Tricyclic overdose causing sustained monomorphic ventricular tachycardia.
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Adult↗
Biomedical subjects
M R Gold
Publications and source records attributed to M R Gold.
Selective activation of p42 mitogen-activated protein (MAP) kinase in murine B lymphoma cell lines by membrane immunoglobulin cross-linking. Evidence for protein kinase C-independent and -dependent mechanisms of activation.
Cross-linking of membrane immunoglobulin (mIg), the B lymphocyte antigen receptor, with anti-receptor antibodies stimulates tyrosine phosphorylation of a number of proteins, including one of 42 kDa. Proteins with a similar molecular mass are tyrosine-phosphorylated in response to receptor stimulation in other cell types and have been identified as serine/threonine kinases, termed mitogen-activated protein (MAP) kinases or extracellular signal-regulated kinases (ERKs). The MAP kinases constitute a family of related kinases, at least three of which have molecular masses of 40-45 kDa. In this paper we show that mIg cross-linking stimulated the myelin basic protein phosphotransferase activity characteristic of MAP kinase in both mature and immature murine B cell lines. This enzyme activity co-purified on three different columns with a 42 kDa protein that was tyrosine-phosphorylated (pp42) in response to mIg cross-linking and which reacted with a panel of anti-(MAP kinase) antibodies. Although immunoblotting with the anti-(MAP kinase) antibodies showed that these B cell lines expressed both 42 kDa and 44 kDa forms of MAP kinase, only the 42 kDa form was activated and tyrosine-phosphorylated to a significant extent. Activation of protein kinase C (PKC) with phorbol esters also resulted in selective tyrosine phosphorylation and activation of the 42 kDa MAP kinase. This suggested that mIg-induced MAP kinase activation could be due to stimulation of PKC by mIg. However, mIg-stimulated MAP kinase activation and pp42 tyrosine phosphorylation was only partially blocked by a PKC inhibitor, the staurosporine analogue Compound 3. In contrast, Compound 3 completely blocked the ability of phorbol esters to stimulate MAP kinase activity and induce tyrosine phosphorylation of pp42. Thus mIg may activate MAP kinase by both PKC-dependent and -independent mechanisms.
Amino Acid Sequence↗
The membrane IgM-associated proteins MB-1 and Ig-beta are sufficient to promote surface expression of a partially functional B-cell antigen receptor in a nonlymphoid cell line.
The B-cell antigen receptors consist of membrane immunoglobulins (mIgs) noncovalently associated with two accessory proteins, MB-1 and Ig-beta. We used transfection into a nonlymphoid cell line to test whether MB-1 and Ig-beta were sufficient to promote cell surface expression of mIgM capable of signal transduction. Expression of MB-1 and Ig-beta, but not MB-1 alone, allowed high-level surface expression of mIgM in the AtT20 endocrine cell line, which presumably lacks other B-cell-specific components. The reconstituted antigen receptor was capable of mediating some of the signaling reactions characteristic of mIgM in B lymphocytes. Crosslinking mIgM on transfected AtT20 cells stimulated tyrosine phosphorylation of MB-1 and Ig-beta and also increased the amount of phosphatidylinositol 3-kinase activity that could be precipitated with anti-phosphotyrosine antibodies. When total cell lysates were analyzed by anti-phosphotyrosine immunoblotting, however, no induced phosphorylation of more abundant proteins was detected. Moreover, crosslinking of the receptor in AtT20 cells did not stimulate inositol phospholipid breakdown. Thus, the transfected B-cell antigen receptor could initiate some signal transduction events but AtT20 cells may lack components required for other signaling events associated with mIgM.
Animals↗
Membrane Ig cross-linking regulates phosphatidylinositol 3-kinase in B lymphocytes.
