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BACKGROUND A number of patients with neurally mediated syncope (NMS) have isolated QRS complexes of very low voltage (≤0.3 mV) in the frontal plane leads on the 12-lead electrocardiogram (ECG). HYPOTHESIS The aim of this study was to assess the importance of QRS voltage in predicting response to tilt-table testing (TTT) in patients with suspected NMS. METHODS We included 216 patients (age: 49 ± 20 years, 103 men) with suspected NMS who had either a positive or negative response to TTT (n = 91 TTT+, and n = 125 TTT-). The QRS voltage was measured in mV on 12-lead ECGs performed within 3 days of the TTT. The lowest QRS voltage (QRSmin), as well as the voltage in each of the 12 leads was also determined. RESULTS Very low voltage (QRSmin ≤ 0.3 mV) in the frontal leads was significantly more prevalent in the TTT+ group than in the TTT- group (74 vs 22%, respectively; P < .001). Patients in the TTT+ group had significantly lower QRSmin when compared to patients in the TTT- group. QRSmin predicted a positive tilt-table test in a multivariate model that also included patient gender, height, history of presyncope, QRS duration, and left ventricular end-diastolic diameter indexed to height. ROC analysis showed that QRSmin of ≥0.3 mV discriminated between TTT+ and TTT- patients with a sensitivity of 78% and specificity of 68%. CONCLUSION Isolated very low QRS voltage in the frontal leads predicts a positive response to TTT in patients with suspected NMS.

At the age of twenty-one, Fred Hampton Sr., was assassinated, by a joint operation between the Cook County State’s Attorney’s Office and the Federal Bureau of Investigation. Beyond his assassination, and his involvement with the Black Panthers, Hampton has left many influences in American society. His impact continued after his death, thus he should be remembered and studied as an important figure in the modern Civil Rights and Black Power eras. His impact and legacy have extended far beyond his lifetime and far beyond Chicago and deserves more scholarly attention.

Background Ventricular tachycardia (VT) and ventricular fibrillation (VF) remain a challenging problem in patients with implantable cardioverter-defibrillators (ICDs). Objectives This study aimed to determine whether ranolazine administration decreases the likelihood of VT, VF, or death in patients with an ICD. Methods This was double-blind, placebo-controlled clinical trial in which high-risk ICD patients with ischemic or nonischemic cardiomyopathy were randomized to 1,000 mg ranolazine twice a day or placebo. The primary endpoint was VT or VF requiring appropriate ICD therapy or death, whichever occurred first. Pre-specified secondary endpoints included ICD shock for VT, VF, or death and recurrent VT or VF requiring ICD therapy. Results Among 1,012 ICD patients (510 randomized to ranolazine and 502 to placebo) the mean age was 64 ± 10 years and 18% were women. During 28 ± 16 months of follow-up there were 372 (37%) patients with primary endpoint, 270 (27%) patients with VT or VF, and 148 (15%) deaths. The blinded study drug was discontinued in 199 (39.6%) patients receiving placebo and in 253 (49.6%) patients receiving ranolazine (p = 0.001). The hazard ratio for ranolazine versus placebo was 0.84 (95% confidence interval: 0.67 to 1.05; p = 0.117) for VT, VF, or death. In a pre-specified secondary analysis, patients randomized to ranolazine had a marginally significant lower risk of ICD therapies for recurrent VT or VF (hazard ratio: 0.70; 95% confidence interval: 0.51 to 0.96; p = 0.028). There were no other significant treatment effects in other pre-specified secondary analyses, which included individual components of the primary endpoint, inappropriate shocks, cardiac hospitalizations, and quality of life. Conclusions In high-risk ICD patients, treatment with ranolazine did not significantly reduce the incidence of the first VT or VF, or death. However, the study was underpowered to detect a difference in the primary endpoint. In prespecified secondary endpoint analyses, ranolazine administration was associated with a significant reduction in recurrent VT or VF requiring ICD therapy without evidence for increased mortality. (Ranolazine Implantable Cardioverter-Defibrillator Trial [RAID]; NCT01215253)

The study was prompted by our observation that some patients with neurally mediated syncope (NMS) have an isolated QRS complex, of very low voltage (≤0.3 mV cutoff), in 1 of the frontal leads on the 12-lead electrocardiogram.To prospectively evaluate whether the presence of isolated very low voltage (VLV) predicts recurrence of NMS.We included 205 patients (aged 50 ± 17 years) with a median of 3 syncopal episodes. Tilt testing was performed in all patients and was positive in 87 (42%). The patients were followed for a median of 14 months.VLV in frontal leads was present in 92 patients (45%). During the follow-up period 60 patients experienced recurrence of syncope. The actuarial total syncope recurrence rate at 1 year was 32% (95% confidence interval [CI 23%-44%) in patients with isolated VLV in frontal plane leads, and 14% (95% CI 8%-24%) in patients without VLV (log-rank test P.0001). The significant relationship between the presence of isolated VLV in the frontal leads and syncope recurrence was retained in Cox multivariate analysis that included the history of presyncope and syncope as well as the left ventricular end-diastolic diameter. The presence of isolated VLV in frontal leads was associated with a 3-fold increase of the risk of recurrent syncope.Isolated very low QRS voltage in the frontal leads predicts recurrence of NMS independent of clinical factors that predict recurrence of syncope in such patients. This phenomenon may help generate new diagnostic tools and insights into the pathogenesis of NMS.

