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Biomedical subjects

M R Gold

Publications and source records attributed to M R Gold.

At least 19 recordsLinked to original sources
PubMed2000

Effect of second-phase duration on the strength-duration relation for human transvenous defibrillation.

BACKGROUND: The mechanism by which biphasic waveforms improve defibrillation efficacy is unclear. In addition, the optimal shape of the biphasic waveforms remains controversial. Animal experiments suggest that prolonging the duration of the second phase longer than the first worsens defibrillation thresholds (DFT). The purpose of this study was to determine the strength-duration relation for the second phase of a biphasic defibrillation waveform in humans. METHODS AND RESULTS: This was a prospective, randomized study of biphasic DFT in 36 patients; a uniform dual-coil transvenous lead system was used. In each patient, 3 DFTs were determined with the pulse duration for the second phase of the defibrillation waveform varying between 1 and 18 ms. The duration of the first phase was fixed at 6 ms and the capacitance was 150 microF. There was a significant increase in the leading edge voltage at DFT only when the second-phase pulse duration was decreased to 1 ms. There was no increase in DFT voltage even when the second-phase pulse duration was increased from 2 to 18 ms. Similar relations were observed for stored energy, leading edge current, or phase 2 energy. The normalized average current delivered during phase 2 decreased monotonically with increasing phase 2 duration. CONCLUSIONS: In humans, the biphasic DFT voltage or energy is increased only when the second phase of the waveform is <2 ms. The DFT voltage is insensitive to increasing the second phase of the defibrillator waveform to as long as 18 ms, or 3 times the duration of the first phase of the waveform.

Coronary Disease↗
PubMed2000

An alpha-helical cationic antimicrobial peptide selectively modulates macrophage responses to lipopolysaccharide and directly alters macrophage gene expression.

Certain cationic antimicrobial peptides block the binding of LPS to LPS-binding protein and reduce the ability of LPS to induce the production of inflammatory mediators by macrophages. To gain a more complete understanding of how LPS activates macrophages and how cationic peptides influence this process, we have used gene array technology to profile gene expression patterns in macrophages treated with LPS in the presence or the absence of the insect-derived cationic antimicrobial peptide CEMA (cecropin-melittin hybrid). We found that CEMA selectively blocked LPS-induced gene expression in the RAW 264.7 macrophage cell line. The ability of LPS to induce the expression of >40 genes was strongly inhibited by CEMA, while LPS-induced expression of another 16 genes was relatively unaffected. In addition, CEMA itself induced the expression of a distinct set of 35 genes, including genes involved in cell adhesion and apoptosis. Thus, CEMA, a synthetic alpha-helical peptide, selectively modulates the transcriptional response of macrophages to LPS and can alter gene expression in macrophages.

Animals↗
PubMed2000

Electrophysiologic testing to identify patients with coronary artery disease who are at risk for sudden death. Multicenter Unsustained Tachycardia Trial Investigators.

BACKGROUND: The mortality rate among patients with coronary artery disease, abnormal ventricular function, and unsustained ventricular tachycardia is high. The usefulness of electrophysiologic testing for risk stratification in these patients is unclear. METHODS: We performed electrophysiologic testing in patients who had coronary artery disease, a left ventricular ejection fraction of 40 percent or less, and asymptomatic, unsustained ventricular tachycardia. Patients in whom sustained ventricular tachyarrhythmias could be induced were randomly assigned to receive either antiarrhythmic therapy guided by electrophysiologic testing or no antiarrhythmic therapy. The primary end point was cardiac arrest or death from arrhythmia. Patients without inducible tachyarrhythmias were followed in a registry. We compared the outcomes of 1397 patients in the registry with those of 353 patients with inducible tachyarrhythmias who were randomly assigned to receive no antiarrhythmic therapy in order to assess the prognostic value of electrophysiologic testing. RESULTS: Patients were followed for a median of 39 months. In a Kaplan-Meier analysis, two-year and five-year rates of cardiac arrest or death due to arrhythmia were 12 and 24 percent, respectively, among the patients in the registry, as compared with 18 and 32 percent among the patients with inducible tachyarrhythmias who were assigned to no antiarrhythmic therapy (adjusted P<0.001). Overall mortality after five years was 48 percent among the patients with inducible tachyarrhythmias, as compared with 44 percent among the patients in the registry (adjusted P=0.005). Deaths among patients without inducible tachyarrhythmias were less likely to be classified as due to arrhythmia than those among patients with inducible tachyarrhythmias (45 and 54 percent, respectively; P=0.06). CONCLUSIONS: Patients with coronary artery disease, left ventricular dysfunction, and asymptomatic, unsustained ventricular tachycardia in whom sustained ventricular tachyarrhythmias cannot be induced have a significantly lower risk of sudden death or cardiac arrest and lower overall mortality than similar patients with inducible sustained tachyarrhythmias.

