Biomedical subjects

M R Gold

Publications and source records attributed to M R Gold.

At least 127 records · Page 7Linked to original sources

PubMed1995

Signal transduction by the B-cell antigen receptor.

The antigen receptor of B lymphocytes (BCR) plays important roles in recognition of foreign antigens and self-components to allow the immune system to make appropriate antibody responses. The BCR is a complex between membrane immunoglobulin and the Ig-alpha and Ig-beta heterodimer. Site-directed mutagenesis experiments have shown that the mu heavy chain transmembrane domain plays a key role in the association of mIgM with Ig-alpha/Ig-beta. In the absence of complex formation, mIgM is retained in the endoplasmic reticulum, and this function is also specified by the mu chain transmembrane domain. The ability of various mutant mIgM molecules to associate with Ig-alpha/Ig-beta correlates well with their ability to induce signal transduction reactions such as protein tyrosine phosphorylation and phosphoinositide breakdown. Thus, the signaling ability of the BCR appears to reside in the Ig-alpha/Ig-beta heterodimer. The cytoplasmic domains of Ig-alpha and Ig-beta each contain an ITAM sequence, which is defined by its limited homology with subunits of the T-cell antigen receptor and of Fc receptors. Moreover, chimeric proteins containing these ITAMs and surrounding sequences from the cytoplasmic domains of Ig-alpha or Ig-beta exhibit signaling function characteristics of the intact BCR. The Ig-alpha and Ig-beta chimeras are each capable of inducing all of the BCR signaling events tested and thus represent redundant functions. Cross-linking these chimeras leads to their phosphorylation and to binding of the intracellular tyrosine kinases Lyn and Syk. The BCR expressed in the nonlymphoid AtT20 cells, which express the Src-family tyrosine kinase Fyn but not Syk, was not able to trigger vigorous signaling reactions. Introduction of the active form of Syk into these cells restored some signaling events. These results are consistent with a model in which the ITAMs act to initiate the BCR signaling reactions by binding and activating tyrosine kinases.

Animals↗

PubMed1995

Acute electrophysiologic effects of amiodarone in patients with congestive heart failure.

Patients with severe congestive heart failure (CHF) are at increased risk for atrial and ventricular arrhythmias and sudden cardiac death. Amiodarone is generally well tolerated by this population and has a low proarrhythmic potential. Because of its peculiar kinetics, amiodarone requires a prolonged loading period, necessitating lengthy hospitalizations in a monitored setting. This study was planned prospectively to assess the electrophysiologic effects of an abbreviated high-dose oral load of amiodarone in patients with severe CHF and known or suspected life-threatening ventricular arrhythmias. Fifteen patients with stable CHF and known or suspected life-threatening ventricular arrhythmias underwent baseline electrophysiologic study. The study was repeated after administration of oral amiodarone, 50 mg/kg/day for 2 days in 8 divided doses (mean dose 6.9 +/- 0.4 g). After amiodarone administration, there was prolongation in virtually all conduction times and refractory periods. The prolongation of refractoriness was most pronounced in the atrium. Ventricular effective refractory periods demonstrated reverse frequency dependence. We conclude that a brief high-dose oral load of amiodarone is well tolerated by patients with CHF. It has marked and diffuse electrophysiologic actions suggestive of class I and III effects in addition to antiadrenergic and calcium blocking action. These effects are especially pronounced in the atrium.

Administration, Oral↗

PubMed1995

Prognostic value of the signal-averaged electrocardiogram and a prolonged QRS in ischemic and nonischemic cardiomyopathy.