Preliminary enthusiasm over the encouraging spectrum and in vitro activities of siderophore conjugates, such as MB-1, was recently tempered by unexpected variability in in vivo efficacy. The need for these conjugates to compete for iron with endogenously produced siderophores has exposed a significant liability for this novel antibacterial strategy. Here, we have exploited dependence on efflux for siderophore secretion in Pseudomonas aeruginosa and provide evidence that efflux inhibition may circumvent this in vivo -relevant resistance liability.

Ventricular tachycardia (VT) and ventricular fibrillation (VF) remain a challenging problem in patients with implantable cardioverter-defibrillators (ICDs).This study aimed to determine whether ranolazine administration decreases the likelihood of VT, VF, or death in patients with an ICD.This was double-blind, placebo-controlled clinical trial in which high-risk ICD patients with ischemic or nonischemic cardiomyopathy were randomized to 1,000 mg ranolazine twice a day or placebo. The primary endpoint was VT or VF requiring appropriate ICD therapy or death, whichever occurred first. Pre-specified secondary endpoints included ICD shock for VT, VF, or death and recurrent VT or VF requiring ICD therapy.Among 1,012 ICD patients (510 randomized to ranolazine and 502 to placebo) the mean age was 64 ± 10 years and 18% were women. During 28 ± 16 months of follow-up there were 372 (37%) patients with primary endpoint, 270 (27%) patients with VT or VF, and 148 (15%) deaths. The blinded study drug was discontinued in 199 (39.6%) patients receiving placebo and in 253 (49.6%) patients receiving ranolazine (p = 0.001). The hazard ratio for ranolazine versus placebo was 0.84 (95% confidence interval: 0.67 to 1.05; p = 0.117) for VT, VF, or death. In a pre-specified secondary analysis, patients randomized to ranolazine had a marginally significant lower risk of ICD therapies for recurrent VT or VF (hazard ratio: 0.70; 95% confidence interval: 0.51 to 0.96; p = 0.028). There were no other significant treatment effects in other pre-specified secondary analyses, which included individual components of the primary endpoint, inappropriate shocks, cardiac hospitalizations, and quality of life.In high-risk ICD patients, treatment with ranolazine did not significantly reduce the incidence of the first VT or VF, or death. However, the study was underpowered to detect a difference in the primary endpoint. In prespecified secondary endpoint analyses, ranolazine administration was associated with a significant reduction in recurrent VT or VF requiring ICD therapy without evidence for increased mortality. (Ranolazine Implantable Cardioverter-Defibrillator Trial [RAID]; NCT01215253).

The relationship between obstructive sleep apnea (OSA) and increased risk for atrial fibrillation (AF) has been well established in previous studies. The relationship between OSA and silent AF is unknown. We hypothesized that patients with OSA but no known history of AF are at an increased risk for the arrhythmia and may be detectable by prolonged electrocardiogram (ECG) monitoring. In this study, we examined whether 7 days of extended cardiac monitoring with an ECG event recorder is an effective screening tool to detect intermittent, silent AF in patients with severe OSA.The study was a prospective observational study. Randomly chosen patients with newly diagnosed severe OSA, apnea-hypopnea index (AHI) ≥ 30, were included. Demographic, medical history, and sleep data were collected. Patients with a history of AF or symptoms of palpitations were excluded from participating. Seven consecutive days of ambulatory ECG event recording (with Model ER920W, eCardio, Houston, TX) were performed prior to the initiation of CPAP treatment.A total of 20 subjects, with a BMI of 38.8 ± 12.2, successfully completed the study. The mean age group was 52.6 ± 12.6 years and mean AHI 63.5 ± 29.2. The majority of subjects (70 %) had no abnormal cardiac rhythms detected. AF lasting for 7 s was seen in one subject, and paroxysmal atrial tachycardia lasting for 3.6 s was seen in another. Clinically relevant AF was not detected in any of the subjects.In patients with severe OSA without a known history of AF, 7 days of extended cardiac monitoring with an ECG event recorder did not detect clinically meaningful, silent AF.

Herein we describe the structure-aided design and synthesis of a series of pyridone-conjugated monobactam analogues with in vitro antibacterial activity against clinically relevant Gram-negative species including Pseudomonas aeruginosa , Klebsiella pneumoniae , and Escherichia coli . Rat pharmacokinetic studies with compound 17 demonstrate low clearance and low plasma protein binding. In addition, evidence is provided for a number of analogues suggesting that the siderophore receptors PiuA and PirA play a role in drug uptake in P. aeruginosa strain PAO1.