Cross-linking of the B cell AgR results in activation of mature B cells and tolerization of immature B cells. The initial signaling events stimulated by membrane immunoglobulin (mIg) cross-linking are tyrosine phosphorylation of a number of proteins. Among the targets of mIg-induced tyrosine phosphorylation are the tyrosine kinases encoded by the lyn, blk, fyn, and syk genes, the mIg-associated proteins MB-1 and Ig-beta, phospholipase C-gamma 1 and -gamma 2, as well as many unidentified proteins. In this report we show that mIg cross-linking also regulates phosphatidylinositol 3-kinase (PtdIns 3-kinase), an enzyme that phosphorylates inositol phospholipids and plays a key role in mediating the effects of tyrosine kinases on growth control in fibroblasts. Cross-linking mIg on B lymphocytes greatly increased the amount of PtdIns 3-kinase activity which could be immunoprecipitated with anti-phosphotyrosine (anti-tyr(P) antibodies. This response was observed after mIg cross-linking in mIgM- and mIgG-bearing B cell lines and after cross-linking either mIgM or mIgD in murine splenic B cells. Thus, regulation of PtdIns 3-kinase is a common feature of signaling by several different isotypes of mIg. This response was rapid and peaked 2 to 3 min after the addition of anti-Ig antibodies. The anti-Ig-stimulated increase in PtdIns 3-kinase activity associated with anti-Tyr(P) immunoprecipitates could reflect increased tyrosine phosphorylation of PtdIns 3-kinase, increased activity of the enzyme, or both. In favor of the first possibility, the tyrosine kinase inhibitor herbimycin A blocked the increase in ant-Tyr(P)-immunoprecipitated PtdIns 3-kinase activity as well as the anti-Ig-induced tyrosine phosphorylation. Moreover, this response was not secondary to phospholipase C activation but rather seemed to be a direct consequence of mIg-induced tyrosine phosphorylation. Activation of the phosphoinositide pathway by a transfected M1 muscarinic acetylcholine receptor expressed in WEHI-231 B lymphoma cells did not increase the amount of PtdIns 3-kinase activity which could be precipitated with anti-Tyr(P) antibodies. Similarly, inhibition of the phosphoinositide pathway did not abrogate the ability of mIg cross-linking to stimulate this response. Thus, mIg-induced tyrosine phosphorylation regulates PtdIns 3-kinase, an important mediator of growth control in fibroblasts and potentially an important regulatory component in B cells as well.
Animals↗
Electrophysiologic response to moricizine in patients with sustained ventricular arrhythmias.
OBJECTIVE: To assess the short-term efficacy and safety of moricizine in patients receiving electrophysiologically guided therapy for sustained ventricular arrhythmias refractory to treatment with class IA antiarrhythmic agents. DESIGN: Uncontrolled clinical trial. SETTING: Referral-based teaching medical center. PATIENTS: Twenty-one patients (18 of whom had coronary artery disease) with a mean left ventricular ejection fraction of 32% +/- 11% who presented with sustained ventricular tachycardia (13 patients), syncope (4 patients), or cardiac arrest (4 patients). INTERVENTIONS: Moricizine, 743 +/- 85 mg daily. MEASUREMENTS: Electrophysiologic testing in the drug-free state and after administration of moricizine unless sustained arrhythmias occurred. MAIN RESULTS: Sustained ventricular tachycardia was inducible in the absence of antiarrhythmic drugs in 20 patients and was not suppressed by moricizine in any patient. Four patients had six episodes of spontaneous ventricular tachycardia while receiving moricizine. A probable proarrhythmic response occurred in four patients. CONCLUSION: In patients with compromised left ventricular function caused by coronary artery disease in whom class IA antiarrhythmics were ineffective, moricizine was ineffective in suppressing sustained ventricular arrhythmias and resulted in proarrhythmic effects in some patients.
Adult↗
Healthy people 2000: access to preventive services for all.
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Adult↗
Bacterial lipopolysaccharide stimulates protein tyrosine phosphorylation in macrophages.
