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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
PubMed2004

Predicting geographical variations in behavioural risk factors: an analysis of physical and mental healthy days.

STUDY OBJECTIVES: To determine the validity of physical and mental unhealthy days as summary measures for county health status and to forward a method for examining county level health trends using a single year of data from the Behavioral Risk Factor Surveillance System (BRFSS). DESIGN: The study analysed geographical variation in physical and mental unhealthy days at the state and county level using the 2000 BRFSS. Whereas state level analyses used individual level data, this research conducted multilevel regression analysis using county level data as independent variables and individual level reports of physical and mental unhealthy days as dependent variables. SETTING: Population based samples of non-institutionalised civilian adult residents from each of the 50 states and the District of Columbia in the United States. MAIN RESULTS: Socioeconomic variables predicted similar mean numbers of physical and mental unhealthy days at both the state and county level, validating the county level analyses. County level disability rates were strongly associated with county mean unhealthy days. Using the regression method we forward, it is possible to analyse county level trends using a single year of BRFSS data. CONCLUSIONS: Physical and mental unhealthy days may be used as valid summary measures of county health status. Regression models may be used to assist local decision makers in assessing the needs of their communities and may be used to improve health resource allocation within states.

Adolescent↗
PubMed2003

T wave alternans for ventricular arrhythmia risk stratification.

Sudden cardiac death remains one of the leading causes of death in Europe and the United States. Accordingly, the ability to identify patients at high risk of sudden cardiac death is important so that appropriate treatments can be used efficiently. Recently, T wave alternans (TWA) has emerged as a promising new test for such risk stratification. TWA is a heart rate dependent measure of arrhythmia vulnerability, with maximal predictive accuracy at sustained, regular heart rates of 100-120 bpm. In the clinical setting these conditions may be achieved by either exercise or atrial pacing. TWA has been shown to predict inducibility of ventricular tachycardia with programmed stimulation and also spontaneous arrhythmic events. TWA has been successfully applied to diverse populations, including patients with coronary artery disease, nonischemic cardiomyopathy, congestive heart failure and those with implantable defibrillators. Despite these encouraging results, the role of TWA to guide clinical therapy still needs to be better elucidated.

Arrhythmias, Cardiac↗
PubMed2001

The Gab1 docking protein links the b cell antigen receptor to the phosphatidylinositol 3-kinase/Akt signaling pathway and to the SHP2 tyrosine phosphatase.

B cell antigen receptor (BCR) signaling causes tyrosine phosphorylation of the Gab1 docking protein. This allows phosphatidylinositol 3-kinase (PI3K) and the SHP2 tyrosine phosphatase to bind to Gab1. In this report, we tested the hypothesis that Gab1 acts as an amplifier of PI3K- and SHP2-dependent signaling in B lymphocytes. By overexpressing Gab1 in the WEHI-231 B cell line, we found that Gab1 can potentiate BCR-induced phosphorylation of Akt, a PI3K-dependent response. Gab1 expression also increased BCR-induced tyrosine phosphorylation of SHP2 as well as the binding of Grb2 to SHP2. We show that the pleckstrin homology (PH) domain of Gab1 is required for BCR-induced phosphorylation of Gab1 and for Gab1 participation in BCR signaling. Moreover, using confocal microscopy, we show that BCR ligation can induce the translocation of Gab1 from the cytosol to the plasma membrane and that this requires the Gab1 PH domain as well as PI3K activity. These findings are consistent with a model in which the binding of the Gab1 PH domain to PI3K-derived lipids brings Gab1 to the plasma membrane, where it can be tyrosine-phosphorylated and then act as an amplifier of BCR signaling.

B-Lymphocytes↗
PubMed2001

Implantable cardiac defibrillators.

The implantable cardioverter defibrillator (ICD) represents an important development in the effort to reduce the incidence of sudden cardiac death (almost 400,000 yearly in the United States). Early generation ICDs, which required epicardial lead systems and abdominal placement of the pulse generator, have been replaced by transvenous leads and pectoral implants. Other important refinements, which include biphasic waveforms, extensive memory capability, antitachycardia pacing, and enhanced sensing algorithms, have greatly improved patient tolerance. Ongoing trials and those in the planning stages will continue to expand the indications for ICDs and will focus on cost-effectiveness.

Arrhythmias, Cardiac↗
PubMed2001

Temporal decline in defibrillation thresholds with an active pectoral lead system.

