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M R Gold

Publications and source records attributed to M R Gold.

At least 73 records · Page 4Linked to original sources
PubMed1998

Dendritic cell survival and maturation are regulated by different signaling pathways.

Although dendritic cell (DC) activation is a critical event for the induction of immune responses, the signaling pathways involved in this process have not been characterized. In this report, we show that DC activation induced by lipopolysaccharide (LPS) can be separated into two distinct processes: first, maturation, leading to upregulation of MHC and costimulatory molecules, and second, rescue from immediate apoptosis after withdrawal of growth factors (survival). Using a DC culture system that allowed us to propagate immature growth factor-dependent DCs, we have investigated the signaling pathways activated by LPS. We found that LPS induced nuclear translocation of the nuclear factor (NF)-kappaB transcription factor. Inhibition of NF-kappaB activation blocked maturation of DCs in terms of upregulation of major histocompatibility complex and costimulatory molecules. In addition, we found that LPS activated the extracellular signal-regulated kinase (ERK), and that specific inhibition of MEK1, the kinase which activates ERK, abrogated the ability of LPS to prevent apoptosis but did not inhibit DC maturation or NF-kappaB nuclear translocation. These results indicate that ERK and NF-kappaB regulate different aspects of LPS-induced DC activation: ERK regulates DC survival whereas NF-kappaB is responsible for DC maturation.

Animals↗
PubMed1998

The Gab1 protein is a docking site for multiple proteins involved in signaling by the B cell antigen receptor.

Gab1 is a member of the docking/scaffolding protein family which includes IRS-1, IRS-2, c-Cbl, p130(cas), and p62(dok). These proteins contain a variety of protein-protein interaction motifs including multiple tyrosine residues that when phosphorylated can act as binding sites for Src homology 2 (SH2) domain-containing signaling proteins. We show in the RAMOS human B cell line that Gab1 is tyrosine-phosphorylated in response to B cell antigen receptor (BCR) engagement. Moreover, tyrosine phosphorylation of Gab1 correlated with the binding of several SH2-containing signaling proteins to Gab1 including Shc, Grb2, phosphatidylinositol 3-kinase, and the SHP-2 tyrosine phosphatase. Far Western analysis showed that the SH2 domains of Shc, SHP-2, and the p85 subunit of phosphatidylinositol 3-kinase could bind directly to tyrosine-phosphorylated Gab1 isolated from activated RAMOS cells. In contrast, the Grb2 SH2 domain did not bind directly to Gab1 but instead to the Shc and SHP-2 associated with Gab1. We also show that Gab1 is present in the membrane-enriched particulate fraction of RAMOS cells and that Gab1/signaling protein complexes are found in this fraction after BCR engagement. Thus, tyrosine-phosphorylated Gab1 may recruit cytosolic signaling proteins to cellular membranes where they can act on membrane-bound targets. This may be a critical step in the activation of multiple BCR signaling pathways.

Adaptor Proteins, Signal Transducing↗
PubMed1998

Activation of the Rap1 GTPase by the B cell antigen receptor.

The B cell antigen receptor (BCR) activates Ras, a GTPase that promotes cell proliferation by activating the Raf-1/MEK/ERK signaling module and other signaling enzymes. In its active GTP-bound form, the Rap1 GTPase may act as a negative regulator of Ras-mediated signaling by sequestering Ras effectors (e.g., Raf-1) and preventing their activation. In this report, we show that BCR engagement activates Rap1 and that this is dependent on production of diacylglycerol (DAG) by phospholipase C-gamma. Activation of Rap1 by the BCR was greatly reduced in phospholipase C-gamma-deficient B cells, whereas both a synthetic DAG and phorbol dibutyrate could activate Rap1 in B cells. We had previously shown that C3G, an activator of Rap1, associates with the Crk adaptor proteins in B cells and that BCR engagement causes Crk to bind to the Cas and Cbl docking proteins. However, the DAG-dependent pathway by which the BCR activates Rap1 apparently does not involve Crk signaling complexes since phorbol dibutyrate could activate Rap1 without inducing the formation of these complexes. Thus, the BCR activates Rap1 via a novel DAG-dependent pathway.

Animals↗
PubMed1998

Comparison of single- and dual-coil active pectoral defibrillation lead systems.