Lipopolysaccharide (LPS), a membrane component of Gram-negative bacteria, stimulates immune responses by activating macrophages, B lymphocytes, and other cells of the immune system. The mechanisms by which LPS activates these cells are poorly characterized. Since protein tyrosine phosphorylation appears to be a major intracellular signaling event that mediates cellular responses, we examined whether LPS alters tyrosine phosphorylation in macrophages. We found that Escherichia coli K235 LPS increased tyrosine phosphorylation of several proteins in the RAW 264.7 murine macrophage cell line and in resident peritoneal macrophages from C3H/HeSNJ mice. Changes in tyrosine phosphorylation were detectable by 4-5 min, reached a maximum by 15 min, and declined after 30-60 min. Protein tyrosine phosphorylation increased following stimulation with LPS at 100 pg/ml and was maximal with 10 ng/ml. Similar changes in tyrosine phosphorylation were induced by Salmonella minnesota R595 LPS and by the biologically active domain of LPS, lipid A, but not by the inactive lipid A derivative N2-monoacylglucosamine 1-phosphate. Phorbol 12-myristate 13-acetate also stimulated protein tyrosine phosphorylation, but some of the modulated proteins were different than those phosphorylated by LPS. Treatment of RAW 264.7 cells with a tyrosine kinase inhibitor, herbimycin A, inhibited both LPS-stimulated tyrosine phosphorylation and LPS-stimulated release of arachidonic acid metabolites. Thus, increased protein tyrosine phosphorylation is a rapid LPS-activated signaling event that may mediate release of arachidonic acid metabolites in RAW 264.7 cells.
Animals↗
Tyrosine phosphorylation of components of the B-cell antigen receptors following receptor crosslinking.
Crosslinking membrane immunoglobulin (mIg), the B-cell antigen receptor, stimulates tyrosine phosphorylation of a number of proteins. Since many receptors are phosphorylated after ligand binding, we asked if components of the mIg receptor complexes were tyrosine-phosphorylated after mIg crosslinking. Both mIgM and mIgD are noncovalently associated with at least two other proteins. mIgM is associated with the MB-1 protein, which is disulfide-linked to a protein designated Ig-beta. mIgD is not associated with MB-1 but is with IgD-alpha, which is also disulfide-linked to Ig-beta. Using immunoprecipitation with a specific anti-MB-1 antiserum followed by anti-phosphotyrosine immunoblotting, we found that crosslinking mIgM stimulated tyrosine phosphorylation of MB-1, Ig-beta, and a previously unidentified 54-kDa polypeptide associated with MB-1. In mature splenic B cells that express both mIgM and mIgD, mIgM crosslinking stimulated tyrosine phosphorylation of the 32-kDa MB-1 protein, whereas mIgD crosslinking stimulated tyrosine phosphorylation of MB-1-related proteins of 33 and 34 kDa. The 32-kDa MB-1 protein was only associated with mIgM, whereas the 33- and 34-kDa MB-1-related proteins were specifically associated with mIgD and are most likely IgD-alpha. Thus, crosslinking either mIgM or mIgD stimulated tyrosine phosphorylation only of the MB-1-related proteins associated with that receptor.
Animals↗
Mutational analysis of antigen receptor regulation of B lymphocyte growth. Evidence for involvement of the phosphoinositide signaling pathway.
Stimulation of the antigen receptor of WEHI-231 B lymphoma cells with anti-receptor antibodies (anti-IgM) induces irreversible growth arrest. Anti-IgM stimulates two kinds of transmembrane signaling events, phosphorylation of proteins on tyrosyl residues and breakdown of inositol phospholipids, which results in increases of inositol phosphates, diacylglycerol, and calcium. The roles of these reactions in mediating the growth arrest of the B lymphoma cells have not been established. To examine this issue, we took a genetic approach. Mutants of WEHI-231 cells were isolated that were resistant to anti-IgM-induced growth arrest. Five out of seven independent mutants analyzed had normal cell-surface expression of antigen receptors. Although each of these five mutants had tyrosine protein phosphorylation patterns comparable to wild-type cells, they exhibited alterations in the phosphoinositide signaling pathway. Four of the mutants had decreased phosphoinositide breakdown, probably due to an alteration in phospholipase C. Decreased second messenger production may be responsible for the growth-resistant phenotype. Full growth arrest was restored upon addition of the calcium ionophore ionomycin, suggesting that the limiting second messenger was intracellular free calcium. The final mutant appeared to be altered in a component(s) that responds to diacylglycerol and calcium. Taken together, these results provide further evidence that the phosphoinositide pathway is at least partly responsible for mediating antigen receptor regulation of B lymphoma cell growth.