Aged↗
PubMed2000

Salmonella typhimurium infection and lipopolysaccharide stimulation induce similar changes in macrophage gene expression.

Changes in macrophage phenotype induced during infection result from the recognition of bacterial products as well as the action of bacterial virulence factors. We used the unprecedented opportunity provided by gene arrays to simultaneously study the expression of hundreds of genes during Salmonella typhimurium infection of macrophages and to assess the contribution of the bacterial virulence factor, LPS, in initiating the host responses to Salmonella. We found that S. typhimurium infection caused significant changes in the expression of numerous genes encoding chemokines, cell surface receptors, signaling molecules, and transcriptional activators at 4 h postinfection of the RAW 264.7 murine macrophage cell line. Our results revealed changes in the expression of several genes that had not been previously implicated in the host responses to S. typhimurium infection, as well as changes in the expression of several genes previously shown to be regulated by S. typhimurium infection. An overlapping spectrum of genes was expressed in response to virulent S. typhimurium and purified S. typhimurium LPS, reinforcing the major role of this surface molecule in stimulating the early response of macrophages to bacterial infection. The macrophage gene expression profile was further altered by activation with IFN-gamma, indicating that host cell responses depend on the activation state of the cell.

Animals↗
PubMed2000

Inequality in quality: addressing socioeconomic, racial, and ethnic disparities in health care.

Socioeconomic and racial/ethnic disparities in health care quality have been extensively documented. Recently, the elimination of disparities in health care has become the focus of a national initiative. Yet, there is little effort to monitor and address disparities in health care through organizational quality improvement. After reviewing literature on disparities in health care, we discuss the limitations in existing quality assessment for identifying and addressing these disparities. We propose 5 principles to address these disparities through modifications in quality performance measures: disparities represent a significant quality problem; current data collection efforts are inadequate to identify and address disparities; clinical performance measures should be stratified by race/ethnicity and socioeconomic position for public reporting; population-wide monitoring should incorporate adjustment for race/ethnicity and socioeconomic position; and strategies to adjust payment for race/ethnicity and socioeconomic position should be considered to reflect the known effects of both on morbidity. JAMA. 2000;283:2579-2584

Empirical Research↗
PubMed2000

Acute hemodynamic effects of right ventricular pacing site and pacing mode in patients with congestive heart failure secondary to either ischemic or idiopathic dilated cardiomyopathy.

The hemodynamic effects of pacing in patients with congestive heart failure (CHF) remain controversial. Early studies reported that pacing from the right ventricular (RV) apex improved acute hemodynamic parameters in patients with left ventricular systolic dysfunction, but these findings were not confirmed in subsequent controlled studies. More recently, it has been proposed that pacing from the RV side of the ventricular septum improves hemodynamic function compared with intrinsic conduction or apical pacing. Either dual-chamber or ventricular pacing have been evaluated, again with inconsistent findings. To assess the effects of pacing site and mode on acute hemodynamic function, we evaluated 21 subjects with CHF and intrinsic conduction disease. Hemodynamics were compared in AAI, VVI, and DDD modes with pacing from the RV apex or high septum. The pacing rate was constant in each patient and the order of testing was randomized. In the absence of ventricular pacing (AAI mode), the mean systemic arterial pressure was 85 +/- 11 mm Hg, the right atrial pressure was 11 +/- 4 mm Hg, the pulmonary capillary wedge pressure was 18 +/- 8 mm Hg and the cardiac index was 2.4 +/- 0.7 L/min/m(2). Compared with AAI pacing, there were no improvements in any hemodynamic parameter with DDD pacing from either RV site. Hemodynamic function worsened with VVI pacing from both RV sites. Subgroup analyses of patients with dilated cardiomyopathy, with prolonged PR interval, or with significant mitral regurgitation also failed to demonstrate an improvement with pacing. We conclude that pacing mode but not RV pacing site affects acute hemodynamic function. Pacing in the DDD mode prevents the deleterious effects of VVI pacing in this patient population.

Aged↗
PubMed2000

Cutting edge: cationic antimicrobial peptides block the binding of lipopolysaccharide (LPS) to LPS binding protein.

