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Engaging physicians and practice leaders through regular performance reporting is a key goal of patient-centered medical home improvement efforts. We developed and implemented an interactive, Web-based performance dashboard for primary care practices with input from provider focus groups. Adapting a business software application, individual physician and practice-level reports included information on visit-based and panel productivity, patient panel demographics, and outcome measures (quality of care, patient experience of care, and resource utilization). User training occurred prior to dissemination. Over 2 rounds of reporting, 69% to 77% of users viewed their report within 30 days and 79% of users found the report informative.

Background: Fractional Flow Reserve (FFR) is a proven technology for guiding percutaneous coronary intervention (PCI), but is not reimbursed despite the fact that it is frequently used to defer PCI., Methods: Costs incurred with use of FFR were compared in both the public and private sectors with the costs that would have been incurred if the technology was not available using consecutive cases over a two year period in a public teaching hospital and its co-located private hospital., Results: FFR was performed on 143 lesions in 120 patients. FFR was < 0.80 in 37 lesions in 34 patients and 25 underwent PCI while 11 had CABG. It was estimated that without FFR 78 lesions in 70 patients would have had PCI with 17 patients having CABG with 35 additional functional tests. Despite a cost of $A1200 per wire, FFR actually saved money. Mean savings in the public sector were $1200 per patient while in the private sector the savings were $5000 per patient., Conclusions: FFR use saves money for the Federal Government in the public sector and for the Private Health Funds in the private sector. These financial benefits are seen in addition to the improved outcomes seen with this technology., (Copyright © 2014. Published by Elsevier B.V.)

Peripheral vascular disease affects ~20 % of the population over 50 years of age and is a complication of type 2 diabetes. Cell therapy studies revealed that cells from older or diabetic donors have a reduced capacity to induce tissue repair compared to healthy and younger cells. This fact greatly impedes the use of autologous cells for treatment. Umbilical cord blood CD34+ cells are a source of angiogenic cells but unlike bone marrow CD34+ angiogenic cells, achieving clinically significant cell numbers has been difficult without in vitro expansion. We report here that culturing CD34+/CD45+ blood cells from frozen umbilical cord blood units in a medium supplemented with FGF4, SCF and FLT3-ligand produced a population of cells that remain CD34+/CD45+ but have an increased capacity for tissue healing. The cultured CD34+ cells were compared directly to non-cultured CD34+ cells in a mouse model of ischemia. Cultured CD34+ cells demonstrated strong paracrine signaling as well as the capacity to differentiate into endothelial cells, smooth muscle and striated muscle. We observed an improvement in blood flow and a significant reduction in foot necrosis. A second study was completed to assess the safety of the cells. No adverse effects were associated with the injection of the cultured cells. Our method described here for culturing umbilical cord blood cells resulted in cells with a strong paracrine effect that induces substantial tissue repair in a murine model of hind limb ischemia and evidence of engraftment and differentiation of the cultured cells into new vasculature and muscle.

Aim: Cell therapy has been shown to be effective in improving LV function postmyocardial infarction (MI). We hypothesized that eNOS-transfected bone marrow cells (BMCs) are safe in a swine model of myocardial infarction (MI). We also hypothesized that endothelial nitric oxide synthase (eNOS) transfection would enhance cell function, as assessed by myocardial functional recovery post-MI., Methods: Fifteen female Yorkshire pigs underwent bone marrow aspiration and creation of MI. Bone marrow cells were cultured for 7 days, and each pig received either autologous BMCs transiently transfected with eNOS plasmid (eNOS-BMC, n = 5), nontransfected BMCs (nt-BMC, n = 4), or phosphate-buffered saline (PBS) control (n = 6). Cardiac MRI was performed at baseline (1 week post-MI) and 6 weeks post-MI., Results: There was no difference in safety outcomes between groups. Absolute left ventricular ejection fraction (LVEF) at 6 weeks showed a trend toward improvement in both cell therapy groups compared with baseline but worsened in the PBS control group. The absolute improvement in LVEF was significantly greater in both cell therapy groups compared with PBS control. Infarct mass was significantly lower in the eNOS-BMC group between baseline and 6 weeks, but the absolute change in infarct mass was not different between groups. Finally, there was a trend toward reduced LV mass in the eNOS-BMC group., Conclusions: Bone marrow cell delivery, with and without eNOS overexpression, is safe and leads to improvement in LVEF when administered in the coronary circulation 7 days following acute MI in swine. Transfection of healthy BMCs with eNOS resulted in some improvement in left ventricular remodeling. Further study is warranted in a preclinical model that approximates the impact of cardiovascular risk factors on BMC function., (© 2013 John Wiley & Sons Ltd.)

Background: The Sgarbossa score has been used to identify acute myocardial infarction on ECG in the presence of LBBB but has relied on elevated CK-MB for validation rather than angiographic evidence of vessel occlusion., Methods: We determined (a) the presence or absence of Sgarbossa criteria with concordant (S-con) or discordant (S-dis) ST changes, (b) the presence of acute coronary occlusion or likely recent occlusion on angiography and (c) the biochemical evidence of myocardial infarction (Troponin T >0.10 μg/L, Troponin I >1.0 μg/L) in patients field-triaged with suspected AMI and LBBB., Results: Between April 2004 and March 2009, 102 patients had field ECGs transmitted by paramedics for triage--8 with S-con, 26 with S-dis and 68 with LBBB alone. Acute coronary occlusion was present in 8/8 with S-con but none of the S-dis or LBBB alone patients, and in all 8 S-con patients reperfusion resulted in resolution of S-con changes. Likely culprit lesions with TIMI 3 flow were found in 3 S-dis patients but stenting did not result in resolution of S-dis. LBBB did not resolve in any patient. Troponin was elevated in 26 patients--11 with occlusion or likely culprit lesions, 15 with non-ischaemic causes., Conclusions: In the absence of S-con, LBBB is not associated with acute coronary occlusion and should not be used as criteria for reperfusion therapy in myocardial infarction., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Purpose: Enhancing clinician-investigator (CI) training at Canadian medical schools is urgently needed to bolster the dwindling work force of medical professionals carrying out patient-oriented research in a wide array of medical fields. The purpose of this study is to obtain, from the 15 Canadian medical schools that offer one or more CI training programs, data on the number of trainees, funding levels, attrition rates or other important metrics to evaluate the outcomes of such training efforts., Methods: All Canadian CI programs were surveyed to collect demographic information for the academic year 2010-2011 and compared this to historical data collected by the Association of Faculties of Medicine of Canada (AFMC) and MD/PhD program funding data from the Canadian Institutes of Health Research (CIHR)., Results: Over the past decade, enrolment in Canadian CI training programs has increased approximately four-fold. Program-specific funding (CIHR) has also increased, but nearly 50% of MD/PhD trainees are still not supported through dedicated CIHR funding., Conclusion: It is too early to know to what extent this increase in both CI and funding will sustain the workforce of Canadian researchers carrying out patient-oriented research. Monitoring of CI training demographics across Canada, beyond this baseline study, will be essential to measure outcomes from CI training programs and to guide response from funding bodies and policy-makers.