Animals↗
Regulation of anti-immunoglobulin-induced B lymphoma growth arrest by transforming growth factor beta 1 and dexamethasone.
Exposure of the murine B lymphoma cell line WEHI-231 to anti-immunoglobulin M (anti-IgM) antibodies results in growth arrest in the G1 phase of the cell cycle followed by programmed cell death. This response may be analogous to the clonal deletion of immature B cells that occurs when the membrane IgM on these cells is engaged by self-antigens or by anti-IgM antibodies. Thus the WEHI-231 cell line has been a useful in vitro system for identifying factors that modulate anti-Ig-induced growth inhibition and/or clonal deletion. For example, both antigen-induced tolerance induction in immature B cells and anti-Ig-induced growth arrest of WEHI-231 cells are prevented by bacterial lipopolysaccharide or by the products of activated T helper cells. Since negative signaling by membrane Ig may also be regulated by additional factors, we asked whether other cytokines or hormones would regulate the growth of WEHI-231 cells or its response to anti-IgM antibodies. We show here that two compounds that are generally immunosuppressive, transforming growth factor beta 1 (TGF-beta 1) and the synthetic corticosteroid, dexamethasone, blocked the ability of lipopolysaccharide and T cell-derived lymphokines to protect WEHI-231 cells from anti-IgM-induced growth arrest. In addition, TGF-beta 1 and dexamethasone slightly inhibited the growth of WEHI-231 cells by themselves and also potentiated the growth inhibitory effects of anti-IgM antibodies. Thus for WEHI-231 cells, TGF-beta 1 and dexamethasone are inhibitory factors which favor growth arrest.
Animals↗
Use-dependent block of atrial sodium current by ethylisopropylamiloride.
Ethylisopropylamiloride (EIPA) is a potent inhibitor of Na(+)-H+ exchange in many tissues and is frequently used to study cellular regulation of pH, but the electrophysiologic effects of EIPA on cardiac cells have not been studied previously. The use-dependent effects of EIPA on the sodium current (INa) of cultured embryonic chick atrial myocytes were investigated using standard whole-cell patch-clamp techniques. With 150-ms depolarizations from -140 to 0 mV, applied at 1-3 Hz in the presence of 10 microM EIPA, a decrement in INa was observed. This use-dependent reduction equaled 31 +/- 6% of control INa at steady state during 1-Hz stimulation. Inhibition increased with stimulation rate and with depolarization of the holding potential to -100 mV, but there was no effect of pulse duration on the EIPA-induced inhibition over the range of 20-500 ms. Moreover, repetitive depolarizations to potentials that did not activate macroscopic current but that did yield pronounced channel inactivation did not result in a decrement in INa. The effect of EIPA increased over the concentration range of 1-30 microM so that with 3-Hz stimuli steady-state inhibition increased from 3 +/- 1 to 85 +/- 5%. Amiloride, which slows repolarization of the cardiac action potential, was at least 100-fold less potent than EIPA in reducing INa. We conclude that EIPA is an "open-channel" blocker of the cardiac sodium current at concentrations comparable to those of many type I antiarrhythmic agents.
Amiloride↗
Acute effects of repetitive depolarization on sodium current in chick myocytes.
Acute effects of repetitive depolarization on the inward Na+ current (INa) of cultured embryonic chick atrial cells were studied using the whole cell patch-clamp technique. Stimulation rates of 1 Hz or greater produced a progressive decrement of peak INa. With depolarizations to 0 mV of 150-ms duration, applied at 2 Hz from a holding potential of -100 mV, the steady-state decrement was approximately 20%. The magnitude of this effect increased with stimulation frequency and with test potential depolarization and decreased with membrane hyperpolarization. Analysis of INa kinetics revealed that reactivation was sufficiently slow to preclude complete recovery from inactivation with interpulse intervals less than 1,000 ms. Moreover, reactivation accelerated markedly with membrane hyperpolarization, in parallel with the response to repetitive stimulation. The multiexponential time course of recovery of peak INa from repetitive depolarization was similar to that observed after single stimuli; however, there was a shift toward a greater proportion of current recovering with the slower of two time constants. It is concluded that incomplete recovery from inactivation is responsible for the decrement in INa observed with short interpulse intervals.