OBJECTIVES: The objective of this study was to characterize temporal changes in defibrillation thresholds (DFTs) after implantation with an active pectoral, dual-coil transvenous lead system. BACKGROUND: Ventricular DFTs rise over time when monophasic waveforms are used with non-thoracotomy lead systems. This effect is attenuated when biphasic waveforms are used with transvenous lead systems; however, significant increases in DFT still occur in a minority of patients. The long-term stability of DFTs with contemporary active pectoral lead systems is unknown. METHODS: This study was a prospective assessment of temporal changes in DFT using a uniform testing algorithm, shock polarity and dual-coil active pectoral lead system. Thresholds were measured at implantation, before discharge and at long-term follow-up (70 +/- 40 weeks) in 50 patients. RESULTS: The DFTs were 9.2 +/- 5.4 J at implantation, 8.3 +/- 5.8 J before discharge and 6.9 +/- 3.6 J at long-term follow-up (p < 0.01 by analysis of variance; p < 0.05 for long-term follow-up vs. at implantation or before discharge). The effect was most marked in a prespecified subgroup with high implant DFTs (> or =15 J). No patient developed an inadequate safety margin (< 9 J) during follow-up. CONCLUSIONS: The DFTs declined significantly after implantation with an active pectoral, dual-coil transvenous lead system, and no clinically significant increases in DFT were observed. Therefore, routine defibrillation testing may not be required during the first two years after implantation with this lead system, in the absence of a change in the cardiac substrate or treatment with antiarrhythmic drugs.

Aged↗
PubMed2001

Using the years-of-healthy-life measure to calculate QALYs.

BACKGROUND: The quality-adjusted life year (QALY) is an attractive outcome measure because it captures both health-related quality of life (HRQL) and life expectancy in a single metric. We present a method for calculating QALYs that is simple, utilizes data that are free of charge, and may improve consistency in burden-of-disease investigations. METHODS: For purposes of illustration, we calculated the burden of disease due to stroke using two abridged life tables, each adjusted for HRQL. The first life table was generated using all-cause mortality and morbidity data (a reference cohort) and the second was generated using all diseases except stroke (a stroke-free cohort). The difference in total QALYs and in quality-adjusted life expectancy (QALE) was determined by subtraction. RESULTS: Approximately 61,328 (95% CI=60,272, 62,383) QALYs were lost to stroke in the life-table cohort. Stroke is responsible for a decrement of 0.03 years of life expectancy and 0.61 years of QALE in the United States. CONCLUSIONS: The "years of health life"measure affords a rapid, inexpensive, and sensitive means for estimating the burden of disease for local health priorities and may assist research efforts in including QALYs as an outcome measure.

Adult↗
PubMed2001

New views of BCR structure and organization.

Recent work has provided new insights into the stoichiometry of BCR subunits, as well as the organization of the BCR before and after engagement by antigen. On resting cells, the BCR may be pre-assembled into oligomeric receptor complexes that generate a basal level of signaling. After antigen binding, the BCR may be organized into larger receptor arrays that reside in lipid rafts - sites where signaling enzymes are concentrated. The critical role of BCR assembly and organization in B cell function is underscored by the recent findings that this process is altered in many B cell tumors.

Animals↗
PubMed2001

Clinical predictors and efficacy of antitachycardia pacing in patients with implantable cardioverter defibrillators: the importance of the patient's sex.

The ICD has become accepted as primary therapy for malignant ventricular arrhythmias. The incorporation of antitachycardia pacing into ICDs has provided a better tolerated alternative to shocks but has the potential disadvantage of delaying definitive therapy. Accordingly, we sought to delineate the characteristics of patients likely to experience unsuccessful termination of pacing and to identify ineffective pacing strategies. Of 519 patients who received ICDs, 11 clinical and tachycardia characteristics in the 162 who received antitachycardia pacing therapy for sustained ventricular arrhythmias were evaluated. Tachycardia episodes were grouped according to outcome of pacing (successful, unsuccessful, acceleration). Of 1,946 episodes, 1,502 (77.2%) were successfully reverted with pacing, 322 (16.5%) were unsuccessful, and 121 (6.2%) were accelerated. Antitachycardia pacing was less successful in women, patients with a history of myocardial infarction, those with more severe left ventricular dysfunction, those who received antiarrhythmic drugs, and those programmed to ramp pacing. Tachycardia acceleration was inversely related to tachycardia cycle length and was more frequent in patients programmed to more aggressive ramp pacing protocols. Women had an almost threefold incidence of tachycardia acceleration compared with men (14% vs 5%, P < 0.001). Antitachycardia pacing is generally successful in terminating ventricular tachycardia and has a low incidence of tachycardia acceleration. Caution should be used with rapid tachycardias and aggressive ramp pacing protocols because of an increased risk of acceleration. Antitachycardia pacing appears less successful and has a higher incidence of complications in women.