We investigated the mechanism by which cationic antimicrobial peptides block the activation of macrophages by LPS. The initial step in LPS signaling is the transfer of LPS to CD14 by LPS binding protein (LBP). Because many cationic antimicrobial peptides bind LPS, we asked whether these peptides block the binding of LPS to LBP. Using an assay that measures the binding of LPS to immobilized LBP, we show for the first time that a variety of structurally diverse cationic antimicrobial peptides block the interaction of LPS with LBP. The relative ability of different cationic peptides to block the binding of LPS to LBP correlated with their ability to block LPS-induced TNF-alpha production by the RAW 264.7 macrophage cell line.

Acute-Phase Proteins↗
PubMed2000

Synthesis and structure-affinity relationships of 1,3, 5-alkylsubstituted cyclohexylamines binding at NMDA receptor PCP site.

A series of 1,3,5-alkylsubstituted cyclohexylamines 2 were synthesized as ligands for the N-methyl-D-aspartate (NMDA) receptor phencyclidine (PCP) binding site. Pure diastereomers with defined configuration of amino group 2-ax and 2-eq were obtained. The optimal size of 1,3,5-substituents was determined for cyclohexylamines 2 with an equatorial amino group in the lowest energy conformation using Hansch analysis. According to the data, the lipophilic part of cyclohexylamines 2 does not discriminate between hydrophobic regions of the PCP binding site but rather recognizes this site as a whole lipophilic pocket.

Amantadine↗
PubMed2000

Pacing for patients with congestive heart failure and dilated cardiomyopathy.

Considerable evidence has now accumulated that permanent pacing may provide symptomatic benefit for at least some patients with CHF. Recently, the most promising results with left ventricular or biventricular pacing have been obtained. The data for improvement in survival with pacing is less compelling. The mortality of CHF associated with systolic dysfunction of the left ventricle remains high and arrhythmic deaths are frequent. Clinical trials such as the Sudden Cardiac Death Heart Failure Trial (SCD-HeFT) are currently underway to investigate the role of the implantable defibrillator in patients with heart failure. The development and general availability of ICDs with biventricular pacing capability may play an increasingly important role in the overall therapeutic plan for this group of patients to allow for optimization of functional status with pacing and protection from sudden cardiac death with defibrillation.

Arrhythmias, Cardiac↗
PubMed2000

ICD therapy in the new millennium.

Remarkable progress has been made in the 15 years since ICD therapy was approved for human use. The early "shock boxes" had almost no diagnostic capabilities and required thoracotomy for epicardial patch implantation with typical duration of hospitalization of about a week. Pulse-generator longevity was less than 2 years. Modern devices provide detailed information about the morphology and rate of electrocardiographic signals before, during, and after arrhythmia therapy. The down-sizing of pulse generators and improvements in lead design and shock waveforms allow the simplicity of defibrillator implantation to approach that of pacemakers, with defibrillation thresholds comparable with those initially observed with epicardial patches. Despite the marked reduction in size and increase in diagnostic capabilities, device longevity is now longer than 6 years. Routine outpatient ICD implantation is presently feasible and will increase in frequency if ongoing primary prevention trials prove beneficial. Further advances in lead technology and arrhythmia discrimination should increase the efficacy and reliability of therapy. Finally, devices have the capabilities to treat multiple problems in addition to life-threatening ventricular arrhythmias including atrial arrhythmias and congestive heart failure.

Defibrillators, Implantable↗
PubMed2000

Short term escape rhythm characteristics after radiofrequency ablation of the atrioventricular junction.

Radiofrequency ablation of the atrioventricular (AV) node has become an established method of treating drug-resistant supraventricular arrhythmias, especially atrial fibrillation. Although it is routine to implant a permanent pacemaker following ablation, one of the potential adverse effects of the procedure is that many patients become pacemaker-dependent and are at risk of an adverse outcome in the event of pacemaker malfunction. Obtaining information about the characteristics of the escape rhythm would be helpful in risk-stratifying these patients and might facilitate modifications of the procedure that would reduce the incidence of this problem. We prospectively studied the clinical parameters and escape rhythm characteristics in 24 patients undergoing radiofrequency ablation of the AV node. Initially, 2 patients had no detectable escape beats and 4 had escape rates <30 beats/min. At 12 hours, 3 of these 4 had adequate (>30 beats/min) escape rates (there were no 12-hour data in 2). The escape rhythm was stable in 17 of the other 18 while 1 had no escape beats at 12 hours. Patients developing right bundle branch block had a greater chance of having an inadequate escape rhythm at 12 hours but this difference was not seen at 24 hours. We conclude that an adequate escape rhythm is usually present immediately after radiofrequency ablation of the AV node and tends to remain stable up to 24 hours. The absence of an escape rhythm immediately after ablation is of limited prognostic value since reliable escape rhythms may emerge subsequently.