Studies of electrocardiographic predictors of mortality in patients with chronic heart failure have reached varying conclusions. Differences in the characteristics of the patients studied may explain the conflicting results regarding both a prolonged QRS and an abnormal signal-averaged electrocardiogram (SAE). We therefore investigated the impact of the etiology of heart failure on the prognostic importance of a prolonged QRS and an abnormal SAE in 200 patients with heart failure. Patients were categorized according to etiology of heart failure and electrocardiographic parameters. The mortality of patients with a prolonged QRS was compared with mortality in those with both abnormal and normal SAEs. This was done for the entire group, and separately for those with ischemic and those with nonischemic cardiomyopathy. The mean follow-up was 18.8 months. Nonischemic patients with a prolonged QRS had significantly worse survival than other patients. However, nonischemic patients with an abnormal SAE did not have a worse prognosis than patients with a normal SAE. One-year survival of patients with a prolonged QRS was 71%, compared with 98% in patients with a normal and 87% in patients with an abnormal SAE (p < 0.05). In contrast, a prolonged QRS was not a predictor of poor prognosis in patients with ischemic cardiomyopathy (81% one year mortality). Patients with ischemic cardiomyopathy and an abnormal SAE tended to have a poorer survival than patients with a normal SAE (73% and 81% one year mortality, respectively). Thus, the etiology of heart failure affects the prognostic importance of both a prolonged QRS and an abnormal SAE.

Aged↗

PubMed1995

Prognostic importance of the length of ventricular tachycardia in patients with nonischemic congestive heart failure.

In patients with congestive heart failure the frequency of ventricular arrhythmias poorly predicts mortality. It is unknown whether the length of ventricular tachycardia is a better predictor of mortality in these patients. We therefore investigated the prognostic importance of the length of the longest run of ventricular tachycardia, the frequency of ventricular tachycardia, and the frequency of ventricular premature depolarizations with 24-hour ambulatory electrocardiographic recordings in 122 patients with heart failure. We also determined whether the cause of heart failure affects the prognostic importance of these parameters. Each ambulatory electrocardiographic recording was evaluated for the frequency of ventricular premature depolarizations and ventricular tachycardia and for the length of the longest run of ventricular tachycardia. For each electrocardiographic parameter patients were divided into groups based on the median value of that parameter. Mortality among groups was compared in all patients and then separately for nonischemic and ischemic patients. Neither the frequency of ventricular premature depolarizations nor the frequency of ventricular tachycardia predicted mortality whether or not cause was considered. When all patients were examined, the length of ventricular tachycardia did predict an increased risk of death. However, when cause was considered, length of ventricular tachycardia predicted mortality only in the nonischemic patients and not in the ischemic patients. We conclude that the length of ventricular tachycardia may be the best electrocardiographic predictor of mortality in patients with nonischemic heart failure.

Aged↗

PubMed1995

Acute hemodynamic effects of atrio-biventricular pacing in humans.

Standard postoperative dual-chamber pacing uses ventricular leads placed on the right ventricle that produce dysynchronous ventricular activation and contraction. The hypothesis that simultaneous stimulation of both ventricles by atrio-biventricular pacing improves hemodynamic performance compared with that observed with standard atrio-monoventricular pacing was tested in 18 patients 12 to 36 hours after elective coronary artery revascularization. Temporary epicardial pacing electrodes were placed on the right atrium and into anterior paraseptal sites on the right and left ventricle. Simultaneous biventricular activation was documented by fusion morphology of surface electrocardiograms and by isochronal epicardial activation mapping during biventricular pacing. Hemodynamic data were acquired after 10 minutes of pacing at a fixed overdrive rate during atrial pacing and during dual-chamber pacing using unipolar right ventricular, unipolar left ventricular, and bipolar biventricular (left ventricular cathode) leads. Atrio-biventricular pacing increased cardiac index and decreased systemic vascular resistance compared with atrial pacing and with atrio-right ventricular and atrio-left ventricular dual-chamber pacing (p < 0.05). These data support the use of atrio-biventricular pacing employing paraseptal electrodes to optimize hemodynamic performance.

Adult↗

PubMed1995

Dual-chamber pacing with a short atrioventricular delay in congestive heart failure: a randomized study.