Cardiac Pacing, Artificial↗
PubMed2001

Clinical experience with a dual-chamber implantable cardioverter defibrillator to treat atrial tachyarrhythmias.

INTRODUCTION: This study evaluated the safety and efficacy of a new dual-chamber implantable cardioverter defibrillator (ICD) to detect and treat atrial tachyarrhythmias in patients with drug-refractory atrial fibrillation (AF) and no indication for a ventricular ICD. METHODS AND RESULTS: A dual-chamber ICD (Medtronic 7250 Jewel AF) was implanted in 144 of 146 patients. The device discriminates atrial tachycardia from AF based on cycle length and regularity, and uses atrial overdrive pacing as well as shocks to terminate tachyarrhythmia episodes. Patients were followed for an average of 12.6+/-6.2 months. Use of antiarrhythmic drugs was 63% at baseline and did not change over time. Kaplan-Meier estimates of 12-month complication-free survival, device therapy survival, and patient survival were 85%, 91%, and 98%, respectively. Positive predictive accuracy of spontaneous atrial tachyarrhythmia detection was 99%, while atrial overdrive pacing and shocks terminated 40% and 87% of treated episodes, respectively. Median duration of successfully treated episodes was 8.9 minutes versus 144 minutes for the therapy failures. There was no reduction in the use of patient-activated shock therapy over time; at the 12-month follow-up evaluation, 94% of patients were in sinus rhythm. Ventricular tachyarrhythmias (67 episodes) were detected and appropriately treated in 7.6% of patients. CONCLUSION: This dual-chamber ICD appears to be safe and well tolerated in patients with drug-refractory symptomatic atrial tachyarrhythmias. The device, used in combination with drugs, effectively treats atrial tachyarrhythmias with pacing and/or shock therapies and decreases the median episode duration. In addition, the device protects from ventricular tachyarrhythmias in patients with AF and structural heart disease.

Aged↗
PubMed2001

Health insurance expansion through states in a pluralistic system.

The United States continues to stand almost alone among developed nations in its lack of universal health care coverage. In this essay, we argue that even though the debate over whether the federal government or states should lead the effort to expand health care coverage under the federal system is relevant in strategizing how to cover the uninsured; the more critical issues stem from the challenge of the mixed and fragmented mode of public-private financing of our pluralistic health care system. We base this argument on (1) an in-depth review of Oregon's and Tennessee's five years of experience with broad coverage reform in the context of the United States health care system and on (2) a more abbreviated review of other state experiences in providing health care coverage. We conclude from our review that when the will exists, states can substantially expand coverage. However, as one moves up the income scale, political support and resources are harder to come by. Further, concerns grow about the interface of public and private coverage, with issues of "crowd out" and other distributional questions dominating the discussion of coverage expansion as policy makers focus less on how to cover people than on how to make sure one kind of coverage doesn't preempt another. Concern for crowd out can then lead to policies that keep out some of the very people policy makers may want to cover. In this context the question whether states or the federal government is more likely to succeed in expanding coverage is eclipsed by the more fundamental challenges raised by pluralism. Neither federal nor state government is likely to be fully successful without first identifying ways of better coordinating public and private activities and resources to provide continuous and affordable coverage.

Health Services Research↗
PubMed2001

Activation and function of the Rap1 GTPase in B lymphocytes.

Rap1 is a monomeric GTPase that is closely related to Ras. In this review, we summarize our recent work showing that the B cell antigen receptor (BCR), as well as chemokine receptors, activate Rap1 via a pathway that involves phospholipase C-dependent production of diacylglycerol (DAG). The possible identities of the DAG-regulated guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) that regulate the activation of Rap1 by the BCR and chemokine receptors will be discussed. Although initially thought to be an antagonist of Ras-mediated signaling, Rap1 does not appear to modulate the ability of the BCR to activate downstream targets of Ras. Instead, activation of Rap1 promotes B cell adhesion as well as B cell migration toward chemokines. Thus, Rap1 may play a key role in a number of processes that are essential for B cell development and activation.

Animals↗
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↗