampsia in Type 1 Diabetes:A prospective study

OBJECTIVE Inflammation and endothelial dysfunction have been associated with the immunobiology of preeclampsia (PE), a significant cause of adverse pregnancy outcomes. The prevalence of PE is elevated several fold in the presence of maternal type 1 diabetes mellitus (T1DM). Although cross-sectional studies of pregnancies among women without diabetes have shown altered inflammatory markers in the presence of PE, longitudinal studies of diabetic women are lacking. In maternal serum samples, we examined the temporal associations of markers of inflammation with the subsequent development of PE in women with T1DM. RESEARCH DESIGN AND METHODS We conducted longitudinal analyses of serum C-reactive protein (CRP), adhesion molecules, and cytokines during the first (mean ± SD, 12.2 ± 1.9 weeks), second (21.6 ± 1.5 weeks), and third (31.5 ± 1.7 weeks) trimesters of pregnancy (visits 1-3, respectively). All study visits took place before the onset of PE. Covariates were BMI, HbA1c, age of onset, duration of diabetes, and mean arterial pressure. RESULTS In women with T1DM who developed PE versus those who remained normotensive, CRP tended to be higher at visits 1 (P = 0.07) and 2 (P = 0.06) and was significantly higher at visit 3 (P <0.05); soluble E-selectin and interferon-?-inducible protein-10 (IP-10) were significantly higher at visit 3; interleukin-1 receptor antagonist (IL-1ra) and eotaxin were higher and lower, respectively, at visit 2 (all P <0.05). These conclusions persisted following adjustment for covariates. CONCLUSIONS In pregnant women with T1DM, elevated CRP, soluble E-selectin, IL-1ra, and IP-10 and lower eotaxin were associated with subsequent PE. The role of inflammatory factors as markers and potential mechanisms of the high prevalence of PE in T1DM merits further investigation.

Plasma Lipoproteins and Preeclampsia in Women with Type 1 Diabetes: A Prospective Study

Context: In nondiabetic pregnancy, cross-sectional studies have shown associations between maternal dyslipidemia and preeclampsia (PE). In type 1 diabetes mellitus (T1DM), the prevalence of PE is increased 4-fold, but prospective associations with plasma lipoproteins are unknown.

Objectives: The aim of this study was to define lipoprotein-related markers and potential mechanisms for PE in T1DM.

Design and Settings: We conducted a multicenter prospective study in T1DM pregnancy.

Patients: We studied 118 T1DM women (26 developed PE, 92 remained normotensive). Subjects were studied at three visits before PE onset [12.2 1.9, 21.6 1.5, and 31.5 1.7 wk gestation (means SD)] and at term (37.6 2.0 wk). Nondiabetic normotensive pregnant women (n 21) were included for reference.

Main Outcome Measures: Conventional lipid profiles, lipoprotein subclasses [defined by size (nuclear magnetic resonance) and by apolipoprotein content], serum apolipoproteins (ApoAI, ApoB, and ApoCIII), and lipolysis (ApoCIII ratio) were measured in T1DM women with and without subsequent PE.

Results: In women with vs. without subsequent PE, at the first and/or second study visits: lowdensity lipoprotein (LDL)-cholesterol, particle concentrations of total LDL and large (but not small) LDL, serum ApoB, and ApoB:ApoAI ratio were all increased (P 0.05); peripheral lipoprotein lipolysis was decreased (P0.01). These early differences remained significant in covariate analysis (glycated hemoglobin, actual prandial status, gravidity, body mass index, and diabetes duration) but were not present at the third study visit. High-density lipoprotein and very low-density lipoprotein subclasses did not differ between groups before PE onset.

Conclusions: Early in pregnancy, increased cholesterol-rich lipoproteins and an index suggesting decreased peripheral lipolysis were associated with subsequent PE in T1DM women. Background maternal lipoprotein characteristics, perhaps masked by effects of late pregnancy, may influence PE risk.

The role of angiogenic and antiangiogenic factors in the second trimester in the prediction of preeclampsia in pregnant women with type 1 diabetes

OBJECTIVE To assess the association between circulating angiogenic and antiangiogenic factors in the second trimester and risk of preeclampsia in women with type 1 diabetes.

RESEARCH DESIGN AND METHODS Maternal plasma concentrations of placental growth factor (PlGF), soluble fms-like tyrosine kinase 1 (sFlt-1), and soluble endoglin (sEng) were available at 26 weeks of gestation in 540 women with type 1 diabetes enrolled in the Diabetes and Preeclampsia Intervention Trial.

RESULTS Preeclampsia developed in 17% of pregnancies (n = 94). At 26 weeks of gestation, women in whom preeclampsia developed later had significantly lower PlGF (median [interquartile range]: 231 pg/mL [120–423] vs. 365 pg/mL [237–582]; P < 0.001), higher sFlt-1 (1,522 pg/mL [1,108–3,393] vs. 1,193 pg/mL [844–1,630] P < 0.001), and higher sEng (6.2 ng/mL [4.9–7.9] vs. 5.1 ng/mL[(4.3–6.2]; P < 0.001) compared with women who did not have preeclampsia. In addition, the ratio of PlGF to sEng was significantly lower (40 [17–71] vs. 71 [44–114]; P < 0.001) and the ratio of sFlt-1 to PlGF was significantly higher (6.3 [3.4–15.7] vs. 3.1 [1.8–5.8]; P < 0.001) in women who later developed preeclampsia. The addition of the ratio of PlGF to sEng or the ratio of sFlt-1 to PlGF to a logistic model containing established risk factors (area under the curve [AUC], 0.813) significantly improved the predictive value (AUC, 0.850 and 0.846, respectively; P < 0.01) and significantly improved reclassification according to the integrated discrimination improvement index (IDI) (IDI scores 0.086 and 0.065, respectively; P < 0.001).

