Effects of Hypoxia and Transferrin on Toxicity and DNA Binding of Ruthenium Antitumor Agents in Hela Cells

Nuclear DNA binding and inhibition of growth of HeLa cells in culture were determined after 24 h incubation with the ruthenium anticancer agents cis-[Cl2(NH3)4Ru]Cl (CCR) and (ImH)trans-[(Im)2Cl4Ru] (ICR) as a function of [Ru], Po2, and added transferrin. Consistent with the “activation-by-reduction” hypothesis, cytotoxicity and DNA binding for both complexes increased under reduced oxygen conditions. Consistent with the “transferrin- transport” hypothesis, inhibition of cell growth also increased with added transferrin for both complexes. Despite their differences in charge, reduction potentials and substitution rates, both complexes behaved remarkably similarly indicating a common mechanism of action for both. Under atmospheric Conditions (Po2 = 159 torr), CCR inhibited HeLa cell growth with IC50 = 3.5 μM, while that for ICR was 2.0 μM. The binding of both complexes to DNA (RuDNA/PDNA) correlated with toxicity and was approximately linear in the concentration of the ruthenium complex in the culture medium, [Ru]. For both complexes, IC50 values decrease and DNA binding increases with decreasing log(Po2). In general, DNA binding at all oxygen pressures for both complexes is in the range of one Ru per 1000-2000 DNA base pairs at [Ru] = IC50

Ultra-Efficient and Power Dense Electric Motors for U. S. Industry

The primary purpose of this project was to combine the ease-of-installation and ease-of-use attributes of industrial induction motors with the low-loss and small size and weight advantages of PM motors to create an ultra-efficient, high power density industrial motor that can be started across-the-line or operated from a standard, Volts/Hertz drive without the need for a rotor position feedback device. PM motor products that are currently available are largely variable speed motors that require a special adjustable speed drive with rotor position feedback. The reduced size and weight helps to offset the magnet cost in order make these motors commercially viable. The scope of this project covers horsepower ratings from 20 ? 500. Prototypes were built and tested at ratings ranging from 30 to 250 HP. Since fans, pumps and compressors make up a large portion of industrial motor applications, the motor characteristics are tailored to those applications. Also, since there is extensive use of adjustable frequency inverters in these applications, there is the opportunity to design for an optimal pole number and operate at other than 60 Hz frequency when inverters are utilized. Designs with four and eight pole configurations were prototyped as part of this work. Four pole motors are the most commonly used configuration in induction motors today. The results of the prototype design, fabrication, and testing were quite successful. The 50 HP rating met all of the design goals including efficiency and power density. Tested values of motor losses at 50 HP were 30% lower than energy efficient induction motors and the motor weight is 35% lower than the energy efficient induction motor of the same rating. Further, when tested at the 30 HP rating that is normally built in this 286T frame size, the efficiency far exceeds the project design goals with 30 HP efficiency levels indicating a 55% reduction in loss compared to energy efficient motors with a motor weight that is a few percentage points lower than the energy efficient motor. This 30 HP rating full load efficiency corresponds to a 46% reduction in loss compared to a 30 HP NEMA Premium? efficient motor. The cost goals were to provide a two year or shorter efficiency-based payback of a price premium associated with the magnet cost in these motors. That goal is based on 24/7 operation with a cost of electricity of 10 cents per kW-hr. Similarly, the 250 HP prototype efficiency testing was quite successful. In this case, the efficiency was maximized with a slightly less aggressive reduction in active material. The measured full load efficiency of 97.6% represents in excess of a 50% loss reduction compared to the equivalent NEMA Premium Efficiency induction motor. The active material weight reduction was a respectable 14.5% figure. This larger rating demonstrated both the scalability of this technology and also the ability to flexibly trade off power density and efficiency. In terms of starting performance, the 30 ? 50 HP prototypes were very extensively tested. The demonstrated capability included the ability to successfully start a load with an inertia of 25 times the motor?s own inertia while accelerating against a load torque following a fan profile at the motor?s full nameplate power rating. This capability will provide very wide applicability of this motor technology. The 250 HP prototype was also tested for starting characteristics, though without a coupled inertia and load torque. As a result it was not definitively proven that the same 25 times the motor?s own inertia could be started and synchronized successfully at 250 HP. Finite element modeling implies that this load could be successfully started, but it has not yet been confirmed by a test

Directional atherectomy: combining basic research and intervention

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Two years after molecular diagnosis of familial hypercholesterolemia: Majority on cholesterol-lowering treatment but a minority reaches treatment goal