Recent studies have provided new insights into the pathophysiology of congestive heart failure. Organ-specific responses to circulatory disturbances may differ via a hypoperfusion state and a venous congestion state. The liver and the kidneys serve as a good example of a differential injury pattern based on the predominant circulatory insult. Cardiorenal syndrome appears to be a kidney-specific response to predominantly right-sided backward heart failure ("congestive state"), rather than forward heart failure. Despite significant progress in our understanding of cardiorenal interactions, there is no specific therapy for the cardiorenal syndrome, which is a marker of the severity of the heart failure state.

A case of congenital long QT syndrome unmasked by acute MI A 29 years old female presented with acute inferior STEMI. Patient received primary PCI. Post PCI EKG showed sinus rhythm, normal axis, resolution of ST segments and QTc of 589 ms. Patient was discharge after uneventful hospital stay.

Cardiac troponin T (cTnT) elevations have been reported to occur after implantable cardioverter-defibrillator (ICD) discharges, but their prognostic significance is unknown.To evaluate whether cTnT elevations occurring after ICD discharges have an impact on survival.Prospective observational study.174 patients (mean (SD) age 68 (12) years, 32 women) who received spontaneous (n = 66) or induced (n = 108) ICD discharges were studied. The mean (SD) left ventricular ejection fraction was 29 (11)%.Troponin T was measured between 12 and 24 h after ICD discharge. Patients received between 1 and 19 discharges (mean (SD) 2.4 (2.4)), with total delivered energy ranging from 6 to 288 J (mean (SD) 41 (63) J). The relationship between cTnT levels and all-cause mortality was assessed in univariate and multivariate analyses.During a median follow-up period of 41.8 months (range 3-123), 56 patients died. Patients with a post-discharge cTnT level of/=0.05 ng/ml had worse survival than those with cTnT0.05 ng/ml. The significant relationship between raised cTnT and survival was retained in Cox multivariate analysis adjusted for total ICD energy delivered during an arrhythmia episode, age, sex, presence of coronary artery disease, left ventricular ejection fraction and serum creatinine.Elevation of troponin T after ICD discharge, even when it occurs after device testing, is a risk factor for mortality that is independent of other common clinical factors that predict survival in such patients.

Imaging the coronary venous (CV) tree to delineate the coronary sinus and its tributaries can facilitate electrophysiological procedures, such as cardiac resynchronization therapy (CRT) and catheter ablation. Venography also allows visualization of the left atrial (LA) veins, which may be a potential conduit for ablative or pacing strategies given their proximity to foci that can trigger atrial fibrillation.The aim of this study was to provide a detailed description of CV anatomy using rotational venography in patients undergoing CRT.Coronary sinus (CS) size and the presence, size, and angulation of its tributaries were determined from the analysis of rotational CV angiograms from 51 patients (age 68 +/- 11 years; n = 12 women) undergoing CRT.The CS, posterior veins, and lateral veins were identified in 100%, 76%, and 91% of patients. Lateral veins were less prevalent in patients with a history of lateral myocardial infarction than in patients without such a history (33% vs. 96%; P = .014). The diameters of the CS and its tributaries were fairly variable (7.3-18.9 mm for CS, 1.3-10.5 mm for CS tributaries). The CS was larger in men than in women and in cases of ischemic than in cases of nonischemic cardiomyopathy (all P.05). The vein of Marshall, the most constant LA vein, was identified in 37 patients; its diameter is 1.7 +/- 0.5 mm, and its takeoff angle is 154 degrees +/- 15 degrees , making the vein potentially accessible for cannulation.Differences in CV anatomy that are related to either gender or coronary artery disease could have important practical implications during the left ventricular lead implantation. The anatomical features of the vein of Marshall make it a feasible potential conduit for epicardial LA pacing.

ICD Shocks Increase TWA. Introduction: While implantable defibrillator shocks save lives, shock can lead to ventricular arrhythmias. However, the mechanism of shock-related proarrhythmia remains unclear. We evaluated the impact of ICD shock on repolarization instability, a factor associated with ventricular arrhythmogenesis. Methods and Results: Sixty-five patients with ICDs underwent ambulatory ECG monitoring during defibrillation testing 3 months postimplant. TWA was analyzed continuously in the time domain during baseline, sedated, and post-shock states. RR, QRS, and QT intervals and catecholamines were also measured continuously. Adequate pre- and post-shock Holter data were recorded in 55 patients, 48 male, mean 64 ± 12 years, 50 with coronary disease, 48 with prior spontaneous or induced arrhythmia. TWA significantly increased after shock, from 9.6 ± 0.5 to 11.9 ± 0.6 µV, as did QRS duration, epinephrine, and norepinephrine levels, compared with sedated and baseline states. RR intervals decreased minimally. TWA changes with shock were not associated with RR or QRS duration changes, but were associated with changes in epinephrine. Conclusions: ICD shock, even in the sedated state, increases repolarization instability as measured by TWA, an effect mediated in part by sympathetic stimulation. This association between shock and TWA may have important mechanistic and clinical implications for optimization of defibrillation therapy. (J