Aims: Takotsubo cardiomyopathy (TC) is an increasingly recognized syndrome in which patients present with chest pain and ST changes, and are observed to have reversible LV apical ballooning in the absence of angiographically significant coronary artery stenosis. Although the pathophysiology remains unclear, the syndrome occurs almost exclusively in women, and is often triggered by stress. Recent small studies have reported association of TC with functional variants in the G-protein-coupled receptor kinase 5 (GRK5) gene, as well as in the β1-adrenergic receptor (β1AR) and β2AR., Methods and Results: We tested these associations in a larger cohort of 92 TC patients. In addition we examined for the association of polymorphisms in the oestrogen receptor α (ERα) and catechol-O-methyl transferase (COMT) with the occurrence of TC, by comparing the allele frequency of these variants in the TC cohort with that in previously genotyped large Caucasian cohorts. Ninety-two patients with TC were recruited from four Australian centres; they had an age range of 41-90 years (mean ± SD = 66.3 ± 9) and 89/92 were female. There were no significant differences in allelic frequency in the TC group vs. the historic control database for any of the loci., Conclusion: In the largest genotyped TC cohort in the literature, we have found no association of genetic variants in the ERα, β1AR, β2AR, or COMT genes, or with the previously implicated GRK5, with occurrence of the syndrome.

Objectives: Diabetes mellitus (DM) is associated with impairment of endothelial progenitor cells (EPCs), but the effects of metabolic syndrome (MS) on EPCs have been less well characterized. We hypothesized that in the presence of MS, the number and functionality of EPCs would be markedly reduced, and would be similar to DM., Methods: Mononuclear cells were isolated from the bone-marrow (BM) and peripheral blood of lean Zucker, obese Zucker, a model of MS, and Zucker diabetic fatty rats. Cultured BM-EPCs underwent in vitro functional testing and the ability of BM-EPCs to promote neovascularization in vivo was assessed in a model of hindlimb ischemia in athymic mice., Results: While circulating EPC numbers were similarly reduced in both MS and DM rats, BM-derived EPC numbers were less affected. In vitro testing of cultured BM-EPCs from obese Zucker demonstrated a marked reduction in EPC differentiation, a greater propensity to apoptosis, a reduced migratory response and matrigel tubule formation, similar to findings in Zucker diabetic fatty rats. When delivered to the ischemic hindlimb of athymic mice, the recovery of perfusion using both BM-EPCs from obese Zucker and Zucker diabetic fatty rats were diminished, as compared to lean Zuckers., Conclusion: In the presence of the MS, BM-derived EPCs develop marked functional impairment, resulting in severely reduced angiogenic capacity in vivo. Similar to DM, EPC dysfunction may play a prominent role in the pathogenesis of vascular complications in the MS, and may potentially limit the use of BM-derived EPCs for therapeutic angiogenesis., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Measurements of second-harmonic scattering (SHS) from concentrated aqueous solutions of urea are reported for the first time using scanning microscopy. SHS signal was measured as a function of solution concentration (C) over a range of saturation conditions from undersaturated (S = 0.15) to supersaturated (5 = 1.86), where S = C/C(sat) and C(sat) is the saturation concentration. The results show a non-linear increase in SHS signal against concentration, with local maxima near S = 0.95 and 1.75 suggesting a change in solution structure near these points. Rayleigh scattering images indicate the presence of particles in nearly saturated (S = 0.95) urea solutions. Time-dependent SHS measurements indicate that signals originate from individual events encountered during scanning of the focal volume through the solution, consistent with second harmonic generation (SHG) from particles. SHG from aqueous dispersions of barium titanate (BaTiO3) nanoparticles with diameters <200 nm, showed signals approximately 20 times larger than urea solutions. The results suggest the existence of a population of semi-ordered clusters of urea that changes with solution concentration.

Aims: Patients aged ≥80 years are often excluded or under-represented in trials assessing treatment modalities in STEMI. We assessed in-patient outcomes in elderly patients undergoing contemporary primary PCI (PPCI)., Methods and Results: From Sept 2005 to July 2011 patients undergoing PPCI in our centre were identified. Demographic details, procedural data and in-patient outcomes were collated. Those aged ≥80 years were compared with those aged <80 years. In the study period 1,218 patients required PPCI, of which 224(18.4%) were ≥80 years. The elderly cohort were more likely to be female (44.3% vs. 20.3%; p<0.001), and have significant comorbidities. Times from first medical contact until TIMI 3 flow were similar between the two groups (medien 102 min vs. 109 min; p=0.19). There was no difference in rates of PCI success (97.3% vs. 98.3%; p=0.24), drug-eluting stent use (63.5% vs. 63.3%; p=1.00) and number of stents used. In-patient outcomes were worse in the elderly cohort with significantly higher rates of death (11.2% vs. 3.7%; p<0.001) and acute kidney injury (12.9% vs. 4.0%; p<0.001), with a trend towards more post-procedure cardiovascular accidents (CVA), access site complications and reinfarction. Length of stay was significantly longer in the elderly cohort (median days 5 vs. 3; p<0.001)., Conclusions: Important demographic differences exist in very elderly patients presenting with STEMI compared to younger patients though procedural data and PCI success rates are similar between the two groups. Those aged ≥80 years have significantly worse in-patient outcomes though death rates are not as high as historical data suggests.

Background: STEMI and unstable acute coronary syndromes are associated with widespread adrenergic activation which may increase radial artery (RA) spasm, requiring cross-over to the femoral artery (FA) during percutaneous coronary intervention (PCI). We assessed the incidence of failed trans-radial artery PCI in emergency cases compared with non-emergency cases., Methods: PCI procedures performed by default radial artery operators were assessed in our centre over a 25 month period. Those who had both RA and FA access were identified to assess if the double punctures were elective or due to failure of the RA approach. Cross-over rates were compared between emergency and non-emergency cases., Results: 680 cases of PCI were performed, 153 in an emergency setting. In non-emergency cases 403/527 (76.5%) were performed via the RA. In the emergency setting 139/153 (90.8%) were completed by the RA. Previous CABG with multiple arterial conduits was the most common reason for elective FA PCI in both groups. The RA to FA cross-over rate was low with no significant difference between the emergency and non-emergency groups (emergency 1.4%, non-emergency 1.2%, p=1.0). In both groups there was no significant difference between RA and FA procedures in terms of fluoroscopy times (emergency: mean 13.1 ± 7.9 min vs 16.1 ± 16.1 min, p=.25, non-emergency: 16.6 ± 10.3 min vs 18.7 ± 13.6 min, p=.07) or contrast volumes (emergency: mean 231 ± 126 ml vs 229 ± 102 ml, p=.77, non-emergency: 223 ± 85 ml vs 237 ± 91 ml, p=.15)., Conclusions: The vast majority of PCI can be successfully performed via the RA. Cross-over rates to the FA are low and are not more common in emergency patients., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Non-photochemical laser-induced nucleation (NPLIN) of glacial acetic acid (GAA) is demonstrated. The fraction of samples nucleated depends linearly on peak laser power density at low powers (<100 MW cm(-2)) with a threshold of (9.0 ± 4.2) MW cm(-2); at higher laser powers the fraction reaches a plateau of 0.75 ± 0.24 (2σ uncertainties). A simple model based on polarizability of pre-nucleating clusters gives a value of the solid-liquid interfacial tension γ(SL) = 15.5 mJ m(-2). It is hoped that the results will stimulate new developments in experimental and theoretical studies of cluster structure and nucleation in liquids.