CONCLUSIONS These data suggest that angiogenic and antiangiogenic factors measured during the second trimester are predictive of preeclampsia in women with type 1 diabetes. The addition of the ratio of PlGF to sEng or the ratio of sFlt-1 to PlGF to established clinical risk factors significantly improves the prediction of preeclampsia in women with type 1 diabetes.

Preeclampsia is characterized by the development of hypertension and new-onset proteinuria during the second half of pregnancy (1,2), leading to increased maternal morbidity and mortality (3). Women with type 1 diabetes are at increased risk for development of preeclampsia during pregnancy, with rates being two-times to four-times higher than that of the background maternity population (4,5). Small advances have come from preventive measures, such as low-dose aspirin in women at high risk (6); however, delivery remains the only effective intervention, and preeclampsia is responsible for up to 15% of preterm births and a consequent increase in infant mortality and morbidity (7).

Although the etiology of preeclampsia remains unclear, abnormal placental vascular remodeling and placental ischemia, together with maternal endothelial dysfunction, hemodynamic changes, and renal pathology, contribute to its pathogenesis (8). In addition, over the past decade accumulating evidence has suggested that an imbalance between angiogenic factors, such as placental growth factor (PlGF), and antiangiogenic factors, such as soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sEng), plays a key role in the pathogenesis of preeclampsia (8,9). In women at low risk (10–13) and women at high risk (14,15), concentrations of angiogenic and antiangiogenic factors are significantly different between women who later develop preeclampsia (lower PlGF, higher sFlt-1, and higher sEng levels) compared with women who do not.

Few studies have specifically focused on circulating angiogenic factors and risk of preeclampsia in women with diabetes, and the results have been conflicting. In a small study, higher sFlt-1 and lower PlGF were reported at the time of delivery in women with diabetes who developed preeclampsia (16). In a longitudinal prospective cohort of pregnant women with diabetes, Yu et al. (17) reported increased sFlt-1 and reduced PlGF in the early third trimester as potential predictors of preeclampsia in women with type 1 diabetes, but they did not show any difference in sEng levels in women with preeclampsia compared with women without preeclampsia. By contrast, Powers et al. (18) reported only increased sEng in the second trimester in women with pregestational diabetes who developed preeclampsia.

The aim of this study, which was significantly larger than the previous studies highlighted, was to assess the association between circulating angiogenic (PlGF) and antiangiogenic (sFlt-1 and sEng) factors and the risk of preeclampsia in women with type 1 diabetes. A further aim was to evaluate the added predictive ability and clinical usefulness of angiogenic factors and established risk factors for preeclampsia risk prediction in women with type 1 diabetes.

Long-term renal outcomes of patients with type 1 diabetes mellitus and microalbuminuria:an analysis of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications cohort

Microalbuminuria is a common diagnosis in the clinical care of patients with type 1 diabetes mellitus. Long-term outcomes after the development of microalbuminuria are variable.

Metabolism of very low- and low-density lipoproteins isolated from normolipidaemic type 2 (non-insulin-dependent) diabetic patients by human monocyte-derived macrophages

The very low- and low-density lipoprotein fractions were isolated from 16 normolipidaemic Type 2 (non-insulin-dependent) diabetic patients in good to fair glycaemic control and from corresponding age-, sex-, and race-matched, non-diabetic control subjects. Rates of cholesteryl ester synthesis averaged 268 +/- 31 vs 289 +/- 40 pmol 14C-cholesteryl oleate.mg cell protein-1.20 h-1 for very low- and 506 +/- 34 vs 556 +/- 51 pmol 14C-cholesteryl oleate.mg cell protein-1.20 h-1 for low-density lipoproteins isolated from the Type 2 diabetic patients and control subjects, respectively, when they were incubated with human macrophages. A group of approximately one-third of the patients was selected for separate analyses because very low-density lipoproteins isolated from these patients did stimulate more cholesteryl ester synthesis when incubated with macrophages. There were no significant differences in the lipid composition of the lipoproteins isolated from the three groups of subjects. The relative proportion of apoprotein C to apoprotein E was significantly decreased (p less than 0.002) in the very low-density lipoproteins from diabetic patients and was further decreased in samples from these selected diabetic patients. The apoprotein C-I content of very low-density lipoproteins isolated from diabetic patients was increased compared to control subjects and was further increased in samples from the selected diabetic patients (p less than 0.02). There were no significant differences in the proportions of apoproteins C-III-0, C-III-1, or C-III-2 among the three groups. These studies suggest that in normolipidaemic Type 2 diabetic patients, the apoprotein composition of VLDL is abnormal and this may alter VLDL macrophage interactions and thus contribute to the increased prevalence of atherosclerosis in diabetic patients.

Non-enzymatic glycosylation of skin collagen in patients with type 1 (insulin-dependent) diabetes mellitus and limited joint mobility

Forearm skin biopsies were obtained from diabetic subjects with and without limited joint mobility, and from non-diabetic control subjects. Collagen purified from these samples was assayed for non-enzymatic glycosylation. The level in all diabetic patients was significantly greater than that in control subjects (p less than 0.001), but those diabetic patients with limited joint mobility had a level of collagen glycosylation similar to that in those with normal joints (15.3 +/- 1.3 and 16.5 +/- 1.3 nmol fructose/10 mg protein, respectively; mean +/- SEM). Glycosylation of collagen in the diabetic patients correlated with glycosylated haemoglobin measured at the time of skin biopsy (r = 0.60). These results do not support the hypothesis that non-enzymatic glycosylation of collagen, as reflected by the ketoamine link, plays an important role in the development of limited joint mobility in diabetes.