Action Potentials↗
HMOs and managed care.
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Data Collection↗
Esmolol and ventilatory function in cardiac patients with COPD.
To assess the effects of acute cardioselective beta blockade on ventilatory function in patients with COPD and active cardiac disorders, 50 patients were studied during intravenous infusion of esmolol. All patients had an obstructive ventilatory component on baseline pulmonary function testing, and 58 percent had a significant bronchodilator response to inhaled albuterol. Esmolol infusion (8 to 24 mg/min) produced large decreases in heart rate (84 +/- 2 to 69 +/- 2 beats/min, p less than 0.01) and SBP (124 +/- 3 to 106 +/- 3 mm Hg, p less than 0.01). Despite this marked hemodynamic response, there was no significant group effect of beta blockade on pulmonary function. No patient experienced dyspnea or wheezing with acute esmolol infusion; however, three patients (6 percent) developed asymptomatic decreases of FEV1. It is concluded that acute beta blockade with esmolol can be achieved in patients with COPD and cardiac disorders with little risk of bronchospasm.
Adrenergic beta-Antagonists↗
Hypomagnesemia is a frequent finding in the emergency department in patients with chest pain.
STUDY OBJECTIVE: To evaluate the frequency of low blood levels of total and ultrafilterable magnesium (total and ultrafilterable hypomagnesemia) in patients with chest pain in the emergency department, and to determine if hypomagnesemia is associated with other clinically important diagnostic and outcome variables in cardiac care. SETTING: An emergency department of a university teaching hospital. DESIGN: Prospective study of extracellular magnesium homeostasis in patients with chest pain in the emergency department and a cohort of patients without chest pain with a clinical indication for blood sampling. PATIENTS: During a 4-month period, 147 patients presenting to the emergency department were studied: 67 patients (mean +/- SD age, 61.4 +/- 13 years) with a chief complaint of chest pain (study group) and 80 patients (55.6 +/- 19 years) with other diagnoses (control group). RESULTS: Total and ultrafilterable hypomagnesemia occurred more frequently in patients with chest pain (20/67 [30%] and 9/67 [13%]) than in the control group (12/80 [15%] and 3/80 [4%]). Patients with a chief complaint of chest pain who were receiving diuretic medications were hypomagnesemic more frequently (9/16 [56%]) than patients not receiving diuretics (12/51 [23%]). In patients with chest pain admitted to the hospital with a diagnosis of "rule out" myocardial infarction, the frequency of hypokalemia was greater among hypomagnesemic patients (6/14 [43%]) than normomagnesemic patients (3/31 [10%]). A similar frequency of hypomagnesemia was noted in patients with a final diagnosis of myocardial infarction (4/15 [27%]) when compared with other patients admitted with chest pain (10/31 [32%]) in whom myocardial infarction was excluded. No association was noted among hypomagnesemia and length of hospital stay or the occurrence of hypotension or dysrhythmias. CONCLUSIONS: Total and ultrafilterable hypomagnesemia are frequent occurrences in patients with and without chest pain in the emergency department. Diuretic use is associated with hypomagnesemia in patients presenting with chest pain in the emergency department. These results support the concept that hypomagnesemia is common in patients with chest pain in the emergency department and is associated with hypokalemia but is not predictive of whether the patient with chest pain has had an acute myocardial infarction.
Chest Pain↗
Barriers to cholesterol testing in a rural community.