Background: The prognosis of patients with relapsed Hodgkin's lymphoma, especially those who relapse after stem-cell transplantation, is poor, and the development of new agents for this patient population is an unmet medical need. We tested the safety and efficacy of mocetinostat, an oral isotype-selective histone deacetylase inhibitor, in patients with relapsed classical Hodgkin's lymphoma., Methods: Patients with relapsed or refractory classical Hodgkin's lymphoma aged 18 years or older were treated with mocetinostat administered orally three times per week, in 28-day cycles. Two doses were assessed (85 mg and 110 mg). Patients were treated until disease progression or prohibitive toxicity. The primary outcome was disease control rate, defined as complete response, partial response, or stable disease (for at least six cycles), analysed by intention to treat. This trial has been completed and is registered with ClinicalTrials.gov, number NCT00358982., Findings: 51 patients were enrolled. Initially, 23 patients were enrolled in the 110 mg cohort. Subsequently, because toxicity-related dose reductions were necessary in the 110 mg cohort, we treated 28 additional patients with a dose of 85 mg. On the basis of intent-to-treat analysis, the disease control rate was 35% (eight of 23 patients) in the 110 mg group and 25% (seven of 28) in the 85 mg group. 12 patients (24%) discontinued treatment because of adverse events, nine (32%) in the 85 mg cohort and three (13%) in the 110 mg cohort. The most frequent treatment-related grade 3 and 4 adverse events were neutropenia (four patients [17%] in the 110 mg group, three [11%] in the 85 mg group); fatigue (five patients [22%] in the 110 mg group, three [11%] in the 85 mg group); and pneumonia (four patients [17%] in the 110 mg group, two [7%] in the 85 mg group). Four patients, all in the 110 mg cohort, died during the study, of which two might have been related to treatment., Interpretation: Mocetinostat, 85 mg three times per week, has promising single-agent clinical activity with manageable toxicity in patients with relapsed classical Hodgkin's lymphoma., Funding: MethylGene Inc, Montreal, Canada; Celgene Corporation, Summit, NJ, USA; Tufts Medical Center, Boston, MA, USA., Competing Interests: AY received consulting fees in relation to this study from Methylgene. He also provided consultancy to Celgene, Seattle Genetics, Novartis, Syndax, and Sanofi. JB, ZL, MD, and TP are employees of Methylgene. RW is an employee of Celgene. REM is a previous employee of Methylgene and has stock ownership in the company. YO, GB, JK, MF, SN, AC, DB, AG, YJ, JKP and LJM dclare that they have no conflict of interest, (Copyright © 2011 Elsevier Ltd. All rights reserved.)

We report the observation of non-photochemical laser-induced nucleation (NPLIN) of sodium chlorate from its melt using nanosecond pulses of light at 1064 nm. The fraction of samples that nucleate is shown to depend linearly on the peak power density of the laser pulses. Remarkably, we observe that most samples are nucleated by the laser back into the enantiomorph (dextrorotatory or levorotatory) of the solid prior to melting. We do not observe a significant dependence on polarization of the light, and we put forward symmetry arguments that rule out an optical Kerr effect mechanism. Our observations of retention of chirality can be explained by decomposition of small amounts of the sodium chlorate to form sodium chloride, which provide cavities for retention of clusters of sodium chlorate even 18 °C above the melting point. These clusters remain sub-critical on cooling, but can be activated by NPLIN via an isotropic polarizability mechanism. We have developed a heterogeneous model of NPLIN in cavities, which reproduces the experimental data using simple physical data available for sodium chlorate.

Circulating angiogenic cells (CACs), represent a potential new therapeutic tool for the treatment of cardiovascular diseases, but their regenerative function is impaired in patients with coronary artery disease (CAD) and cardiac risk factors. The objective of this study is to assess the effect of lentiviral overexpression of endothelial nitric oxide synthase (eNOS) on the activity of CACs from patients with CAD and cardiac risk factors. In vitro and in vivo assays were employed to evaluate the regenerative capacity of the cells compared to CACs derived from healthy volunteers. Lentiviral eNOS transduction of cells from CAD patients significantly improved chemotactic migration compared with sham transduction, and increased the ability of CACs to induce angiogenic tube formation when cocultured with human umbilical vein endothelial cells (HUVECs) on Matrigel. In addition, eNOS transduction restored the ability of patient-derived CACs to enhance neovascularization and improve ischemic hind limb perfusion, approaching the efficacy of cells from healthy donors. These data indicate that CAC dysfunction seen in high-risk patients can be partially reversed by eNOS overexpression, suggesting that ex vivo gene delivery may improve the efficacy of autologous cell therapy for cardiovascular disease.

Cardiac magnetic resonance imaging is a noninvasive technique for assessing heart structure and function without the need for ionizing radiation. Its ability to precisely outline regions of myocardial ischemia and infarction gives it an important role in guiding interventional cardiologists in revascularization. Its ability to characterize and precisely quantify abnormal regurgitant flow volumes or abnormal shunts also makes it a valuable tool for many noncoronary interventions. This review will discuss the evidence for cardiac magnetic resonance in guiding complex therapies in the catheter laboratory, as well as practical issues that need to be addressed to allow the application of this powerful tool to an increasing number of our patients., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Heat shock factor 1 (HSF1) is a stress-induced transcription factor that promotes expression of genes that protect mammalian cells from the lethal effects of severely elevated temperatures (>42°C). However, we recently showed that HSF1 is activated at a lower temperature (39.5°C) in T cells, suggesting that HSF1 may be important for preserving T cell function during pathogen-induced fever responses. To test this, we examined the role of HSF1 in clearance of Listeria monocytogenes, an intracellular bacterial pathogen that elicits a strong CD8(+) T cell response in mice. Using temperature transponder microchips, we showed that the core body temperature increased approximately 2°C in L. monocytogenes-infected mice and that the fever response was maintained for at least 24 h. HSF1-deficient mice cleared a low-dose infection with slightly slower kinetics than did HSF1(+/+) littermate controls but were significantly more susceptible to challenges with higher doses of bacteria. Surprisingly, HSF1-deficient mice did not show a defect in CD8(+) T cell responses following sublethal infection. However, when HSF1-deficient mice were challenged with high doses of L. monocytogenes, increased levels of serum tumor necrosis factor alpha (TNF-α) and gamma interferon (IFN-γ) compared to those of littermate control mice were observed, and rapid death of the animals occurred within 48 to 60 h of infection. Neutralization of TNF-α enhanced the survival of HSF1-deficient mice. These results suggest that HSF1 is needed to prevent the overproduction of proinflammatory cytokines and subsequent death due to septic shock that can result following high-dose challenge with bacterial pathogens.