OBJECTIVES: The purpose of this study was to compare defibrillation thresholds with lead systems consisting of an active left pectoral electrode and either single or dual transvenous coils. BACKGROUND: Lead systems that include an active pectoral pulse generator reduce defibrillation thresholds and permit transvenous defibrillation in nearly all patients. A further improvement in defibrillation efficacy is desirable to allow for smaller pulse generators with a reduced maximal output. METHODS: This prospective study was performed in 50 consecutive patients. Each patient was evaluated with two lead configurations with the order of testing randomized. Shocks were delivered between the right ventricular coil and either an active can alone (single coil) or an active can with the proximal atrial coil (dual coil). The right ventricular coil was the cathode for the first phase of the biphasic defibrillation waveform. RESULTS: Delivered energy at the defibrillation threshold was 10.1+/-5.0 J for the single-coil configuration and 8.7+/-4.0 J for the dual-coil configuration (p < 0.02). Moreover, 98% of patients had low (<15 J) thresholds with the dual-coil lead system, compared with 88% of patients with the single-coil configuration (p=0.05). Leading edge voltage (p < 0.001) and shock impedance (p < 0.001) were also decreased with the dual-coil configuration, although peak current was increased (p < 0.001). CONCLUSIONS: A dual-coil, active pectoral lead system reduces defibrillation energy requirements compared with a single-coil, unipolar configuration.

Aged↗
PubMed1998

The effect of delivered energy on defibrillation shock impedance.

The impedance of internal defibrillator shocks is an important determinant of defibrillation efficacy. To assess the effect of delivered energy on impedance, we studied 97 patients with 4 different lead systems. The lead systems evaluated were two epicardial patches, a hybrid system of a patch and right atrial coil, a dual coil transvenous lead and a transvenous lead with a subcutaneous patch. Impedances were measured for 6 shock energies between 0.1 and 30 J. Shock impedance increased at low energies for all lead systems (p < 0.001), although the rate of increase varied markedly between systems. The energy factor (FE), which is the ratio of impedances for the 0.1 and 10 J shocks, was least for the platinum transvenous lead (1.2 +/- 0.02) and greatest for the titanium hybrid lead (4.2 +/- 0.2). Reversing the polarity of the hybrid lead markedly attenuated the impedance rise. These findings indicate that there is at least a modest rise (20%) of shock impedance at very low delivered energies. The largest increases noted with titanium lead systems are primarily due to polarization. Titanium transvenous leads should be avoided when low energy shocks are utilized such as for the cardioversion of ventricular tachycardia or atrial fibrillation.

Arrhythmias, Cardiac↗
PubMed1998

Reversible prolonged pacemaker failure due to electrocautery.

Despite improved technology, permanent pacemakers remain susceptible to electromagnetic interference, including electrocautery. We describe sudden, apparently irreversible output loss in a pacemaker associated with the use of electrocautery, despite standard precautionary measures. When tested by the manufacturer several weeks later, pulse generator function was normal and it was functioning in the "reset" mode. We postulate that pacemaker failure was related to current drain causing "lockout" of the voltage control oscillator, the mechanism responsible for regulating pulse width. Further reduction in battery voltage, due either to exposure to cold temperatures while the device was being transported to the manufacturer or to further use of electrocautery during device explanation, may have allowed it to reach the "reset" level, permitting normal function to resume.

Aged↗
PubMed1998

A comparison of pectoral and abdominal transvenous defibrillator implantation: analysis of costs and outcomes.

Traditionally cardioverter-defibrillator implantation was performed by surgeons under general anesthesia. However, with advances in lead and pulse generator technology, the surgical implantation technique has been simplified and routine pectoral pulse generator placement without general anesthesia is now possible. To assess the economic benefit of pectoral implantation, we analyzed 43 consecutive initial transvenous defibrillator implantations. The patients were grouped according to whether the implant was abdominal by a surgeon in the operating room (n = 23) or pectoral by an electrophysiologist in a laboratory (n = 20). The duration of hospitalization was significantly longer in the operating room than in the laboratory group (8.1 +/- 3.4 vs 5.8 +/- 2.4 days, p = 0.01), which was due primarily to the postoperative stay which averaged 1.9 days longer. Total costs were $40,274 +/- 6,861 for the operating room cohort and $32,546 +/- 3,634 for the lab group (p < 0.001). This reduction was due to a 32% lowering of professional costs and an 18% lowering of facility costs. We conclude that pectoral defibrillator implantation is cost effective and results in significant reductions of hospital stay.

Abdominal Muscles↗
PubMed1998

Inappropriate shocks from implanted cardioverter defibrillators caused by sensing of diaphragmatic myopotentials.