BACKGROUND: The purpose of this study was to investigate the factors that determine whether residents in a rural community have their cholesterol tested. METHODS: A population-based survey was conducted in 1987 as part of a community-oriented primary care project that sought to define and address the causes of and burden caused by increased cardiovascular disease in an economically depressed agricultural region of New York. All of the residents living in two towns in the region who were over 16 years of age and who lived in their homes year-round were surveyed. Demographic information was obtained from the participants, as well as information about previous cholesterol testing and their cardiovascular-risk knowledge and behaviors. The serum cholesterol of each participant was measured. RESULTS: Of the 557 households contacted, 508 (91%) households participated. A total of 1063 persons over 16 years of age were surveyed, and 973 (92%) were screened for cholesterol. Overall, 24% reported prior cholesterol testing. Logistic regression analysis identified several independent factors that were associated with a reduced likelihood of ever having had a cholesterol test. These factors included: (1) age under 45 years, (2) having less than 12 years of education, (3) having an income of less than $10,000, (4) not having health insurance, (5) not having visited a physician within the previous year, and (6) practicing three or more high-risk cardiovascular behaviors. The participants' cardiovascular knowledge made no independent contribution to having had their cholesterol levels tested. CONCLUSIONS: Many of the factors that prevent cholesterol testing are socially determined. The results of this study suggest that financial and social barriers are two of the major obstacles to residents of rural communities having their cholesterol levels tested.
Adolescent↗
Stimulation of protein tyrosine phosphorylation by the B-lymphocyte antigen receptor.
Signalling by membrane immunoglobulin, the B-lymphocyte antigen receptor, regulates B-cell maturation and activation. Crosslinking of membrane immunoglobulin by antigen or by anti-immunoglobulin antibodies inactivates immature B cells, eliminating many of the B cells capable of producing auto-antibodies. By contrast, crosslinking of membrane immunoglobulin promotes activation of mature B cells for clonal expansion and antibody production against foreign antigens. Crosslinking membrane IgM on the immature B-cell line WEHI-231 induces growth arrest. This response may be analogous to the deletion or inactivation of immature B cells that is induced by antigen or anti-IgM antibodies. Membrane immunoglobulin crosslinking stimulates phosphoinositide hydrolysis, which leads to increases in intracellular calcium and activation of protein kinase C. The induced phosphoinositide breakdown is important for inhibiting WEHI-231 growth (ref. 7 and D. Page, M.R.G., K. Fahey, L. Matsuuchi and A.L.D., manuscript submitted for publication), but may not be sufficient, as agents that elevate calcium and activate protein kinase C cause only partial growth arrest. We now show that in both mature splenic B cells and the immature B-cell line WEHI-231 crosslinking membrane immunoglobulin also stimulates phosphorylation of protein tyrosine, a reaction that has been implicated as a key regulator of cell growth. Most of these phosphorylations were not a consequence of the phosphoinositide pathway. Thus, tyrosine phosphorylation is a second mode of transmembrane signalling by membrane immunoglobulin.
Animals↗
The social origin of cardiovascular risk: an investigation in a rural community.
The effects of socioeconomic disadvantage on behavioral, psychosocial, and physiological risk factors for cardiovascular disease were investigated in an economically depressed agricultural area of New York State. After adjustment for age and sex, at least one and typically two of the three dichotomized socioeconomic factors (manual labor, lack of high school graduation, and poverty) were associated with an increased prevalence of smoking, obesity, frequent salt use, cholesterol consumption, low levels of leisure activity, and social isolation. Education and occupation also made independent contributions to systolic blood pressure. After adjustment for age, sex, behavioral, and social isolation variables, those with both risk factors (less than 12 years of school, and manual labor) had a higher mean systolic blood pressure than those with neither risk factor (9.5 mm Hg; 95 percent confidence interval = 5.5, 13.5). In contrast, after adjustment for the other variables, those with the two risk factors, less than 12 years of school and income below the poverty level, had a lower mean serum cholesterol than those with neither risk factor (11 mg/100 ml; 95 percent confidence interval = 3.1, 18.9). The policy implications of these pervasive social gradients of cardiovascular risk and the paradoxical relationship with serum cholesterol are discussed.
Cholesterol↗