Objective: Restenosis after both angioplasty and stenting is flow dependent. The effects of flow are preventable with the antioxidant pyrrolidine dithiocarbamate (PDTC) after angioplasty but not after stenting. We examined to what extent these observations could be explained by the effect of PDTC on NF-κB and Egr-1, two transcription factors which are both flow- and redox-sensitive., Methods: In a flow-modified rabbit carotid model of angioplasty and stenting, we assessed the effects of altered flow, injury and PDTC on expression of Egr-1 and nuclear binding activity of NF-κB. We also examined the effects of local delivery of decoy oligodeoxynucleotides (ODN) specific for NF-κB and Egr-1 on morphology at 28 days in normal and low flow., Results: The activity of both transcription factors was enhanced by injury (stent>balloon alone) and was further augmented by low flow. PDTC markedly attenuated the activity of NF-κB but not Egr-1. Specific decoy ODN for Egr-1 attenuated intima formation in both stented and balloon injured vessels in both normal and low flow but had no effect on remodelling. In contrast while NF-κB decoy ODN caused a modest but significant reduction in intima formation, there was a striking effect on remodelling in low flow vessels only., Conclusions: We conclude that Egr-1 plays a pivotal role in intima formation under all flow conditions and that NF-κB plays a key role in flow-sensitive remodelling after angioplasty and that NF-κB inhibition likely accounts for a significant part of the morphological effects of PDTC after vessel injury., (Crown Copyright © 2010. Published by Elsevier Ireland Ltd. All rights reserved.)

Enantiomorphic symmetry breaking of stirred samples of molten sodium chlorate is demonstrated, revealing the unexpected involvement of an achiral solid phase. The results should stimulate future computational models of nucleation, including symmetry breaking, and have implications for mechanisms that invoke enantiomorphism in natural minerals to explain biohomochirality.

Drug-eluting stents (DES) are highly effective in reducing restenosis but have a small but significant risk for late stent thrombosis (LAST). Cessation of antiplatelet drugs for noncardiac surgery has been implicated in precipitating LAST, prompting surgery to be done on antiplatelet therapy, with all the attendant bleeding risks, or deferred until 12 months after DES implantation, despite limited data defining the risk for LAST. Using billing data from 2 large health funds, members who had DES insertion (n = 9,321) with subsequent noncardiac surgery (n = 4,126) were mailed a questionnaire regarding their noncardiac procedures, antiplatelet use, and subsequent coronary events. From 1,086 returned, 710 were suitable for inclusion, identifying 11 patients (1.5%) with perioperative myocardial infarctions confirmed by medical records. Angiography showed that only 2 had stent thromboses, while 7 had new culprit lesion (2 patients did not undergo angiography). Before their noncoronary procedures, 66% were receiving dual-antiplatelet therapy, and 30% were taking single agents. Surgery was performed on dual therapy in 18%, on single agents in 23%, and with no antiplatelet therapy in 59%. The mean time to surgery from stent implantation was 348 days, with 56% <12 months. In conclusion, noncardiac surgery after DES implantation is frequent and appears to have low cardiac morbidity despite variable antiplatelet cessation. Perioperative myocardial infarctions occur because of narrowings in nonstented coronary arteries rather than from LASTs., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Magnetic resonance imaging (MRI) can track progenitor cells following direct intramyocardial injection. However, in the vast majority of post-myocardial infarction (MI) clinical trials, cells are delivered by the intracoronary (IC) route, which results in far greater dispersion within the myocardium. Therefore, we assessed whether the more diffuse distribution of cells following IC delivery could be imaged longitudinally with MRI. In 11 pigs (7 active, 4 controls), MI was induced by 90-min balloon occlusion of the left anterior descending coronary artery. Seven (0) days [median (interquartile range)] following MI, bone marrow progenitor cells (BMCs) were colabeled with an iron-fluorophore and a cell viability marker and delivered to the left anterior descending coronary artery distal to an inflated over-the-wire percutaneous transluminal coronary angioplasty balloon. T2*-weighted images were used to assess the location of the magnetically labeled cells over a 6-wk period post-MI. Immediately following cell delivery, hypointensity characteristic of the magnetic label was observed in the infarct border rather than within the infarct itself. At 6 wk, the cell signal hypointensity persisted, albeit with significantly decreased intensity. BMC delivery resulted in significant improvement in infarct volume and ejection fraction (EF): infarct volume in cell-treated animals decreased from 7.1 +/- 1.5 to 4.9 +/- 1.0 ml (P < 0.01); infarct volume in controls was virtually unchanged at 4.64 +/- 2.1 to 4.39 +/- 2.1 ml (P = 0.7). EF in cell-treated animals went from 30.4 +/- 5.2% preinjection to 34.5 +/- 2.5% 6 wk postinjection (P = 0.013); EF in control animals went from 34.3 +/- 4.7 to 31.9 +/- 6.8% (P = 0.5). Immunohistochemical analysis revealed intracellular colocalization of the iron fluorophore and cell viability dye with the labeled cells continuing to express the same surface markers as at baseline. MRI can track the persistence and distribution of magnetically labeled BMCs over a 6-wk period following IC delivery. Signal hypointensity declines with time, particularly in the first week following delivery. These cells maintain their original phenotype during this time course. Delivery of these cells appears safe and results in improvement in infarct size and left ventricular ejection fraction.

Background: Despite the widespread use of pharmacological and/or interventional reperfusion therapies, recovery of cardiac function in myocardial infarction (MI) patients is often modest or even absent. Unlike classical pharmacological treatments, the use of progenitor cells could potentially restore functional tissue in regions that otherwise would form only scar. However, a major limitation of autologous cell therapy is the deleterious influence of age and cardiac risk factors on progenitor cell activity., Trial Design: The ENACT-AMI trial is a phase IIb, double-blind, randomized placebo-controlled trial, using transplantation of autologous early endothelial progenitor cells (EPCs) for patients who have suffered large MI. Circulating mononuclear cells (MNCs) are obtained by apheresis and subjected to differential culture for 3 days to select a population of highly regenerative, endothelial-like, culture modified MNCs (E-CMMs), often referred to as "early EPCs." A total of 99 patients will be randomized to placebo (Plasma-Lyte A), autologous E-CMMs, or E-CMMs transfected with human endothelial nitric oxide synthase delivered by coronary injection into the infarct-related artery. The primary efficacy end point is change from baseline to 6 months in global left ventricular ejection fraction by cardiac MRI; secondary endpoints include regional wall motion, wall thickening, infarct volume, time to clinical worsening, and quality of life., Conclusions: This will be the first clinical trial to include a strategy designed to enhance the function of autologous progenitor cells by overexpressing endothelial nitric oxide synthase, and the first to use combination gene and cell therapy for the treatment of cardiac disease.