Anger can precipitate ventricular arrhythmias in patients with implantable cardioverter-defibrillators (ICDs). Determining electrophysiologic characteristics of anger-triggered arrhythmias may help elucidate the mechanisms that link emotion and arrhythmia.We sought to compare the morphology and initiation pattern between ventricular arrhythmias that are triggered by anger and those that are not.At the time of shock, patients with ICDs recorded levels of defined mood states preceding the shock in a diary. Stored intracardiac electrograms (EGMs) were retrieved and analyzed in relation to corresponding mood states. The EGMs from 56 appropriate shocks in 24 patients (18 male, mean age 66 years, 74% with coronary artery disease) were reviewed and analyzed for morphology, mechanism of initiation (sudden onset vs. premature ventricular contraction [PVC]), pause dependence, and other characteristics.Polymorphic ventricular tachycardia was more common in anger-triggered events, occurring in three (37.5%) of eight anger-triggered events compared with five (10.4%) of 48 of non-anger-triggered events (P.05). Anger-triggered events were more likely to have PVC initiation, occurring in eight (100%) of eight, compared with 30 (68%) of 44 of non-anger-triggered events (P.05). More anger-triggered events were pause dependent: five (62.5%) of eight versus seven (15%) of 37 non-anger-related events (P.01). No difference in response to initial therapy was observed in anger-triggered arrhythmias.Ventricular arrhythmias occurring in the setting of anger are more likely pause dependent and polymorphic. This suggests that in predisposed populations anger may create an arrhythmogenic substrate susceptible to more disorganized rhythms, a possible mechanism linking emotion and sudden death.

Davids JS, McPherson CA, Earley C, Batsford WP, Lampert R. Benefits of cardiac rehabilitation in patients with implantable cardioverter-defibrillators: a patient survey. Objectives To determine whether participation in an outpatient cardiac rehabilitation (OCR) program increases exercise levels and decreases shocks in patients with implantable cardioverter-defibrillators (ICDs). Design Retrospective comparative survey. Setting University tertiary-care ICD clinic. Participants Patients with ICDs and coronary artery disease. Intervention Participation in OCR (nonrandomized). Main Outcome Measures Exercise levels and OCR participation were determined through a telephone survey of patients with ICDs. The incidence of shock-treated arrhythmia was determined by review of charts and ICD data storage disks. Results Of 82 patients (85% men; mean age, 61±8y), 28 (34%) participated in OCR after receiving an ICD. There was no difference in age, sex, ejection fraction, or length of follow-up between OCR and non-OCR groups. Median intensity of regular exercise was 5.3 metabolic equivalents (METS) for OCR patients versus 3.5 METS for non-OCR patients ( P P P Conclusions OCR patients exercised more and had fewer shocks. Physicians and health plans should encourage ICD patients to participate in OCR.

Objectives The purpose of this study was to determine the least expensive strategy for device selection in patients receiving implantable cardioverter-defibrillators (ICDs). Background Device cost for a single-chamber ICD is less than an atrioventricular (dual-chamber) ICD (AV-ICD); however, some patients without clinical need for AV-ICD at implantation might require a later upgrade, potentially offsetting the initial cost advantage of the single-chamber device. Methods Decision analysis was used to estimate expected resource utilization costs of three alternative implantation strategies: 1) single-chamber device in all, with later upgrade to AV-ICD if needed; 2) initial implantation of an AV-ICD in all; and 3) targeted device selection on the basis of results of electrophysiologic testing (presence or absence of induced bradyarrhythmias or atrial arrhythmias). Clinical base estimates were obtained from retrospective review of all patients receiving ICDs between June 1997 and July 2001 at a single university hospital. Economic inputs were collected from national and single-center sources. Results In patients without other indications for electrophysiologic study (EPS), the expected per-person cost was least with the strategy of universal initial AV-ICD implantation ($36,232) compared with initial single-chamber ICD/upgrade as needed ($39,230) or EPS-guided selection ($41,130). Sensitivity analyses demonstrated that universal AV-ICD implantation remained least expensive with upgrade rates as low as 10%. At a 5% upgrade rate, AV-ICD remained cheapest if the device cost-differential narrowed to $1,568. For patients undergoing EPS for risk assessment, EP-guided selection was least expensive. Conclusions The strategy of universal AV-ICD implantation, which provides the benefits of dual-chamber capability while obviating any potential need for future upgrade, is the least costly strategy for most patient populations receiving ICDs.

Psychological Stress and Repolarization. Introduction: Psychological stress can precipitate ventricular arrhythmias in patients with ICDs, as well as sudden death. However, the physiologic pathways remain unknown. We sought to determine whether psychological stress induced in the laboratory setting alters indices of repolarization associated with arrhythmogenesis. Methods and Results: Patients with ICDs and a history of ventricular arrhythmia underwent ambulatory ECG monitoring during a laboratory mental stress protocol (anger recall and mental arithmetic). Continuous changes in repolarization indices which have correlated with temporal and spatial myocardial heterogeneity of repolarization, including T-wave alternans (TWA), T-wave amplitude (Tamp), and T-wave area (Tarea) were analyzed in the time domain. In the 33 patients (85% male, 88% with coronary artery disease, mean ejection fraction 30%), norepinephrine, epinephrine, BP, and HR increased during mental stress. TWA increased from 22 (interquartile range 16-27) at baseline to 29 (21-38) uV during mental stress (P < 0.001). Changes in TWA correlated with changes in HR, systolic BP, and catecholamines. Tamp and Tarea also increased with mental stress (P < 0.01) but did not correlate with changes in other variables. Conclusion: Psychological stress increased TWA, Tamp, and Tarea. Autonomically mediated repolarization changes may be a pathophysiologic link between emotion and arrhythmia in susceptible patients.