OBJECTIVES: This prospective study assessed the initial hemodynamic effects and long-term clinical benefits of dual-chamber pacing with a short atrioventricular (AV) delay in patients with chronic heart failure who had no traditional indication for pacemaker implantation. BACKGROUND: Dual-chamber pacing with a short AV delay has been proposed as a nonpharmacologic treatment for drug-refractory heart failure. Both initial and long-term hemodynamic as well as functional benefits have been reported. All previous studies have used an AV delay of 100 ms. Despite encouraging results, these previous studies have been anecdotal and uncontrolled. METHODS: This double-blind, randomized, crossover trial included 12 subjects with chronic congestive heart failure despite optimal medical therapy. Patients were required to be in sinus rhythm with no evidence of significant bradyarrhythmias. On the day after implantation of a dual-chamber pacemaker, invasive hemodynamic measurements were made at varying AV delays between 100 and 200 ms. Patients were then randomized to either dual-chamber pacing with a 100-ms AV delay or backup mode (VVI at 40 beats/min). After 4 to 6 weeks, crossover to the other pacing mode was programmed. RESULTS: Hemodynamic measurements on the day after pacemaker implantation demonstrated no benefit of pacing with any AV delay compared with intrinsic conduction. At the optimal AV interval for each patient, neither cardiac output (4.5 +/- 1.5 vs 4.7 +/- 1.6 liters/min [mean +/- SD]) nor wedge pressure (16 +/- 10 vs 17 +/- 8 mm Hg) improved significantly from baseline measurements during intrinsic conduction. The long-term pacing protocol was completed in nine patients. Ejection fraction was 16 +/- 6% with dual-chamber (VDD mode) pacing and 18 +/- 4% in backup mode (p = NS). No patient had an increase in ejection fraction by > or = 5% with VDD pacing, nor did any patient improve in New York Heart Association functional class with short AV delay dual-chamber pacing. Also, there were no significant reductions in body weight or diuretic requirements during this pacing period. CONCLUSIONS: Dual-chamber pacing with a short AV delay does not improve hemodynamic and clinical status or ejection fraction measured on the day after pacemaker implantation in patients with chronic congestive heart failure. Routine use of pacemaker therapy with a short AV delay aas a primary treatment of heart failure in patients without standard arrhythmic indications is unwarranted.

Aged↗

PubMed1995

Signal transduction by the antigen receptors of B and T lymphocytes.

B and T lymphocytes of the immune system recognize and destroy invading microorganisms but are tolerant to the cells and tissues of one's own body. The basis for this self/non-self-discrimination is the clonal nature of the B and T cell antigen receptors. Each lymphocyte has antigen receptors with a single unique antigen specificity. Multiple mechanisms ensure that self-reactive lymphocytes are eliminated or silenced whereas lymphocytes directed against foreign antigens are activated only when the appropriate antigen is present. The key element in these processes is the ability of the antigen receptors to transmit signals to the interior of the lymphocyte when they bind the antigen for which they are specific. Whether these signals lead to activation, tolerance, or cell death is dependent on the maturation state of the lymphocytes as well as on signals from other receptors. We review the role of antigen receptor signaling in the development and activation of B and T lymphocytes and also describe the biochemical signaling mechanisms employed by these receptors. In addition, we discuss how signal transduction pathways activated by the antigen receptors may alter gene expression, regulate the cell cycle, and induce or prevent programmed cell death.

Amino Acid Sequence↗

PubMed1995

Spurious discharges due to late insulation break in endocardial sensing leads for cardioverter defibrillators.

Despite their similarity to permanent pacemaker leads, endocardial sensing leads for cardioverter defibrillators have a relatively high failure rate. We describe four patients with endocardial rate sensing leads who developed inappropriate discharges 10-30 months after implantation due to small breaks in the lead insulation. This problem may become increasingly common as the number of cardioverter defibrillator implants with transvenous leads continues to grow and should be considered in the differential diagnosis of late sensing failure or inappropriate device discharges.

Aged↗

PubMed1995

Effect of intracellular and extracellular acidosis on sodium current in ventricular myocytes.