Thienopyridines are a class of drug targeting the platelet adenosine diphosphate (ADP) 2 receptor. They significantly reduce platelet activity and are therefore clinically beneficial in settings where platelet activation is a key pathophysiological feature, particularly myocardial infarction. Ticlopidine, the first of the class introduced to clinical practice, was soon challenged and almost completely replaced by clopidogrel for its better tolerability. More recently, prasugrel and ticagrelor have been shown to provide a more powerful antiplatelet action compared to clopidogrel but at a cost of higher risk of bleeding complications. Cangrelor, a molecule very similar to ticagrelor, is currently being evaluated against clopidogrel. Considering the key balance of ischemic protection and bleeding risk, this paper discusses the background to the development of prasugrel, ticagrelor, and cangrelor and aims to characterise their risk-benefit profile and possible implementation in daily practice.

Objective: Insulin has both growth-promoting and protective vascular effects in vitro, however the predominant effect in vivo is unclear. We investigated the effects of insulin in vivo on neointimal growth after arterial injury., Methods and Results: Rats were given subcutaneous control (C) or insulin implants (3U/d;I) 3 days before arterial (carotid or aortic) balloon catheter injury. Normoglycemia was maintained by oral glucose and, after surgery, by intraperitoneal glucose infusion (saline in C). Insulin decreased intimal area (P<0.01) but did not change intimal cell proliferation or apoptosis. However, insulin inhibited cell migration into the intima (P<0.01) and increased expression of smooth muscle cell (SMC) differentiation markers (P<0.05). Insulin also increased reendothelialization (P<0.01) and the number of circulating progenitor cells (P<0.05)., Conclusions: These results are the first demonstration that insulin has a protective effect on both SMC and endothelium in vivo, resulting in inhibition of neointimal growth after vessel injury.

A majority of malignant melanomas harbor an oncogenic mutation in either BRAF or NRAS. If BRAF and NRAS transform melanoma cells by a similar mechanism, then additional genetic aberrations would be similar (or random). Alternatively, distinct mutation-associated changes would suggest the existence of unique cooperating requirements for each mutation group. We first analyzed a panel of 52 melanoma cell lines (n = 35, 11, 6 for BRAF*, NRAS*, and BRAF/NRAS(wt/wt), respectively) by array-based comparative genomic hybridization for unique alterations that associate with each mutation subgroup. Subsequently, those DNA copy number changes that correlated with a mutation subgroup were used to predict the mutation status of an independent panel of 43 tumors (n = 17, 13, 13 for BRAF*, NRAS*, and BRAF/NRAS(wt/wt), respectively). BRAF mutant tumors were classified with a high rate of success (74.4%, P = 0.002), whereas NRAS mutants were not significantly distinguished from wild types (26/43, P = 0.12). Copy number gains of 7q32.1-36.3, 5p15.31, 8q21.11, and 8q24.11 were most strongly associated with BRAF* tumors and cell lines, as were losses of 11q24.2-24.3. BRAF* melanomas appear to be associated with a specific profile of DNA copy number aberrations that is distinct from those found in NRAS* and BRAF/NRAS(wt/wt) tumors. These findings suggest that although both BRAF and NRAS appear to function along the same signal transduction pathway, each may have different requirements for cooperating oncogenic events. The genetic loci that make up this profile may harbor therapeutic targets specific for tumors with BRAF mutations., (Copyright 2009 Wiley-Liss,Inc.)

Background: Computed tomography (CT) has become the preferred method for evaluation of the abdomen for victims of blunt trauma. Grading of liver injuries, primarily by CT, has been advocated as a measure of severity and, by implication, the likelihood for intervention or complications. We have sought to determine if grading of liver injuries, as a clinical tool, affects immediate or extended management of patients., Methods: We have retrospectively reviewed all patients sustaining blunt liver injuries as diagnosed by CT over a five-year period at a Level I trauma center to determine if grading of injury influenced management. The AAST organ scaling system was utilized (major grade 4-5, minor grade 1-3), as well as the ISS, AIS, mortality, morbidity, and treatment. There were 133 patients available for review. The patients were grouped into major (n = 20) and minor (n = 113) liver injuries and operative (n = 12) and nonoperative (n = 121) management., Results: Major liver injuries had a higher ISS (39 + 13 vs. 27 + 15, p = 0.001) and were more likely to require operative intervention (5/20 vs. 7/113, p = 0.02). Mortality in this group was not different (major vs. minor), and there were no differences in the incidence of complications. Twelve patients (9%) required operation, all for hemodynamic instability, all within 24 h, and 11/12 within 6 h. At operation 8/12 patients had other sources of bleeding beside the liver injury, and 7/12 had minor hepatic injuries. The operative patients had higher ISS and AIS scores (head/neck, chest, abdomen, extremities) than those managed nonoperatively. More patients died in the operative group (6/12 vs. 8/121, p = 0.0003). There were more pulmonary (6/12 vs. 16/121, p = 0.005), cardiovascular (6/12 vs. 19/121, p = 0.01), and infectious (5/12 vs. 20/121, p = 0.049) complications in the operative group. There were 14 deaths overall; 13/14 were due to traumatic brain injury, and 8/14 required urgent operation for hemorrhage., Conclusions: In conclusion, grading of liver injuries does not seem to influence immediate management. Physiologic behavior dictated management and need for operative intervention, as well as prognosis. However, both major hepatic injuries and need for early operation reflected overall severity and the possibility of associated injuries.

Azacitidine is a pyrimidine nucleoside analog of cytidine with hypomethylating and antileukemia activity. Azacitidine has been shown to have survival benefits in patients with high-risk myelodysplastic syndrome (MDS), and has activity in the treatment of acute myelogenous leukemia (AML). It is administered by subcutaneous (s.c.) or intravenous (i.v.) injection daily at a dose of 75 mg/m(2) for 7 days every 4 weeks. An oral formulation would facilitate dosing, reduce administration side effects and potentially maximize azacitidine pharmacologic action. Previously, oral formulations of this class of agent have failed due to rapid catabolism by cytidine deaminase and hydrolysis in aqueous environments. Development of a film-coated formulation has circumvented this difficulty. In a formulation feasibility pilot study, four subjects with solid malignant tumors, AML or MDS received single oral doses of 60 or 80 mg azacitidine. Subjects demonstrated measurable plasma concentrations of azacitidine, allowing bioavailability comparisons to be made to historical pharmacokinetic data for s.c. azacitidine. Subjects safely tolerated 80 mg, a dose for which the mean bioavailability was 17.4% of historic s.c. exposure. No severe drug-related toxicities were observed. These data suggest that oral azacitidine is bioavailable in humans and should be studied in formal phase 1 trials.