Inappropriate shocks remain one of the major problems associated with the use of implantable cardioverter defibrillators (ICD). We describe 3 patients who had inappropriate shocks due to oversensing of diaphragmatic myopotentials. In all 3, oversensing could be demonstrated during deep inspiration or Valsalva maneuver. The problem was remedied in one by insertion of a separate rate sensing lead in the right ventricular outflow tract, in the second by decreasing the rate of antibradycardia pacing of the ICD, and in the third by decreasing the sensitivity of the ICD. We conclude that the possibility of sensed diaphragmatic myopotentials should be considered at the time of ICD implant so that appropriate preventive measures can be taken.

Aged↗
PubMed1998

Implications and treatment of atrial fibrillation after cardiothoracic surgery.

Atrial fibrillation (AF) is the most commonly encountered arrhythmia that occurs after cardiothoracic surgery. It develops in up to 40% of patients, most frequently in the first few postoperative days. The strongest risk factors for AF are age and male gender. The pathogenesis of this arrhythmia probably involves increased sympathetic activity in the setting of slowed atrial conduction. The development of postoperative AF is associated with an increased morbidity, higher costs, and prolonged hospitalization. The use of prophylactic beta-blockers and procainamide reduces the incidence of AF whereas digoxin, verapamil, and amiodarone appear less effective. Once AF occurs, the mainstay of treatment remains rate control, anticoagulation, and restoration of sinus rhythm.

Adrenergic beta-Antagonists↗
PubMed1998

Toward consistency in cost-utility analyses: using national measures to create condition-specific values.

OBJECTIVES: The authors developed an "off-the-shelf" source of health-related quality of life (HRQL) scores for cost-effectiveness analysts unable to collect primary data. METHODS: The authors derived and conducted preliminary validation on a set of health-related quality of life scores for chronic conditions using nationally representative data from the National Health Interview Survey (NHIS) and the Healthy People 2000 Years of Healthy Life measure developed to monitor the health (longevity and health-related quality of life) of Americans during this decade. The measure comprises two domains, role function and self-rated health, and is scaled from 0 (death) to 1 (best health state). Health-related quality of life scores for chronic conditions were calculated using the Years of Healthy Life scores associated with chronic conditions reported in the 1987-1992 National Health Interview Survey. Preliminary validation was examined by comparing the health-related quality of life scores with those obtained in two other studies. RESULTS: Tables provide health-related quality of life scores for persons with and without conditions. The scores had reasonable face validity, ranging from 0.87 for allergic rhinitis to 0.27 for hemiplegia. Correlations of the health-related quality of life condition weight scores with those from two other studies were 0.78 and 0.86. CONCLUSIONS: These condition weights may prove useful to investigators conducting cost-effectiveness analyses using secondary data, where community ratings of health-related quality of life for chronic conditions are required. Use of a standard set of health-related quality of life weights gathered from a national sample can enhance the comparability of cost-effectiveness analyses. Improvements in national data collection techniques, with empirical gathering of preferences, will further strengthen this measure.

Activities of Daily Living↗
PubMed1998

Temporal stability of defibrillation thresholds with an active pectoral lead system.

INTRODUCTION: Monophasic defibrillation thresholds rise over time with a variety of lead systems. These chronic changes are attenuated or eliminated by biphasic waveforms, although the effect appears dependent upon the lead system. With the downsizing of pulse generator size to allow for routine pectoral implantation, active can lead systems have now become standard. However, the temporal stability of such lead systems has not been evaluated previously. METHODS AND RESULTS: This study was a prospective assessment of the changes of active pectoral defibrillation thresholds over time. Thresholds were measured at implant, predischarge, and at a mean follow-up of 50 days in 46 patients with a uniform testing protocol and shock polarity. The lead system was a dual-coil Endotak DSP lead with an active pectoral pulse generator. Defibrillation thresholds were 9.9+/-5.5 J at implantation, 8.5+/-6.0 J predischarge, and 7.6+/-5.5 J at follow-up (ANOVA, P = 0.007). Moreover, only two patients developed an increased threshold > 5 J, and no patient had an inadequate safety margin at follow-up. CONCLUSION: These results indicate that active pectoral defibrillation thresholds are stable over the first 2 months postimplantation and question the need for routine serial defibrillation threshold testing.

Aged↗
PubMed1998

Effect of shock polarity on biphasic defibrillation thresholds using an active pectoral lead system.