Among 58 consecutive patients who underwent electrophysiologic testing for risk assessment and who subsequently received a third-generation implantable cardioverter-defibrillator, 39 had ventricular tachycardia induced in the baseline state and 19 had ventricular tachycardia induced only after administration of intravenous procainamide, increasing the yield of electrophysiologic risk assessment by 49%. At follow-up, ventricular arrhythmias requiring implantable cardioverter-defibrillator termination occurred in 14 of 39 patients inducible in the baseline state and in 7 of 19 patients inducible only with intravenous procainamide. The provocative use of intravenous procainamide during electrophysiologic risk assessment increases the detection rate for risk of sustained ventricular arrhythmias with no loss of positive predictive value.

Pacemakers and cardioverter-defibrillators are implanted in patients with cardiovascular disease for an ever-increasing array of indications. Intensivists provide care frequently for patients who have these devices, and thus, they must be familiar with common problems and nuances that may contribute to critical illness. Close collaboration of the critical care physician and cardiologist/electrophysiologist assures that pacemakers and defibrillators are tuned to optimize the hemodynamic milieu of critically ill patients. Many recent advances in the sophistication of implanted devices are reviewed herein.

Human Daxx is a protein that functions, in part, as a transcriptional co-repressor through its interaction with a growing number of nuclear,DNA-associated proteins. To determine the mechanism by which hDaxx represses transcription, we used conventional chromatography to isolate endogenous hDaxx. We determined that hDaxx has an apparent molecular weight of 360 kDa,which is consistent with the fact that multiple domains of hDaxx are required for transcriptional repression and suggests that hDaxx associates with multiple proteins. Using co-fractionation and co-immunoprecipitation we demonstrate that hDaxx associates with proteins that are critical for transcriptional repression, such as histone deacetylase II, constituents of chromatin such as core histones H2A, H2B, H3 and H4, and Dek, a chromatin-associated protein reported to change the topology of DNA in chromatin in vitro. We also demonstrate a requirement for the SPT domain and the first paired amphipathic helix of hDaxx for its association with histone deacetylase II and acetylated histone H4, respectively. Finally, we provide evidence suggesting that the association of hDaxx with chromatin-related proteins is dependent on the post-translational phosphorylation status of hDaxx. A working model for the repressive action of hDaxx through its association with chromatin related proteins is presented.

The problem of multidrug resistance in serious Gram-negative bacterial pathogens has escalated so severely that new cellular targets and pathways need to be exploited to avoid many of the preexisting antibiotic resistance mechanisms that are rapidly disseminating to new strains. The discovery of small-molecule inhibitors of LpxC, the enzyme responsible for the first committed step in the biosynthesis of lipid A, represents a clinically unprecedented strategy to specifically act against Gram-negative organisms such as Pseudomonas aeruginosa and members of the Enterobacteriaceae. In this report, we describe the microbiological characterization of LpxC-4, a recently disclosed inhibitor of this bacterial target, and demonstrate that its spectrum of activity extends to several of the pathogenic species that are most threatening to human health today. We also show that spontaneous generation of LpxC-4 resistance occurs at frequencies comparable to those seen with marketed antibiotics, and we provide an in-depth analysis of the mechanisms of resistance utilized by target pathogens. Interestingly, these isolates also served as tools to further our understanding of the regulation of lipid A biosynthesis and enabled the discovery that this process occurs very distinctly between P. aeruginosa and members of the Enterobacteriaceae. Finally, we demonstrate that LpxC-4 is efficacious in vivo against multiple strains in different models of bacterial infection and that the major first-step resistance mechanisms employed by the intended target organisms can still be effectively treated with this new inhibitor., IMPORTANCE New antibiotics are needed for the effective treatment of serious infections caused by Gram-negative pathogens, and the responsibility of identifying new drug candidates rests squarely on the shoulders of the infectious disease community. The limited number of validated cellular targets and approaches, along with the increasing amount of antibiotic resistance that is spreading throughout the clinical environment, has prompted us to explore the utility of inhibitors of novel targets and pathways in these resistant organisms, since preexisting target-based resistance should be negligible. Lipid A biosynthesis is an essential process for the formation of lipopolysaccharide, which is a critical component of the Gram-negative outer membrane. In this report, we describe the in vitro and in vivo characterization of novel inhibitors of LpxC, an enzyme whose activity is required for proper lipid A biosynthesis, and demonstrate that our lead compound has the requisite attributes to warrant further consideration as a novel antibiotic.