Aortoostial dissection is a serious but rare complication of coronary intervention that may require surgical aortic repair. Here we present four cases which were immediately sealed with stenting of the coronary ostium abruptly terminating spread of the aortic dissection and obviating the need for surgical repair. Long-term outcome in this small series was universally event free. Review of the literature suggests that such a strategy is frequently successful without major added risk. We propose that immediate ostial stenting (irrespective of whether the dissection starts from the ostium or further downstream in the coronary) should be strongly considered in all cases as it may prevent the need for high-risk emergent surgical aortic repair.

Microsomal PGE synthase-1 (mPGES-1) is an inducible enzyme that acts downstream of cyclooxygenase and specifically catalyzes the conversion of PGH(2) to PGE(2). The present study demonstrates the effect of genetic deletion of mPGES-1 on the developing immunologic responses and its impact on the clinical model of bovine collagen-induced arthritis. mPGES-1 null and heterozygous mice exhibited decreased incidence and severity of arthritis compared with wild-type mice in a gene dose-dependent manner. Histopathological examination revealed significant reduction in lining hyperplasia and tissue destruction in mPGES-1 null mice compared with their wild-type littermates. mPGES-1 deficient mice also exhibited attenuation of mechanical nociception in a gene dose-dependent manner. In addition, mPGES-1 null and heterozygous mice showed a marked reduction of serum IgG against type II collagen, including subclasses IgG1, IgG2a, IgG2b, IgG2c, and IgG3, compared with wild-type mice, which correlated with the reduction in observed inflammatory features. These results demonstrate for the first time that deficiency of mPGES-1 inhibits the development of collagen-induced arthritis, at least in part, by blocking the development of a humoral immune response against type II collagen. Pharmacologic inhibition of mPGES-1 may therefore impact both the inflammation and the autoimmunity associated with human diseases such as rheumatoid arthritis.

Since their identification in 1997, bone marrow derived endothelial progenitor cells (EPCs) have been studied for their role in the endogenous maintenance and repair of endothelium and their potential regenerative capacity beyond the endothelium. In particular, EPCs have been tested in cell therapy approaches with the aim of developing novel therapies for conditions currently lacking effective treatment options. In this review, we discuss the scientific background and clinical experience using EPC delivery or mobilization for the treatment of post-angioplasty restenosis, acute myocardial infarction and pulmonary arterial hypertension. Although these approaches are safe, efficacy has yet to be proven in large randomized clinical trials. Unfortunately, the biology of EPCs is still poorly understood. The success of future clinical trials depends on a better understanding of EPC biology and intelligent design., (Copyright 2007 Wiley-Liss, Inc.)

Restenosis after balloon angioplasty and stenting is exacerbated by low flow. Flow-dependent restenosis after angioplasty but not stenting is prevented by the antioxidant pyrrolidine dithiocarbamate (PDTC). c-jun may play a role in these events as AP-1 activity is both flow and redox sensitive. Carotid arteries of cholesterol fed rabbits underwent stenting or balloon injury in the presence of low or normal flow. c-jun mRNA expression was enhanced by low flow and injury (stent>balloon) and inhibited by the antioxidant PDTC irrespective of the injury type. The effect of locally delivered DZ13 (a DNAzyme specific for c-jun) or scrambled DZ13 (inactive DNAzyme) was assessed by histomorphometry at 28 days. Low flow significantly increased intimal hyperplasia in B and S relative to normal flow (P<0.05). The active DNAzyme DZ13 markedly reduced intimal hyperplasia (P<0.001) and increased lumen size (P<0.05) in balloon-injured but not in stented segments, and abrogated the effect of low flow on restenosis after angioplasty, similar to the morphological effects of PDTC. We conclude that c-jun expression is enhanced by low flow and by injury (stent>balloon) and markedly attenuated by PDTC, and that c-jun is an important mediator of flow-dependent restenosis in balloon-injured but not stented vessels.

Aims: We investigated the net benefit in the outcome of reducing treatment delay through field triage and emergency department (ED) bypass in patients with ST-elevation myocardial infarction (STEMI) treated with primary angioplasty., Methods and Results: In a prospective registry study, consecutive patients with suspected STEMI were assigned to: (i) pre-hospital ECG and triage or (ii) ECG and triage at the closest ED, solely based on ambulance availability. Four district hospitals and one regional heart centre serviced the 890,000 population metropolitan area and primary angioplasty was the only reperfusion strategy employed. Baseline characteristics were similar in STEMI patients triaged in the field (108) and the EDs (193). Symptom onset to balloon times: 154 [inter-quartile range (IQR) 120-233) vs. 249 (IQR 184-405) min (P<0.001) and peak creatine kinase in early presenters (<2 h): 1435 (95 %CI: 904-1966) U/L vs. 2320 (95% CI: 1881-2762) U/L (P=0.009) were lower in field- than in ED-triaged patients. Mortality in the PCI treated were 1.1 and 8.2% [P=0.025, RR 0.14 (95% CI: 0.01-1.08)] and overall mortality were 1.9 and 7.3% [P=0.046, RR 0.26 (95% CI: 0.05-1.11)]., Conclusion: Field-triage and ED bypass were feasible means of reducing treatment delay in patients with suspected STEMI and resulted in smaller infarct size in early presenters and a trend towards a reduction in mortality.

Tako-tsubo cardiomyopathy (TTC) is an important differential diagnosis of acute coronary occlusive myocardial infarction that should be understood by all clinicians. Although TTC is frequently clinically indistinguishable from acute left anterior descending coronary artery occlusion, it is readily differentiated with coronary angiography. The increasing frequency of acute angiography and revascularisation for patients with acute myocardial infarction has resulted in TTC being far more frequently diagnosed. Most common in postmenopausal women, TTC is frequently precipitated by physical or emotional stress, and after an acute phase during which the patient may be significantly haemodynamically compromised, there is rapid recovery and an excellent prognosis. After diagnosis the patient can be reassured and advised of the low rates of recurrence. Currently, no specific preventive therapy has been proven to be effective.

Mutations in the BRAF gene are found in the majority of cutaneous malignant melanomas and subsets of other tumors. These mutations lead to constitutive activation of BRAF with increased downstream ERK (extracellular signal-regulated kinase) signaling; therefore, the development of RAF kinase inhibitors for targeted therapy is being actively pursued. A methodology that allows sensitive, cost-effective, high-throughput analysis of BRAF mutations will be needed to triage patients for specific molecular-based therapies. Pyrosequencing is a high-throughput, sequencing-by-synthesis method that is particularly useful for analysis of single nucleotide polymorphisms or hotspot mutations. Mutational analysis of BRAF is highly amenable to pyrosequencing because the majority of mutations in this gene localize to codons 600 and 601 and consist of single or dinucleotide substitutions. In this study, DNAs from a panel of melanocyte cell lines, melanoma cell lines, and melanoma tumors were used to validate a pyrosequencing assay to detect BRAF mutations. The assay demonstrates high accuracy and precision for detecting common and variant exon 15 BRAF mutations. Further, comparison of pyrosequencing data with 100K single nucleotide polymorphism microarray data allows characterization of BRAF amplification events that may accompany BRAF mutation. Pyro-sequencing serves as an excellent platform for BRAF genotyping of tumors from patients entering clinical trial.