INTRODUCTION: The downsizing of implantable defibrillator pulse generators has made pectoral placement routine. A further reduction of defibrillation thresholds (DFTs) may simplify implantation defibrillation testing and allow for smaller, lower output pulse generators while maintaining an adequate defibrillation safety margin. One factor that may affect defibrillation efficacy is shock polarity. METHODS AND RESULTS: Sixty consecutive patients undergoing dual-coil, active left pectoral defibrillator implantation were evaluated. Paired, biphasic DFTs were measured in normal (RV apex = cathode) and reverse (RV apex = anode) polarity with order of testing randomized. Reverse polarity conferred a 15% reduction of mean DFTs (8.5 +/- 5.0 J normal, 7.2 +/- 4.6 J reverse polarity, P = 0.02). The effect of polarity appeared most pronounced among the patients with a high DFT (> or = 15 J) resulting in a 31% reduction with reverse polarity (16.7 +/- 2.5 J normal, 11.5 +/- 5.9 J reverse, P = 0.03). CONCLUSION: Reversing shock polarity results in significantly lower biphasic DFTs with an active pectoral lead system, particularly in the subgroup of patients with a high normal polarity threshold. Reversing polarity in these patients may simplify acute defibrillation testing and allow for lower output devices.

Arrhythmias, Cardiac↗
PubMed1998

Effect of heart rate on T wave alternans.

INTRODUCTION: T wave alternans (TWA) is a promising technique for detecting arrhythmia vulnerability. Previous studies in animals demonstrated that the magnitude of TWA is dependent on heart rate. However, the effects of heart rate on TWA in humans and the clinical relevance of this effect remain controversial. METHODS AND RESULTS: This was a prospective evaluation of pacing rate and monitoring lead configuration on TWA in subjects undergoing electrophysiologic study. Measurements of TWA were performed on 45 patients in the absence of antiarrhythmic drugs. Recordings were made in normal sinus rhythm and during atrial pacing at 100 and 120 beats/min. Sustained monomorphic ventricular tachycardia (VT) was induced in 29 patients with programmed stimulation. TWA in the vector magnitude lead increased with heart rate, independent of VT inducibility (0.4 +/- 0.7 microV, 1.6 +/- 1.9 microV, and 2.4 +/- 2.1 microV in sinus rhythm and at 100 and at 120 beats/min, respectively; P < 0.001). In addition, the diagnostic performance of TWA for inducible VT was dependent on heart rate (sensitivity 4%, 42%, and 65%, and specificity 100%, 93%, and 63% at 77, 100, and 120 beats/min, respectively). By analyzing orthogonal leads rather than the vector magnitude lead, the sensitivity is increased from 42% to 59% at 100 beats/min, but the specificity is reduced from 93% to 72%. CONCLUSION: These results indicate that TWA in humans is strongly dependent on heart rate with regard to both magnitude and diagnostic performance. The optimal heart rate for the measurement of TWA is between 100 and 120 beats/min and multiple leads should be monitored.

Cardiac Pacing, Artificial↗
PubMed1998

Listeria monocytogenes invasion of epithelial cells requires the MEK-1/ERK-2 mitogen-activated protein kinase pathway.

PD98059, a specific inhibitor of MEK-1 mitogen-activated protein (MAP) kinase kinase, blocked Listeria monocytogenes invasion into HeLa epithelial cells. The effects of PD98059 were reversible, as adherent extracellular bacteria were internalized upon removal of the drug. Previously, we reported that L. monocytogenes could activate ERK-1 and ERK-2 MAP kinases through the action of listeriolysin O (LLO) on the host cell (P. Tang, I. Rosenshine, P. Cossart, and B. B. Finlay, Infect. Immun. 64:2359-2361, 1996). We have now found that two other MAP kinase pathways, those of p38 MAP kinase and c-Jun N-terminal kinase, are also activated by wild-type L. monocytogenes. Mutants lacking functional LLO (hly mutants) were still invasive but only activated ERK-2 and only activated it at later (90-min) postinfection times. Two inhibitors of L. monocytogenes invasion, cytochalasin D, which disrupts actin polymerization, and wortmannin, which blocks phosphatidylinositol (PI) 3-kinase activity, did not block ERK-2 activation by wild-type L. monocytogenes and hly mutants. However, genistein, an inhibitor of tyrosine kinases, and PD98059 both blocked invasion and decreased ERK-2 activation. These results suggest that MEK-1 and ERK-2 activities are essential for L. monocytogenes invasion into host epithelial cells. This is the first report to show that a MAP kinase pathway is required for bacterial invasion.