Aged↗
PubMed2000

Targets of B-cell antigen receptor signaling: the phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase-3 signaling pathway and the Rap1 GTPase.

In this review, we discuss the role of phosphatidylinositol 3-kinase (PI3K) and Rap 1 in B-cell receptor (BCR) signaling. PI3K produces lipids that recruit pleckstrin homology domain-containing proteins to the plasma membrane. Akt is a kinase that the BCR activates in this manner. Akt phosphorylates several transcription factors as well as proteins that regulate apoptosis and protein synthesis. Akt also regulates glycogen synthase kinase-3, a kinase whose substrates include the nuclear factor of activated T cells (NF-AT)cl and beta-catenin transcriptional activators. In addition to Akt, PI3K-derived lipids also regulate the activity and localization of other targets of BCR signaling. Thus, a key event in BCR signaling is the recruitment of PI3K to the plasma membrane where its substrates are located. This is mediated by binding of the Src homology (SH) 2 domains in PI3K to phosphotyrosine-containing sequences on membrane-associated docking proteins. The docking proteins that the BCR uses to recruit PI3K include CD19, Cbl, Gab1, and perhaps Gab2. We have shown that Gab1 colocalizes PI3K with SH2 domain-containing inositol phosphatase (SHIP) and SHP2, two enzymes that regulate PI3K-dependent signaling. In contrast to PI3K, little is known about the Rap1 GTPase. We showed that the BCR activates Rap1 via phospholipase C-dependent production of diacylglycerol. Since Rap1 is thought to regulate cell adhesion and cell polarity, it may be involved in B-cell migration.

Animals↗
PubMed2000

Signal-averaged isoharmonic body surface maps of patients with ischemic cardiomyopathy.

INTRODUCTION: Prevention of sudden arrhythmic cardiac death depends on accurate identification of individuals at high risk. Previous studies of signals recorded directly from arrhythmogenic tissue suggested that the predictive value of the signal-averaged ECG could be enhanced by expanded temporal, spectral, and spatial analysis. Accordingly, we performed a prospective study of 192-lead signal-averaged body surface maps from 43 patients with ischemic cardiomyopathy referred for electrophysiologic study. Three groups were included: 15 patients with clinical ventricular tachycardia (VT), 12 patients with inducible VT, and 16 patients with non-VT. METHODS AND RESULTS: The patients were well matched with regard to age, gender, infarct location, ejection fraction (28% +/- 9%), QRS duration, and incidence of nonsustained VT (96%). Isoharmonic maps of the entire cardiac cycle were constructed for each patient. The peaks of the 1-7 Hz isoharmonic maps distinguished patients with clinical VT from non-VT and inducible VT patients (1,152 +/- 273, 852 +/- 283, and 808 +/- 272, respectively; P = 0.003). After prospective observation for 22 +/- 16 months, the combined endpoint of spontaneous sustained VT, ventricular fibrillation, appropriate defibrillator therapy, and death was predicted by inducibility of VT (relative risk 3.8, P = 0.008) and by the signal-averaged isoharmonic body surface map (relative risk 3.1, P = 0.02). CONCLUSION: These results confirm the diagnostic utility of signal-averaged isoharmonic body surface maps in a rigorously defined patient population.

Aged↗
PubMed2000

Sensing lead failure in implantable defibrillators: a comparison of two commonly used leads.

INTRODUCTION: Despite major technological advances, structural problems in implantable cardioverter defibrillator (ICD) endocardial sensing leads remain a significant problem. There are two types of ICD sensing leads: (1) dedicated bipolar leads and (2) integrated lead systems that include defibrillation coils. The long-term performance of these two lead systems has not been directly compared. METHODS AND RESULTS: We prospectively examined the incidence of lead failure manifested by inappropriate arrhythmia detection in 247 consecutive patients undergoing abdominal ICD implant at a single center between 1991 and 1995. A total of 107 patients received BT-10 (dedicated bipolar) leads and 140 patients received Endotak (integrated bipolar) leads. Over a mean follow-up of 860 +/- 442 days, there were 19 (17.8%) lead failures with the BT-10 lead (261 to 1,505 days postimplant) compared with only 6 (4.3%; P < 0.01) with the Endotak lead (410 to 1,211 days postimplant). Lead failure was due to an insulation defect in all cases, with the problem occurring in the proximal lead (within the pulse generator pocket) in all but one case. Lead survival was significantly better with the Endotak lead (P = 0.015, risk ratio = 3.0, 95% confidence intervals 1.2 to 7.6). CONCLUSION: Late lead failure due to insulation defects in BT-10 sensing leads (causing inappropriate ICD activation) is a relatively common and progressive phenomenon, with difficulties becoming apparent as long as 4 years after implant. This problem is a likely cause of inappropriate shocks in patients with BT-10 leads. Implantation of a new sensing lead should be considered at the time of elective pulse generator replacement, even in the absence of demonstrable oversensing.