Background: Current guidelines recommend using antiseptic- or antibiotic-impregnated central venous catheters (CVCs) if, following a comprehensive strategy to prevent catheter-related blood stream infection (CR-BSI), infection rates remain above institutional goals based on benchmark values. The purpose of this study was to determine if chlorhexidine/silver sulfadiazine-impregnated CVCs could decrease the CR-BSI rate in an intensive care unit (ICU) with a low baseline infection rate., Methods: Pre-intervention and post-intervention observational study in a 24-bed surgical/trauma/burn ICU from October, 2002 to August, 2005. All patients requiring CVC placement after March, 2004 had a chlorhexidine/silver sulfadiazine-impregnated catheter inserted (post-intervention period)., Results: Twenty-three CR-BSIs occurred in 6,960 catheter days (3.3 per 1,000 catheter days)during the 17-month control period. After introduction of chlorhexidine/silver sulfadiazine-impregnated catheters, 16 CR-BSIs occurred in 7,732 catheter days (2.1 per 1,000 catheter days; p = 0.16). The average length of time required for an infection to become established after catheterization was similar in the two groups (8.4 vs. 8.6 days; p = 0.85). Chlorhexidine/silver sulfadiazine-impregnated catheters did not result in a statistically significant change in the microbiological profile of CR-BSIs, nor did they increase the incidence of resistant organisms., Conclusions: Although chlorhexidine/silver sulfadiazine-impregnated catheters are useful in specific patient populations, they did not result in a statistically significant decrease in the CR-BSI rate in this study, beyond what was achieved with education alone.

Purpose: Male breast cancer has been linked extensively to mutations of BRCA2 and, to a lesser extent, BRCA1. The aim of this study was to perform a comprehensive analysis of point mutations and genomic rearrangements in the BRCA1 and BRCA2 genes in 41 men with breast cancer., Patients and Methods: Deleterious point mutations were identified in 15 men (37%): 4 (10%) and 11 (27%) in BRCA1 and BRCA2, respectively. In the remaining 26 men, we screened for large genomic rearrangements in BRCA1 and BRCA2 using multiplex ligation-dependent probe amplification., Results: We did not detect any large genomic rearrangements. Men with BRCA1 or BRCA2 mutations were more likely to have a family history of prostate cancer (P = 0.025). Three of 4 male breast tumors with BRCA1 mutations (75%) were estrogen receptor positive. Whereas some studies have reported an 8%-0 rate of large BRCA2 genomic rearrangement in familial male breast cancer cases, we did not detect any such genomic rearrangements in BRCA1 or BRCA2 for our cohort., Conclusion: Despite this negative finding, our study, to the best of our knowledge, is one of the first to comprehensively screen for mutations, including large genomic rearrangement mutations, in BRCA1 and BRCA2 in men with breast cancer in the United States.

Probucol [4,4'-[(1-methylethylidene)bis(thio)]bis-[2,6-bis(1,1-dimethylethyl)phenol]] was withdrawn from the United States market because it failed to inhibit atherosclerosis in human femoral arteries, yet the drug was shown subsequently to inhibit atherosclerosis in human carotid arteries, and probucol monosuccinate ester is presently being tested in a phase III clinical trial as an antiatherosclerotic compound based on its anti-inflammatory properties. Inflammatory macrophages are implicated in arterial remodeling associated with atherosclerosis, and probucol inhibits experimental atherosclerosis in part by decreasing macrophages in lesions. However, the impact of probucol on remodeling is unknown, although such knowledge could help explain why the drug's benefit on human atherosclerosis is controversial. We therefore examined the effect of probucol on remodeling of the common carotid artery in apolipoprotein E-deficient mice. We observed that during de novo atherosclerosis, plaque growth was fully compensated by expansive remodeling, such that lumen area was unaffected. Early lesions were composed almost entirely of macrophages, and their contribution to lesion area progressively decreased thereafter. Probucol significantly decreased plaque area, expression of vascular cell adhesion molecule-1, and proliferation of intimal cells, resulting in delayed macrophage accumulation in the vessel. Probucol also decreased the production and activity of matrix metalloproteinases-2 and -9, independent of the plasmin protease system, and this was associated with an inhibition of expansive remodeling, resulting in lumen loss. These studies show that probucol attenuates compensatory remodeling associated with de novo atherosclerosis, probably via its anti-inflammatory properties. Our findings suggest that lumen volume is not a suitable surrogate to assess the antiatherosclerotic activity of probucol and related drugs.

Background: Tako-tsubo cardiomyopathy (TTC) is an acute reversible cause of segmental myocardial dysfunction that is poorly understood. We have noted a variant of this condition where a tiny segment at the apex retains some contractile function. This paper delineates the frequency of this variant relative to the classical form and the clinical differences between patients suffering from the two forms., Methods: All cases of TTC (n = 35) were identified from our infarct angiography database and separated on the basis of apical sparing (n = 14) or no apical sparing (n = 21)., Results: Compared with the classical form, those with apical sparing were significantly younger (63 +/- 12 vs 72 +/- 13 years) and were more likely premenopausal (5/14 vs 0/21) and had higher ejection fractions (35 +/- 6% vs 32 +/- 4%). There was a trend towards higher recurrence (4/21 vs 0/14). There were no differences in time or season of presentation, precipitant stressor, premorbid drug therapy, haemodynamics at catheterization or acute outcomes., Conclusion: The apical sparing variant of TTC is common, accounting for 40% of cases. While the patients are younger and more likely premenopausal, there are no other distinguishing features between the classical and the variant form.

MicroRNAs (miRNAs) are endogenous noncoding RNAs, which negatively regulate gene expression. To determine genomewide miRNA DNA copy number abnormalities in cancer, 283 known human miRNA genes were analyzed by high-resolution array-based comparative genomic hybridization in 227 human ovarian cancer, breast cancer, and melanoma specimens. A high proportion of genomic loci containing miRNA genes exhibited DNA copy number alterations in ovarian cancer (37.1%), breast cancer (72.8%), and melanoma (85.9%), where copy number alterations observed in >15% tumors were considered significant for each miRNA gene. We identified 41 miRNA genes with gene copy number changes that were shared among the three cancer types (26 with gains and 15 with losses) as well as miRNA genes with copy number changes that were unique to each tumor type. Importantly, we show that miRNA copy changes correlate with miRNA expression. Finally, we identified high frequency copy number abnormalities of Dicer1, Argonaute2, and other miRNA-associated genes in breast and ovarian cancer as well as melanoma. These findings support the notion that copy number alterations of miRNAs and their regulatory genes are highly prevalent in cancer and may account partly for the frequent miRNA gene deregulation reported in several tumor types.