Conduction slowing is an essential element in the generation of ischemic ventricular arrhythmias and is determined in part by the inward Na+ current (INa). Because intracellular acidosis is an early consequence of ischemia, we hypothesized that lowering intracellular pH (pHi) would reduce or kinetically modulate INa and thus affect cardiac conduction. To test this hypothesis, the whole cell patch-clamp method was used to measure INa in neonatal rat ventricular myocytes exposed to varying extracellular pH (pHo 6.4-7.4), while perfusing the cells with acidic solutions (pHi 6.2-7.2). With simultaneous acidification of pHo and pHi there was a progressive increase in time to peak current, a 31% decrease in peak INa (298 +/- 18 to 206 +/- 16 pA/pF), and a complex slowing of inactivation kinetics. At the most extreme levels of acidification, there was a 5-mV hyperpolarizing shift in steady-state inactivation and a 6-mV depolarizing shift in activation. Independent changes of pHo and pHi indicate that the reduction of peak INa is a function of pHo. However, steady-state inactivation is modulated by pHi. The time course of activation and inactivation appears to depend on both pHo and pHi. We conclude that both intracellular and extracellular acidosis are significant but distinct modulators of INa amplitude and kinetics in cardiac myocytes.

Acidosis↗

PubMed1994

Overdrive pacing for atrial flutter.

To determine the incidence and predictors of conversion to normal sinus rhythm, a total of 124 procedures using a standard pacing protocol were performed in 101 consecutive inpatients referred for pace termination of atrial flutter. Normal sinus rhythm was achieved in 75 pace termination procedures (60%), including 10 in which atrial fibrillation occurred initially and later converted spontaneously. Sustained atrial fibrillation was provoked in 39 procedures, and atrial flutter persisted in 10. Clinical and laboratory parameters, including use of antiarrhythmic drugs, were not helpful in predicting the outcome of pacing. Of 17 patients undergoing repeat pacing for recurrent flutter, concordant results were obtained in only 4. It is concluded that: (1) overdrive pacing is only a moderately effective means of restoring sinus rhythm in patients with atrial flutter, although some change in rhythm occurs in the vast majority; (2) pacing-induced atrial fibrillation may be unstable and spontaneously converts to sinus rhythm in > 20% of cases; (3) there are no clinically useful predictors of success; (4) antiarrhythmic drugs do not facilitate pacing-induced conversion to sinus rhythm; and (5) failure to convert to sinus rhythm with 1 episode of flutter does not preclude success on subsequent occasions.

Aged↗

PubMed1994

Activation and serine phosphorylation of the p56lck protein tyrosine kinase in response to antigen receptor cross-linking in B lymphocytes.

We show that cross-linking the B cell AgR with anti-Ig Abs activates p56lck (Lck) in both the immature B cell line WEHI-231 and mature resting B cells from mouse spleen. Anti-Ig-stimulated Lck activity peaked after 1 to 2 min, but remained elevated for at least 15 min. Consistent with the proposed role for src family tyrosine kinases in AgR signaling, we found that Lck could phosphorylate the cytoplasmic tails of the Ig-alpha and Ig-beta components of the B cell AgR in vitro. Lck phosphorylated both of the tyrosines in the Ig-beta AgR homology motif and one of the two tyrosines in the Ig-alpha AgR homology motif. Finally, we show that AgR ligation in B cells caused a significant portion of the Lck to migrate with an apparent molecular mass of 60 kDa on SDS-PAGE gels. Conversion of p56lck to p60lck was maximal at 5 to 15 min, at which times Lck activity in the cells was decreasing. This Lck "band shift" has been observed previously in activated T cells and correlates with phosphorylation of Lck at serine 59. We show that the 60-kDa form of Lck induced by AgR cross-linking in B cells is also phosphorylated at serine 59. Phosphorylation of Lck at this site in vitro decreases its activity. Thus, in B cells, AgR cross-linking activates Lck and subsequently activates a kinase that phosphorylates Lck at serine 59, a potential negative regulatory site.

Amino Acid Sequence↗

PubMed1994

B cell antigen receptor cross-linking induces phosphorylation of the p21ras oncoprotein activators SHC and mSOS1 as well as assembly of complexes containing SHC, GRB-2, mSOS1, and a 145-kDa tyrosine-phosphorylated protein.