A high-throughput phenotypic screen for novel antibacterial agents led to the discovery of a novel pyrazolopyrimidinedione, PPD-1, with preferential activity against methicillin-resistant Staphylococcus aureus (MRSA). Resistance mapping revealed the likely target of inhibition to be lysyl tRNA synthetase (LysRS). Preliminary structure–activity relationship (SAR) studies led to an analog, PPD-2, which gained Gram-negative antibacterial activity at the expense of MRSA activity and resistance to this compound mapped to prolyl tRNA synthetase (ProRS). These targets of inhibition were confirmed in vitro, with PPD-1 showing IC50s of 21.7 and 35 μM in purified LysRS and ProRS enzyme assays, and PPD-2, 151 and 0.04 μM, respectively. The highly attractive chemical properties of these compounds combined with intriguing preliminary SAR suggest that further exploration of this compelling novel series is warranted.

Background It has been nearly a decade since Goldman's computer-driven algorithm to predict myocardial infarction was validated. Despite the potential to avoid admission of patients without acute myocardial infarction (AMI) to the coronary care unit (CCU), the routine use of computer-generated protocols has not been widely adopted. Methods Two hundred consecutive patients admitted to a university-affiliated community hospital with the suspected diagnosis of AMI as determined by physicians without the aid of the Goldman protocol underwent a blinded prospective evaluation to assess the performance of the Goldman algorithm in predicting the presence of AMI. Over the same time period, the Goldman algorithm was applied by retrospective chart review in 762 patients with non-AMI admitting diagnoses. Prospective history, physical examination, and electrocardiographic data were obtained within 24 hours of admission to the CCU by a physician blinded to each patient's clinical course. Retrospective chart reviews were conducted for 762 patients with chest pain given with non-AMI diagnoses. Results The diagnosis of AMI was confirmed in 68.5% (137/200) of patients with suspected AMI admitted to the CCU. In prospective parallel evaluations the Goldman algorithm predicted the presence of AMI in 167 (83.5%) of these 200 patients. All 137 confirmed patients with AMI were correctly identified by the Goldman algorithm. All major in-hospital complications occurred in the 137 patients who were diagnosed as having AMI. Of the 762 patients with chest pain with non-AMI diagnoses, only 27 (3.5%) sustained an AMI. The Goldman algorithm predicted the presence of AMI in 85% (23/27) of these patients. Adherence to the use of Goldman's algorithm in the triage of chest pain could have prevented 16.5% of CCU admissions for AMI. Conclusions Routine adherence to the Goldman algorithm for the evaluation of patients with acute chest pain could have decreased the number of CCU admissions for suspected AMI by 16.5%. Because major in-hospital complications occurred only in patients with AMI, this strategy would result in significant cost savings to our health care system without jeopardizing patient safety. (Am Heart J 1999;138:705-9.)

The Pax3-FKHR fusion protein is present in alveolar rhabdomyosarcoma and results from the t(2;13) (q35;q14) chromosomal translocation. Its oncogenic activity is dependent on a combination of protein-DNA and protein-protein interactions mediated by the Pax3 homeodomain recognition helix. In this report we demonstrate that human Daxx (hDaxx) interacts with Pax3 in vivo and with DNA-bound Pax3 in vitro. This interaction is mediated primarily through the homeodomain recognition helix with the additional involvement of the octapeptide domain and its N-terminal flanking amino acids. Through this interaction hDaxx represses the transcriptional activity of Pax3 by approximately 80%. The Pax3-FKHR fusion is unresponsive to this repressive effect despite an observed endogenous interaction with hDaxx in a rhabdomyosarcoma tumor cell line. Therefore, these data support the model that fusion of FKHR to Pax3 not only adds a strong transactivation domain, but also deregulates transcriptional control of Pax3 by overriding the natural repressive effect of hDaxx.

Although the problem of ICD sensing of paced ventricular stimuli has been resolved by incorporation of VVI pacing into current ICDs, many patients required separate DDD pacemakers. We report a problematic PM-ICD interaction: the inability to prevent sensing of paced atrial stimuli ("atrial sensing") leading to double-counting in DDD-PM-requiring patients with transvenous (TV) ICDs with aggressive autogain sensing (CPI Ventak PRxII or III). Four of eight patients receiving both transvenous DDD PMs and ICDs (CPI Endotak lead, at the RV apex), had atrial sensing, leading to double counting, despite intraoperative testing of multiple atrial locations with an active fixation lead. Five patients had a PRxII/III ICD, four with atrial sensing (80%), and three a PRx without atrial sensing. Patients with atrial sensing were not distinguished by any clinical or device related variable. In patients with atrial sensing (all with heart block), the PM was programmed to VDD mode. No patient has received inappropriate therapy or failed to sense VF in follow-up. In many patients with TV ICDs who required DDD pacing, no atrial position can be found without ICD sensing of atrial stimuli. While in patients with heart block this problem can be circumvented by programming to the VDD mode, in patients with sinus incompetence it may only be resolved by the combination ICD-DDD PM, currently in development.