Androstadienes↗
PubMed1997

Comparison of power- and temperature-guided radiofrequency modification of the atrioventricular node. Polaris Investigator Group.

The purpose of this study was to compare the performance and clinical outcome of radiofrequency ablation of the substrate of atrioventricular (AV) nodal reentrant tachycardia (AVNRT) when guided by power output or temperature monitoring. Two sequential multicenter studies of power-controlled and open-loop, temperature-controlled radiofrequency ablation were analyzed in 171 patients undergoing AV node modification for the treatment of AVNRT. After successful ablation of AVNRT, complete elimination of slow AV node pathway function was accomplished more often with than without temperature monitoring (92% vs 69%, p = 0.005). Greater power was delivered to each patient with than without temperature monitoring (median 47 W, range 10 to 57, vs median 35 W, range 5 to 68, p = 0.001). Acute elimination of tachycardia (100% vs 96%), 3-month recurrence (6% vs 8%), procedural times (162 vs 170 minutes), fluoroscopy times (24.6 vs 29.5 minutes), complications (6% vs 3%), and catheter removals to check for coagulum (8% vs 6%) did not differ between patients treated with and without temperature monitoring, respectively. Power- and temperature-controlled radiofrequency techniques are highly successful with low complication rates for slow pathway ablation. Temperature monitoring may allow the safe delivery of more power, and the more complete elimination of slow AV node pathway function.

Atrioventricular Node↗
PubMed1997

Strength-duration relationship for human transvenous defibrillation.

BACKGROUND: One of the basic characteristics of electrical defibrillation is the strength-duration relationship, or the effect of pulse width on defibrillation efficacy. This relationship is important for understanding the mechanism of defibrillation and for the design of optimal waveforms. However, a detailed evaluation of the strength-duration relationship for human transvenous defibrillation has not been performed previously. METHODS AND RESULTS: This was a prospective study of 29 patients undergoing initial defibrillator implantation with a uniform dual coil, transvenous lead. In each patient defibrillation thresholds were measured for either short (2, 3, 4, 6 ms) or long (6, 12, 18 ms) pulse durations, with the order of testing randomized. The shock waveform was a truncated monophasic pulse from a capacitor of 150 microF. The leading edge voltage at defibrillation threshold was 566+/-100 V for 2-ms pulses. Voltages declined exponentially with increasing pulse width reaching an asymptote by 6 ms (451+/-68 V, P<.05). Defibrillation threshold voltage was insensitive to longer pulse widths. Stored energy at defibrillation threshold showed a similar relationship with pulse width. In contrast, mean current decreased monotonically over the full range of pulse durations evaluated, and there was no evidence of a rheobase. CONCLUSIONS: The shape of the strength-duration curve and the lack of rheobase current indicate a fundamental difference between cardiac stimulation and defibrillation. The relationship between pulse duration and defibrillation threshold voltage or stored energy is well modeled by a parallel capacitor resistor circuit with a time constant of 5.3 ms.

Aged↗
PubMed1997

Lead system optimization for transvenous defibrillation.

Lead systems that include an active pectoral shell reduce defibrillation thresholds and permit transvenous defibrillation in nearly all patients. A further improvement in defibrillation efficacy is desirable to allow for smaller pulse generators with a reduced maximum output. Accordingly, the purpose of this study was to compare defibrillation thresholds with multiple transvenous lead systems including those with an active pectoral shell to determine which system would optimize defibrillation energy requirements. This prospective study was performed on 21 consecutive patients. Each subject was evaluated with 3 lead configurations with the order of testing randomized. The configurations were a dual coil transvenous lead (lead), the distal right ventricular coil and pectoral pulse generator shell (unipolar), and all 3 components (triad). The right ventricular coil was the cathode for the first phase of the biphasic defibrillation waveform. Delivered energy at defibrillation threshold was 11.2 +/- 3.4 J for the lead configuration, 10.1 +/- 5.2 J for the unipolar configuration, and 7.8 +/- 3.6 J for the triad configuration (p <0.01). Leading edge voltage (p <0.01) and shock impedance (p <0.001) were also decreased for the triad configuration compared with the lead or unipolar configurations, whereas peak current was minimized with the unipolar configuration (p <0.01). We conclude that the combination of a dual coil, transvenous lead and an active pectoral shell reduces defibrillation energy requirements compared with either the lead alone or unipolar configuration. Moreover, the defibrillation thresholds were < or =15 J in all patients using the triad lead system.

Defibrillators, Implantable↗