Ligation of the B cell AgR activates p21ras (Ras). We have investigated the effects of AgR ligation on three proteins that have been implicated as regulators of Ras: SHC, GRB-2, and mSOS1. We show that AgR cross-linking in B cells stimulated tyrosine and serine phosphorylation of SHC. This correlated with the formation of complexes containing SHC, GRB-2, mSOS1, and an unidentified 145-kDa tyrosine-phosphorylated protein. These complexes were present in the cytosol, as well as in the membrane fraction of the cells, where Ras is located. By using a GRB-2 fusion protein to probe blots, we showed that SHC was the major protein that GRB-2 bound to in anti-Ig-stimulated B cells. This argues that SHC couples GRB-2/mSOS1 to the 145-kDa protein and that SHC is likely to be essential for mSOS1 function in B cells. Finally, we found that AgR cross-linking stimulated phosphorylation of mSOS1 and that this could be blocked by an inhibitor of protein kinase C. Thus, signaling by the B cell AgR stimulates phosphorylation of SHC and mSOS1 and induces the formation of membrane-associated complexes containing SHC, GRB-2, mSOS1, and a 145-kDa protein. These events may be important for activation of Ras by the AgR.

Adaptor Proteins, Signal Transducing↗

PubMed1994

High dose oral amiodarone loading exerts important hemodynamic actions in patients with congestive heart failure.

OBJECTIVES: The purpose of this study was to use invasive monitoring to analyze the hemodynamic effects of both a large single dose and a 48-h loading regimen of amiodarone in patients with severe heart failure. BACKGROUND: Amiodarone is frequently used as an antiarrhythmic agent in patients with congestive heart failure, but the impact of this agent on cardiac function remains controversial. Recent successful experience with a rapid oral load of amiodarone makes invasive testing of the hemodynamic effects of oral amiodarone in such patients now feasible. METHODS: After baseline hemodynamic assessment (using balloon-tipped pulmonary artery catheters) and electrocardiographic measurements, 16 patients received 12.5 mg/kg body weight of amiodarone orally. Hemodynamic measurements were obtained hourly for 4 h. Patients then received this dose an additional seven times over the next 2 days. Hemodynamic variables and QRS, QT and PR intervals were measured after 48 h of treatment. RESULTS: Vasodilation was seen between 1 and 3 h after drug administration. Systemic vascular resistance decreased 326 +/- 135 dynes.s.cm-5, cardiac index increased 0.24 +/- 0.08 liters/min per m2 and mean arterial pressure decreased 6 +/- 3 mm Hg (mean +/- SEM, all p < 0.05). After 48 h of amiodarone administration, heart rate decreased 23 +/- 3 beats/min (p < 0.005), stroke volume increased 9 +/- 3 ml (p < 0.005), cardiac index decreased 0.23 +/- 0.09 ml/min per m2 (p < 0.05), pulmonary capillary wedge pressure increased 4 +/- 1 mm Hg (p < 0.01), right atrial pressure increased 3 +/- 1 mm Hg (p < 0.005) and QT and PR intervals were markedly prolonged (p < 0.01). CONCLUSIONS: Although the first dose caused vasodilation, a complete loading regimen of amiodarone produced a decreased heart rate with elevated filling pressures and decreased cardiac index.

Administration, Oral↗

PubMed1994

Multiple cytokines activate phosphatidylinositol 3-kinase in hemopoietic cells. Association of the enzyme with various tyrosine-phosphorylated proteins.