Background: The risk of premature cardiovascular disease in patients with familial hypercholesterolemia (FH) can be profoundly reduced by cholesterol-lowering therapy, and current guidelines for FH advocate ambitious low-density lipoprotein cholesterol (LDL-C) goals. In the present study, we determined whether these goals are reflected in current clinical practice once FH has been diagnosed. Methodology/Principal Findings: In 2008, we sent questionnaires to all subjects (aged 18-65 years) who were molecularly diagnosed with FH in the year 2006 through the screening program in the Netherlands. Of these 1062 subjects, 781 completed the questionnaire (46% males; mean age: 42±12 years; mean LDL-C at molecular diagnosis (baseline): 4.1±1.3 mmol/L). The number of persons that used cholesterol-lowering therapy increased from 397 (51%) at baseline to 636 (81%) after diagnosis. Mean treated LDL-C levels decreased significantly to 3.2±1.1 mmol/L two years after diagnosis. Only 22% achieved the LDL-C target level of ≤2.5 mmol/L. Conclusions/Significance: The proportion of patients using cholesterol-lowering medication was significantly increased after FH diagnosis through

Histologic characteristics of tissue excised during directional coronary atherectomy in stable and unstable angina pectoris

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Acute complications of percutaneous transluminal coronary angioplasty for total occlusion

The incidence of major complications after percutaneous coronary angioplasty (PTCA) of a totally occluded artery was assessed retrospectively. A total of 1649 PTCA procedures were analyzed. After exclusion of procedures for acute myocardial infarction or total occlusion that resulted from restenosis, 90 patients wer

Directional atherectomy for treatment of restenosis within coronary stents: clinical, angiographic and histologic results

Abstract OBJECTIVES: The safety and long-term results of directional coronary atherectomy in stented coronary arteries were determined. In addition, tissue studies were performed to characterize the development of restenosis. METHODS: Directional coronary atherectomy was performed in restenosed stents in nine patients (10 procedures) 82 to 1,179 days after stenting. The tissue was assessed for histologic features of restenosis, smooth muscle cell phenotype, markers of cell proliferation and cell density. A control (no stenting) group consisted of 13 patients treated with directional coronary atherectomy for restenosis 14 to 597 days after coronary angioplasty, directional coronary atherectomy or laser intervention. RESULTS: Directional coronary atherectomy procedures within the stent were technically successful with results similar to those of the initial stenting procedure (2.31 +/- 0.38 vs. 2.44 +/- 0.35 mm). Of five patients with angiographic follow-up, three had restenosis requiring reintervention (surgery in two and repeat atherectomy followed by laser angioplasty in one). Intimal hyperplasia was identified in 80% of specimens after stenting and in 77% after coronary angioplasty or atherectomy. In three patients with stenting, 70% to 76% of the intimal cells showed morphologic features of a contractile phenotype by electron microscopy 47 to 185 days after coronary intervention. Evidence of ongoing proliferation (proliferating cell nuclear antigen antibody studies) was absent in all specimens studied. Although wide individual variability was present in the maximal cell density of the intimal hyperplasia, there was a trend toward a reduction in cell density over time. CONCLUSIONS: Although atherectomy is feasible for the treatment of restenosis in stented coronary arteries and initial results are excellent, recurrence of restenosis is common. Intimal hyperplasia is a nonspecific response to injury regardless of the device used and accounts for about 80% of cases of restenosis. Smooth muscle cell proliferation and phenotypic modulation toward a contractile phenotype are early events and largely completed by the time of clinical presentation of restenosis. Restenotic lesions may be predominantly cellular, matrix or a combination at a particular time after a coronary procedure

Persistently elevated levels of sST2 after acute coronary syndrome are associated with recurrent cardiac events

Purpose Higher soluble ST2 (sST2) levels at admission are associated with adverse outcome in acute coronary syndrome (ACS) patients. We studied the dynamics of sST2 over time in post-ACS patients prior to a recurrent ACS or cardiac death. Methods We used the BIOMArCS case cohort, consisting of 187 patients who underwent serial blood sampling during one-year follow-up post-ACS. sST2 was batch-wise quantified after completion of follow-up in a median of 8 (IQR: 5-11) samples per patient. Joint modelling was used to investigate the association between longitudinally measured sST2 and the endpoint, adjusted for gender, GRACE risk score and history of cardiovascular diseases. Results Median age was 64 years and 79% were men. The 36 endpoint patients had systematically higher sST2 levels than those that remained endpoint free (mean value 29.6 ng/ml versus 33.7 ng/ml, p-value 0.052). The adjusted hazard ratio for the endpoint per standard deviation increase of sST2 was 1.64 (95% confidence interval: 1.09-2.34; p = 0.019) at any time point. We could not identify a steady or sudden increase of sST2 in the run-up to the combined endpoint. Conclusion Asymptomatic post-ACS patients with persistently higher sST2 levels are at higher risk of recurrent ACS or cardiac death during one-year follow-up