Aged↗
PubMed2000

Optimization of transvenous coil position for active can defibrillation thresholds.

INTRODUCTION: Lead systems that include an active pectoral pulse generator are now standard for initial defibrillator implantations. However, the optimal transvenous lead system and coil location for such active can configurations are unknown. The purpose of this study was to evaluate the benefit and optimal position of a superior vena cava (SVC) coil on defibrillation thresholds with an active left pectoral pulse generator and right ventricular coil. METHODS AND RESULTS: This prospective, randomized study was performed on 27 patients. Each subject was evaluated with three lead configurations, with the order of testing randomized. Biphasic shocks were delivered between the right ventricular coil and an active can alone (unipolar), or an active can in common with the proximal coil positioned either at the right atrial/SVC junction (low SVC) or in the left subclavian vein (high SVC). Stored energies at defibrillation threshold were higher for the single-coil, unipolar configuration (11.2 +/- 6.6 J) than for the high (8.9 +/- 4.2 J) or low (8.5 +/- 4.2 J) SVC configurations (P < 0.01). Moreover, 96% of subjects had low (< or = 15 J) thresholds with the SVC coil in either position compared with 81% for the single-coil configuration. Shock impedance (P < 0.001) was increased with the unipolar configuration, whereas peak current was reduced (P < 0.001). CONCLUSION: The addition of a proximal transvenous coil to an active can unipolar lead configuration reduces defibrillation energy requirements. The position of this coil has no significant effect on defibrillation thresholds.

Aged↗
PubMed1999

Tyrosine phosphorylation of shc in response to B cell antigen receptor engagement depends on the SHIP inositol phosphatase.

Tyrosine phosphorylation of Shc in response to B cell Ag receptor (BCR) engagement creates binding sites for the Src homology 2 (SH2) domain of Grb2. This facilitates the recruitment of both Grb2. Sos complexes and Grb2. SHIP complexes to the plasma membrane where Sos can activate Ras and SH2 domain-containing inositol phosphatase (SHIP) can dephosphorylate phosphatidylinositol 3,4,5-trisphosphate. Given the importance of Shc phosphorylation, we investigated the mechanism by which the BCR stimulates this response. We found that both the SH2 domain and phosphotyrosine-binding (PTB) domain of Shc are important for BCR-induced tyrosine phosphorylation of Shc and the subsequent binding of Grb2 to Shc. The unexpected finding that the PTB domain of Shc is required for Shc phosphorylation was investigated further. Because the major ligand for the Shc PTB domain is SHIP, we asked whether the interaction of Shc with SHIP was required for BCR-induced tyrosine phosphorylation of Shc. Using SHIP-deficient DT40 cells, we show that SHIP is necessary for the BCR to induce significant levels of Shc tyrosine phosphorylation. BCR-induced tyrosine phosphorylation of Shc could be restored in the these cells by expressing wild-type SHIP but not by expressing a mutant form of SHIP that cannot bind to Shc. This suggests that BCR-induced tyrosine phosphorylation of Shc may depend on the binding of SHIP to the Shc PTB domain. Thus, we have described a novel role for SHIP in BCR signaling, promoting the tyrosine phosphorylation of Shc.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Interaction of septadian and circadian rhythms in life-threatening ventricular arrhythmias in patients with implantable cardioverter-defibrillators.

Previous studies have shown that life-threatening ventricular arrhythmias display both circadian and septadian (day of the week) periodicity. We hypothesized that assessing the relation between these circadian and septadian rhythms may provide important pathophysiologic information about the mechanism of sudden cardiac death. Using the database from a population of 683 consecutive patients with a third-generation implantable cardioverter-defibrillator (ICD), we examined the time pattern of ICD activations for rapid (prospectively defined as cycle length <280 ms) tachycardias for each day of the week. A total of 5,270 arrhythmic episodes were analyzed. Despite the fact that event distribution was significantly nonuniform (p <0.001) for both circadian and septadian analyses, the circadian pattern was strikingly similar for each day of the week with a relatively broad peak between 9 A.M. and 6 P.M. and a long nadir between 9 P.M. and 6 A.M. We conclude that the trigger factors responsible for the daily circadian distribution of life-threatening ventricular arrhythmias in a population with ICDs are similar throughout the week and may thus be unrelated to the standard work week. These data suggest that the physiologic modulators of circadian and septadian rhythms may be different.

Aged↗