Activation of phosphatidylinositol (PI) 3-kinase is a common sequel to tyrosine kinase activation and appears to be essential for tyrosine kinases to induce proliferation. Since multiple hemopoietic growth factors activate tyrosine kinases, we investigated whether these growth factors activate PI 3-kinase. We show that interleukin-3 (IL-3), interleukin-4 (IL-4), interleukin-5 (IL-5), granulocyte-macrophage colony stimulating factor (GM-CSF), and steel factor (SLF) all activate PI 3-kinase. These cytokines increased the amount of PI 3-kinase activity that could be immunoprecipitated with anti-phosphotyrosine antibodies from the MC-9 mast cell line or from the hemopoietic progenitor cell line FDC-P1. Increases in this assay frequently correlate with PI 3-kinase activation in vivo. To determine directly whether these factors activate PI 3-kinase in vivo, we measured the levels of 3-phosphorylated inositol phospholipids in intact 32P-labeled MC-9 cells. IL-3, IL-4, IL-5, GM-CSF, and SLF all caused increased synthesis of the PI 3-kinase products phosphatidylinositol 3,4-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate with a relative potency of SLF >> IL-3 > IL-5, GM-CSF > IL-4. In contrast, IL-4 caused the largest increase in the in vitro anti-phosphotyrosine immune complex PI 3-kinase assay. Thus, the in vitro assay does not accurately reflect in vivo activation of PI 3-kinase. Cytokine treatment did not stimulate tyrosine phosphorylation of either the 85-kDa regulatory subunit or the 110-kDa catalytic subunit of PI 3-kinase and is therefore not required for activation of PI 3-kinase by these factors. Cytokine treatment did induce PI 3-kinase to associate with other tyrosine-phosphorylated proteins in a cytokine-specific manner. PI 3-kinase associated with c-kit after SLF stimulation, a 170-kDa protein after IL-4 stimulation, and a 70-kDa protein after treatment with IL-3 or GM-CSF. Thus, multiple hemopoietic growth factors that act through different types of receptors activate PI 3-kinase in vivo and induce factor-specific interactions of PI 3-kinase with other tyrosine-phosphorylated proteins.

Animals↗

PubMed1994

Both phosphatidylinositol 3-kinase and phosphatidylinositol 4-kinase products are increased by antigen receptor signaling in B cells.

The effects of Ag binding on B cell development and activation are mediated by intracellular signals initiated by the B cell AgR. In this report, we show that the B cell AgR regulates the production of inositol phospholipids involved in two different signal transduction pathways, the phosphatidylinositol 3-kinase (PtdIns 3-kinase) pathway and the phospholipase C (PLC) pathway. Phosphatidylinositol 3-phosphate (PtdIns3P), phosphatidylinositol 3,4-bisphosphate [PtdIns(3,4)P2], and phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P3] are produced by PtdIns 3-kinase, an enzyme that appears to be an essential component of tyrosine kinase-mediated signaling. Both PtdIns(3,4)P2 and PtdIns(3,4,5)P3 are likely to function as second messengers in vivo because they can activate the zeta isoform of protein kinase C (PKC) in vitro. We show that cross-linking of the B cell AgR with anti-Ig antibodies caused a five- to sixfold increase in the levels of PtdIns(3,4)P2 in both the mature B cell line BAL 17 and the immature B cell line WEHI-231. PtdIns(3,4)P2 levels increased within 15 s of anti-Ig addition and remained elevated for at least 5 min. AgR cross-linking also caused a slower increase in PtdIns3P levels (approximately 50% over control) and a small, transient increase in PtdIns(3,4,5)P3 levels. Thus, the B cell AgR activates the PtdIns 3-kinase pathway. The other inositol phospholipid signaling pathway involves PLC, which cleaves phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2], yielding second messengers that increase intracellular calcium and activate other isoforms of PKC. We analyzed the effects of AgR signaling on PtdIns(4,5)P2 and its precursor, phosphatidylinositol 4-phosphate (PtdIns4P). Consistent with its ability to activate PLC, AgR ligation decreased the levels of PtdIns(4,5)P2. In contrast, AgR cross-linking increased the levels of PtdIns4P. Increased synthesis of PtdIns4P followed by phosphorylation at the D-5 position may prevent depletion of PtdIns(4,5)P2. Thus, signaling by the B cell AgR increases the levels of PtdIns 4-kinase products and PtdIns 3-kinase products. The simplest interpretation of our results is that the B cell AgR activates both PtdIns 3-kinase and PtdIns 4-kinase.

1-Phosphatidylinositol 4-Kinase↗

PubMed1994

Biochemistry of B lymphocyte activation.