Background: Hyperglycemia is associated with complications in the surgical intensive care unit. The purpose of this study was to determine the efficacy and safety of nurse-driven insulin infusion protocols in lowering blood glucose (BG) in critical illness., Study Design: All patients in a 24-bed surgical intensive care unit who required i.v. insulin infusions during 3 noncontiguous 6-month periods from 2002 to 2004 were evaluated. In the preintervention phase, 71 patients received a physician-initiated insulin infusion without a developed protocol. They were compared with 95 patients who received a nurse-driven insulin infusion protocol with a target BG of 120 to 150 mg/dL and to 119 patients who received a more stringent protocol with a target BG of 80 to 110 mg/dL., Results: There was a stepwise decrease in average daily BG levels, from 190 to 163 to 132 mg/dL (p < 0.001). The less stringent protocol decreased the time to achieve a BG level < 150 mg/dL from 14.1 to 7.4 hours compared with physician-driven management (p < 0.05) resulting in similar time on an insulin infusion (53 versus 48 hours). The more intensive protocol brought BG levels < 150 mg/dL in 7.2 hours and < 111 mg/dL in 13.6 hours, but increased the length of time a patient was on an insulin infusion to 77 hours. The incidence of severe hypoglycemia (BG < 40 mg/dL) was statistically similar between the groups, ranging between 1.1% and 3.4%., Conclusions: Implementation of a nurse-driven protocol led to more rapid and more effective BG control in critically ill surgical patients compared with physician management. Tighter BG control can be obtained without a significant increase in hypoglycemia, although this is associated with increased time on an insulin infusion.

Surveillance targeting dead wild birds, in particular American crows (Corvus brachyrhynchos), plays a critical role in West Nile virus (WNV) surveillance in the United States. Using crow decoy surrogates, detection and reporting of crow carcasses within urban and rural environments of DeKalb County, Georgia were assessed for potential biases that might occur in the county's WNV surveillance program. In each of two replicated trials, during July and September 2003, 400 decoys were labeled with reporting instructions and distributed along randomly chosen routes throughout designated urban and rural areas within DeKalb County. Information-theoretic methods were used to compare alternative models incorporating the effects of area and trial on probabilities of detection and reporting. The model with the best empirical support included the effects of area on both detection and reporting of decoys. The proportion of decoys detected in the urban area (0.605, SE=0.024) was approximately twice that of the rural area (0.293, SE=0.023), and the proportion of decoys reported in the urban area (0.273, SE=0.023) was approximately three times that of the rural area (0.103, SE=0.028). These results suggest that human density and associated factors can substantially influence dead crow detection and reporting and, thus, the perceived distribution of WNV. In a second and separate study, the persistence and fate of American crow and house sparrow (Passer domesticus) carcasses were assessed in urban and rural environments in Athens-Clarke, Madison, and Oconee counties, Georgia. Two replicated trials using 96 carcasses of each species were conducted during July and September 2004. For a portion of the carcasses, motion sensitive cameras were used to monitor scavenging species visits. Most carcasses (82%) disappeared or were decayed by the end of the 6-day study. Carcass persistence averaged 1.6 days in rural areas and 2.1 days in urban areas. We analyzed carcass persistence rates using a known-fate model framework in program MARK. Model selection based on Akaike's Information Criteria (AIC) indicated that the best model explaining carcass persistence rates included species and number of days of exposure; however, the model including area and number of days of exposure received approximately equal support. Model-averaged carcass persistence rates were higher for urban areas and for crow carcasses. Six mammalian and one avian species were documented scavenging upon carcasses. Dead wild birds could represent potential sources of oral WNV exposure to these scavenging species. Species composition of the scavenger assemblage was similar in urban and rural areas but "scavenging pressure" was greater in rural areas.

Mutations in BRCA1 and BRCA2 account for a significant proportion of hereditary breast cancers. Earlier studies have shown that inherited and sporadic tumors progress along different somatic genetic pathways and that global gene expression profiles distinguish between these groups. To determine whether genomic profiles similarly discriminate among BRCA1, BRCA2, and sporadic tumors, we established DNA copy number profiles using comparative genomic hybridization to BAC-clone microarrays providing <1 Mb resolution. Tumor DNA was obtained from BRCA1 (n = 14) and BRCA2 (n = 12) mutation carriers, as well as sporadic cases (n = 26). Overall, BRCA1 tumors had a higher frequency of copy number alterations than sporadic breast cancers (P = 0.00078). In particular, frequent losses on 4p, 4q, and 5q in BRCA1 tumors and frequent gains on 7p and 17q24 in BRCA2 tumors distinguish these from sporadic tumors. Distinct amplicons at 3q27.1-q27.3 were identified in BRCA1 tumors and at 17q23.3-q24.2 in BRCA2 tumors. A homozygous deletion on 5q12.1 was found in a BRCA1 tumor. Using a set of 169 BAC clones that detect significantly (P < 0.001) different frequencies of copy number changes in inherited and sporadic tumors, these could be discriminated into separate groups using hierarchical clustering. By comparing DNA copy number and RNA expression for genes in these regions, several candidate genes affected by up- or down-regulation were identified. Moreover, using support vector machines, we correctly classified BRCA1 and BRCA2 tumors (P < 0.0000004 and 0.00005, respectively). Further validation may prove this tumor classifier to be useful for selecting familial breast cancer cases for further mutation screening, particularly, as these data can be obtained using archival tissue.

Background: Drug-eluting stents (DES) are currently being used in preference to bare stents in the public hospital system in 'high risk' lesions on the basis of cost-effectiveness analyses using data from trials which exaggerate their impact and do not include several categories of 'high risk'. This study aimed to assess the real cost-effectiveness of DES using prospectively collected outcome data from consecutive patients in the immediate pre-DES era., Methods and Results: A prospective database on all percutaneous coronary interventions (PCI) performed by one operator in the two years prior to DES introduction (July 2000-June 2002) was used in which 12-month follow-up was complete in 96%. In 490 patients, 510 PCI were undertaken on 650 lesions (298 'high risk') using 686 stents. Angiography-proven clinical restenosis occurred in 31 lesions (5%) in 27 patients (12 focal, 19 diffuse; 11 treated with CABG, 14 with repeat PCI [4 re-restenosed-3 re-rePCI, 1 CABG] and 2 treated medically) with 2 deaths (both post-CABG). If all 'high risk' lesions had been treated with DES (assuming 0% clinical restenosis) then 22 lesions in 18 patients would not have restenosed avoiding 8 CABG and 13 re-PCI. Assuming A 5186 dollars cost for re PCI and A 18,496 dollars for CABG, DES will only be cost neutral for 'high risk' lesions when the premium for DES reduces to 617 dollars (currently 1500 dollars) and for all lesions at 452 dollars., Conclusions: Current strategies for use of DES are not cost-effective. DES should be reserved for restenosis until the price comes down.