Multidrug resistance in Gram-negative bacteria has become so threatening to human health that new antibacterial platforms are desperately needed to combat these deadly infections. The concept of siderophore conjugation, which facilitates compound uptake across the outer membrane by hijacking bacterial iron acquisition systems, has received significant attention in recent years. While standard in vitro MIC and resistance frequency methods demonstrate that these compounds are potent, broad-spectrum antibacterial agents whose activity should not be threatened by unacceptably high spontaneous resistance rates, recapitulation of these results in animal models can prove unreliable, partially because of the differences in iron availability in these different methods. Here, we describe the characterization of MB-1, a novel siderophore-conjugated monobactam that demonstrates excellent in vitro activity against Pseudomonas aeruginosa when tested using standard assay conditions. Unfortunately, the in vitro findings did not correlate with the in vivo results we obtained, as multiple strains were not effectively treated by MB-1 despite having low MICs. To address this, we also describe the development of new in vitro assays that were predictive of efficacy in mouse models, and we provide evidence that competition with native siderophores could contribute to the recalcitrance of some P. aeruginosa isolates in vivo .

Although ICD therapy is an efficient and reliable therapeutic method, internal defibrillation is a traumatic experience; moreover and there is accumulating evidence that internal defibril‐ lation, especially with high defibrillation energy, may adversely affect cardiac function and even patient prognosis [1, 2]. Therefore, considerable research efforts have been focused on better defining defibrillation mechanisms, particularly aiming at and improving defibrillation efficacy and in order to reduce lowering defibrillation energy requirements.

The CPI PRxII is a recently approved, multitiered implantable cardioverter defibrillator (ICD) that delivers high and low energy biphasic shocks, antitachycardia (ATP) and bradycardia pacing, and stores 2.5 minutes of electrograms from the widely spaced shocking electrodes. The PRxII was implanted in 58 patients at Yale-New Haven Hospital between December 1993 and January 1995. At implant, mean biphasic defibrillation threshold (DFT) in patients with testing to failure was 10 J (1-20). All 36 patients who were candidates for a new transvenous system underwent successful nonthoracotomy implantation. Based on noninvasive predischarge EPS results, 30 patients had > or = 1 VT zone: 21 patients had ATP, 9 others had first shock < or = 5 J. During follow-up, 13 patients had been treated for 379 events (range, 1-127). Of 340 events in a zone with ATP, 97% responded to ATP, 3% required shock. First programmed shock converted all events in a VF zone. Details, including RR intervals, were available for all events in 15 of 17 patients receiving appropriate or inappropriate therapy or diverted shocks. One hundred eleven of 148 available electrograms confirmed VT by morphology, rate, and/or presence of AV dissociation. In nine patients, electrogram data altered therapy through diagnosis of inappropriate or diverted therapy, guidance of detection enhancements, or diagnosis of previously unrecognized VTs. We conclude the PRxII achieves low DFTs that obviate the need for thoracotomy and effectively treats ventricular arrhythmias with ATP and shock, with programming guided by noninvasive electrophysiology. Multiple stored electrograms from widely spaced shocking electrodes greatly enhance diagnostic capabilities, facilitating effective treatment.

The incidence of hospital-acquired infections with multidrug-resistant (MDR) Gram-negative pathogens is increasing at an alarming rate. Equally alarming is the overall lack of efficacious therapeutic options for clinicians, which is due primarily to the acquisition and development of various antibiotic resistance mechanisms that render these drugs ineffective. Among these mechanisms is the reduced permeability of the outer membrane, which prevents many marketed antibiotics from traversing this barrier. To circumvent this, recent drug discovery efforts have focused on conjugating a siderophore moiety to a pharmacologically active compound that has been designed to hijack the bacterial siderophore transport system and trick cells into importing the active drug by recognizing it as a nutritionally beneficial compound. MC-1, a novel siderophore-conjugated β-lactam that promotes its own uptake into bacteria, has exquisite activity against many Gram-negative pathogens. While the inclusion of the siderophore was originally designed to facilitate outer membrane penetration into Gram-negative cells, here we show that this structural moiety also renders other clinically relevant antibiotic resistance mechanisms unable to affect MC-1 efficacy. Resistance frequency determinations and subsequent characterization of first-step resistant mutants identified PiuA, a TonB-dependent outer membrane siderophore receptor, as the primary means of MC-1 entry into Pseudomonas aeruginosa . While the MICs of these mutants were increased 32-fold relative to the parental strain in vitro , we show that this resistance phenotype is not relevant in vivo , as alternative siderophore-mediated uptake mechanisms compensated for the loss of PiuA under iron-limiting conditions.

Therapy with implantable cardioverter-defibrillators (ICDs) has been shown to improve survival among several large groups of patients at risk for sudden cardiac death (SCD). Several complicating issues arose from the widespread use of ICDs especially in heart failure (HF) patients. Twenty percent to 35% of HF patients who receive an ICD for primary prevention of SCD will receive an appropriate shock within 1 to 3 years for a life-threatening arrhythmia.1 Almost half of the HF patients who survive a cardiac arrest and receive an ICD for secondary prevention will receive a shock within 1 year of implant.2 Implantable cardioverter-defibrillator (ICD) shocks are usually regarded with a sense of relief given that the ventricular tachyarrhythmia was treated, and the SCD was averted. There is, however, accumulating data from the literature showing that patients with ICDs who receive shocks, whether appropriate or spurious, have worse prognosis than similar patients who do not receive shocks. Current guidelines do not provide a clear approach to managing patients presenting with ICD shocks, who clearly represent a high-risk group. However, current data from the literature suggest that ICD shocks should prompt a thorough evaluation to determine the etiology of the shock and to help guide therapeutic interventions.