The activation of B lymphocytes from resting cells proceeds from the events of early activation to clonal proliferation to final differentiation into either an antibody-secreting plasma cell or a memory B cell. This is a complex activation process marked by several alternative pathways, depending on the nature of the initial antigenic stimulus. Over the past 5-10 years, there has been an explosion of studies examining the biochemical nature of various steps in these pathways. Some of that progress is reviewed here. In particular, we have described in detail what is known about the structure and function of the AgR, as this molecule plays a pivotal role in B cell responses of various types. We have also reviewed recent progress in understanding the mechanism of action of contact-dependent T cell help and of the cytokine receptors, particularly the receptors for IL-2, IL-4, and IL-6. Clearly, all of these areas represent active areas of investigation and great progress can be anticipated in the next few years.

B-Lymphocytes↗

PubMed1993

Health insurance and mortality. Evidence from a national cohort.

OBJECTIVE: To examine the relationship between lacking health insurance and the risk of subsequent mortality. DESIGN: Adults older than 25 years who reported they were uninsured or privately insured in the first National Health and Nutrition Examination Survey, a representative cohort of the US population, were followed prospectively from initial interview in 1971 through 1975 until 1987. PARTICIPANTS: Complete baseline and follow-up information was obtained on 4694 (91%) persons of the 5161 who reported not receiving publicly funded insurance at baseline. MAIN OUTCOME MEASURE: The relationship between insurance status and subsequent mortality was examined using Cox proportional hazards survival analysis. The analysis adjusted for gender, race, and baseline age, education, income, employment status, the presence of morbidity on examination, self-rated health, smoking status, leisure exercise, alcohol consumption, and obesity. The effects of interactions between insurance and all other baseline variables were also examined. RESULTS: By the end of the follow-up period, 9.6% of the insured and 18.4% of the uninsured had died. After adjustment for all other baseline variables, the hazard ratio for lacking insurance was 1.25 (95% confidence interval [CI], 1.00 to 1.55). The effect of insurance on mortality was comparable to that of education, income, and self-rated health. There were no statistically significant (P < .05) interactions. CONCLUSIONS: Lacking health insurance is associated with an increased risk of subsequent mortality, an effect that is evident in all sociodemographic health insurance and mortality groups examined.

Adult↗

PubMed1993

Targets of B lymphocyte antigen receptor signal transduction include the p21ras GTPase-activating protein (GAP) and two GAP-associated proteins.

Cross-linking membrane Ig (mIg) on B cells stimulates tyrosine phosphorylation of proteins involved in signal transduction including the mIg-associated proteins Ig-alpha and Ig-beta, the tyrosine kinases p53/p56lyn, p55blk, p59fyn, and PTK72, phosphatidylinositol 3-kinase, phospholipase C gamma 1 and gamma 2, and the mitogen-activated protein kinase. We now show that the p21ras GTPase-activating protein (GAP) is also a substrate for mIg-activated tyrosine kinases. p21ras is a key regulator of cell growth and GAP may act as both a regulator of p21ras activity and as a downstream effector of p21ras. We found that mIg cross-linking caused a rapid increase in tyrosine phosphorylation of GAP in the immature B cell line WEHI-231, the mature B cell lines BAL 17 and Daudi, and the IgG-bearing B cell line A20. In fibroblasts, tyrosine kinase activation causes GAP to associate with two other tyrosine-phosphorylated proteins, p62 and p190, which have homologies to an RNA-binding protein and a transcriptional repressor, respectively. Similarly, mlg cross-linking induced the association of GAP with a 62-kDa tyrosine-phosphorylated protein in BAL 17, WEHI-231, and Daudi cells. Anti-Ig treatment also increased the amount of a 190-kDa tyrosine-phosphorylated protein associated with GAP in WEHI-231 and Daudi cells. After separation by SDS-PAGE and transfer to nitrocellulose, the tyrosine-phosphorylated p62 and p190 present in anti-GAP immunoprecipitates from B cells were capable of binding radiolabeled recombinant GAP, as previously reported for the GAP-associated p62 and p190 from fibroblasts. The amount of p62 that could be detected in this way after immunoprecipitation with antiphosphotyrosine antibodies was much greater from anti-IgM-treated BAL 17 cells than from unstimulated BAL 17 cells. This probably reflects anti-Ig-induced tyrosine phosphorylation of p62. In any case, GAP, p62, and/or p190 may be involved in signal transduction by mIg in B cells.

Animals↗