Background: The ventriculophasic response (VR) refers to shortening of atrial cycle length during heart block when a QRS complex is interposed between P waves. No formal quantitative definition has heretofore been proposed, nor have its potential clinical correlations been studied. Hypothesis: We hypothesized that VR is present in selected patients who are distinguished by clinical features from those who lack VR. Methods: Pacing devices were temporarily programmed to VVI mode at 30 ppm as electrocardiogram and intracardiac electrograms were recorded at 50 mm/sec paper speed. We measured the percentage decrease in a P-P interval (A-A interval on the atrial electrogram) containing a QRS, compared to the preceding P-P interval. Left ventricular ejection fraction (LVEF) was measured by echocardiogram. Results: Shortening of P-P interval was observed chiefly when the interposed QRS occurred early in the anticipated P-P interval (as judged by the preceding P-P interval). P-P shortening of 0% to 3% occurred randomly. Defining VR as being a >3% P-P interval shortening when an interposed QRS occurred in the first 60% of the anticipated P-P interval, we found that VR was present in 28 (55%) of our patients. It was quite reproducible, was more common in women (81% vs 37% of men; P = 0.004), and positively correlated with LVEF (r = 0.41, P = 0.004). It did not correlate with age, diabetes, or β-blocker use. Conclusions: Using our newly derived definition of VR, we found the phenomenon was present in 55% of our patients. It was reproducible and more commonly seen in women and patients with LVEF ≥40%. © 2011 Wiley Periodicals, Inc. The authors have no funding, financial relationships, or conflicts of interest to disclose.

ObjectivesThis study sought to determine whether T-wave alternans (TWA) induced by anger in a laboratory setting predicts future ventricular arrhythmias in patients with implantable cardioverter-defibrillators (ICDs).BackgroundAnger can precipitate spontaneous ventricular tachycardia/ventricular fibrillation and induce TWA. Whether anger-induced TWA predicts future arrhythmias is unknown.MethodsSixty-two patients with ICDs underwent ambulatory electrocardiography during a mental stress protocol, 3 months after the ICD was implanted. T-wave alternans was analyzed using time-domain methods. After a ≥1 year follow-up, ICD stored data was reviewed to determine incidence of ICD-terminated ventricular tachycardia/ventricular fibrillation.ResultsPatients with ICD-terminated arrhythmias during follow-up (n = 10) had higher TWA induced by anger, 13.2 μV (interquartile range [IQR] 9.3 to 16 μV), compared with those patients without future ventricular arrhythmias, 9.3 μV (IQR 7.5 to 11.5 μV, p < 0.01). Patients in the highest quartile of anger-induced TWA (>11.9 μV, n = 15) were more likely to experience arrhythmias by 1 year than those in the lower quartiles (33% vs. 4%) and during extended follow-up (40% vs. 9%, p < 0.01 for both). In multivariable regression controlling for ejection fraction, prior clinical arrhythmia, and wide QRS, anger-induced TWA remained a significant predictor of arrhythmia, with likelihood in the top quartile 10.8 times that of other patients (95% confidence interval: 1.6 to 113, p < 0.05).ConclusionsAnger-induced TWA predicts future ventricular arrhythmias in patients with ICDs, suggesting that emotion-induced repolarization instability may be 1 mechanism linking stress and sudden death. Whether there is a clinical role for anger-induced TWA testing requires further study.

Objective To review the design and function of pacemakers and implantable cardioverter defibrillators with particular attention to those aspects that are of clinical relevance to perioperative and critical care physicians. Main points Pacemakers and implantable cardioverter defibrillators are complex devices that interact with cardiac function in ways that can significantly influence hemodynamics. A basic appreciation of device technology is essential to understanding both the normal patterns of pacemaker and implantable cardioverter defibrillator usage and the ways in which iatrogenic influences may result in adverse outcomes. The most important concern for pacemaker patients who enter the hospital is exposure to electromagnetic interference. Exposure is mainly from surgical cautery, but other sources are also present. With awareness of these concerns and an understanding of how to prevent adverse interactions, it is possible to safely care for these patients in the critical care setting. Despite recommended precautions, undesirable outcomes may occur and the clinician must be prepared to intervene in an appropriate manner to prevent patient injury.

Background: Prior studies with cardiac markers have focused predominantly on subjects presenting to the emergency department with chest pain or unstable angina, and have relied on serial markers for the diagnosis of acute myocardial infarction. We evaluated the diagnostic utility of a single cardiac troponin T (cTnT) determination at the time of presentation as compared to serial creatine kinase (CK) MB determinations in a broad spectrum of patients with suspected myocardial ischemia. Methods: A total of 267 consecutive patients presenting to the emergency department with suspected myocardial ischemia had a single, blinded cTnT determination drawn at the time of presentation to the emergency department in addition to routine serial electrocardiographic and CK-MB determinations. Results: The specificity (93.7% vs. 87.1%; p