Showing papers by "Tufts University published in 1992"

Long-term morbidity and mortality of overweight adolescents. A follow-up of the Harvard Growth Study of 1922 to 1935.

Abstract: Background. Overweight in adults is associated with increased morbidity and mortality. In contrast, the long-term effect of overweight in adolescence on morbidity and mortality is not known. Methods. We studied the relation between overweight and morbidity and mortality in 508 lean or overweight adolescents 13 to 18 years old who participated in the Harvard Growth Study of 1922 to 1935. Overweight adolescents were defined as those with a body-mass index that on two occasions was greater than the 75th percentile in subjects of the same age and sex in a large national survey. Lean adolescents were defined as those with a body-mass index between the 25th and 50th percentiles. Subjects who were still alive were interviewed in 1988 to obtain information about their medical history, weight, functional capacity, and other risk factors. For those who had died, information on the cause of death was obtained from death certificates. Results. Overweight in adolescent subjects was associated with an increase...

Effects of an Rb mutation in the mouse

Abstract: The retinoblastoma gene is mutated in several types of human cancer and is the best characterized of the tumour-suppressor genes. A mouse strain has been constructed in which one allele of Rb is disrupted. These heterozygous animals are not predisposed to retinoblastoma, but some display pituitary tumours arising from cells in which the wild-type Rb allele is absent. Embryos homozygous for the mutation die between days 14 and 15 of gestation, exhibiting neuronal cell death and defective erythropoiesis.

Recombinant tissue plasminogen activator in acute thrombotic and embolic stroke

Abstract: An open angiography-based, dose rate escalation study on the effect of intravenous infusion of recombinant tissue plasminogen activator (rt-PA) on cerebral arterial recanalization in patients with acute focal cerebral ischemia was performed at 16 centers. Arterial occlusions consistent with acute ischemia in the carotid or vertebrobasilar territory in the absence of detectable intracerebral hemorrhage were prerequisites for treatment. After the 60-minute rt-PA infusion, arterial perfusion was assessed by repeat angiography and computed tomography scans were performed at 24 hours to assess hemorrhagic transformation. Of 139 patients with symptoms of focal ischemia, 80.6% (112) had complete occlusion of the primary vessel at a mean of 5.4 +/- 1.7 hours after symptom onset. No dose rate response of cerebral arterial recanalization was observed in 93 patients who completed the rt-PA infusion. Middle cerebral artery division (M2) and branch (M3) occlusions were more likely to undergo recanalization by 60 minutes than were internal carotid artery occlusions. Hemorrhagic infarction occurred in 20.2% and parenchymatous hematoma in 10.6% of patients over all dose rates, while neurological worsening accompanied hemorrhagic transformation (hemorrhagic infarction and parenchymatous hematoma) in 9.6% of patients. All findings were within prospective safety guidelines. No dose rate correlation with hemorrhagic infarction, parenchymatous hematoma, or both was seen. Hemorrhagic transformation occurred significantly more frequently in patients receiving treatment at least 6 hours after symptom onset. No relationship between hemorrhagic transformation and recanalization was observed. This study indicates that site of occlusion, time to recanalization, and time to treatment are important variables in acute stroke intervention with this agent.

What can the history and physical examination tell us about low back pain

Abstract: BACK pain ranks second only to upper respiratory illness as a symptomatic reason for office visits to physicians.1About 70% of adults have low back pain at some time, but only 14% have an episode that lasts more than 2 weeks. About 1.5% have such episodes with features of sciatica.2,3Most causes of back pain respond to symptomatic and physical measures, but some are surgically remediable and some are systemic diseases (cancer or disseminated infection) requiring specific therapy, so careful diagnostic evaluation is important. Features of the clinical history and physical examination influence not only therapeutic choices but also decisions about diagnostic imaging, laboratory testing, and specialist referral. ANATOMIC/PHYSIOLOGIC ORIGINS OF FINDINGS IN THE LOW BACK Low back pain may arise from several structures in the lumbar spine, including the ligaments that interconnect vertebrae, outer fibers of the annulus fibrosus, facet joints, vertebral periosteum, paravertebral musculature and fascia,

Leukocyte accumulation promoting fibrin deposition is mediated in vivo by P-selectin on adherent platelets.

Abstract: The glycoprotein P-selectin is a cell adhesion molecule of stimulated platelets and endothelial cells, which mediates the interaction of these cells with neutrophils and monocytes. It is a membrane component of cell storage granules, and is a member of the selectin family which includes E-selectin and L-selectin. P-selectin recognizes both lineage-specific carbohydrate ligands on monocytes and neutrophils, including the Lewis x antigen, sialic acid, and a protein component. In inflammation and thrombosis, P-selectin may mediate the interaction of leukocytes with platelets bound in the region of tissue injury and with stimulated endothelium. To evaluate the role of P-selectin in platelet-leukocyte adhesion in vivo, the accumulation of leukocytes within an experimental thrombus was explored in an arteriovenous shunt model in baboons. A Dacron graft implanted within an arteriovenous shunt is thrombogenic, accumulating platelets and fibrin within its lumen. These bound platelets express P-selectin. Here we show that antibody inhibition of leukocyte binding to P-selectin expressed on platelets immobilized on the graft blocks leukocyte accumulation and inhibits the deposition of fibrin within the thrombus. These results indicate that P-selectin is an important adhesion molecule on platelets, mediating platelet-leukocyte binding in vivo, that the presence of leukocytes in thrombi is mediated by P-selectin, and that these leukocytes promote fibrin deposition.

Effective Elastic Properties of Cracked Solids: Critical Review of Some Basic Concepts

Abstract: The problem of effective moduli of cracked solids is critically reviewed. Various approaches to the problem are discussed; they are further assessed by comparing their predictions to results for sample deterministic arrays. These computer experiments indicate that the approximation of noninteracting cracks has a wider than expected range of applicability. Some of the deficiencies of various approximate schemes seem to be related to inadequacy of the conventionally used crack density parameter (insensitive to mutual positions of cracks). An alternative parameter that has this sensitivity, is suggested. Finally, the problem of effective moduli is discussed in the context of {open_quotes}damage mechanics{close_quotes}. It is argued that, contrary to the spirit of many damage models, there is no direct quantitative correlation between progression of a microcracking solid towards fracture and deterioration of its stiffness; thus, the effective moduli may not always serve as a reliable indicator of damage. 84 refs., 14 figs.

Inactivation of the p34cdc2-cyclin B complex by the human WEE1 tyrosine kinase.

Abstract: Entry into mitosis in Schizosaccharomyces pombe is negatively regulated by the wee1+ gene, which encodes a protein kinase with serine-, theonine-, and tyrosine-phosphorylating activities. The wee1+ kinase negatively regulates mitosis by phosphorylating p34cdc2 on tyrosine 15, thereby inactivating the p34cdc2-cyclin B complex. The human homolog of the wee1+ gene (WEE1Hu) was overproduced in bacteria and assayed in an in vitro system. Unlike its fission yeast homolog, the product of the WEE1Hu gene encoded a tyrosine-specific protein kinase. The human WEE1 kinase phosphorylated the p34cdc2-cyclin B complex on tyrosine 15 but not on threonine 14 in vitro and inactivated the p34cdc2-cyclin B kinase. This inhibition was reversed by the human Cdc25C protein, which catalyzed the dephosphorylation of p34cdc2. These results indicate that the product of the WEE1Hu gene directly regulates the p34cdc2-cyclin B complex in human cells and that a kinase other than that encoded by WEE1Hu phosphorylates p34cdc2 on threonine 14.

Time and the Observer: the Where and When of Consciousness in the Brain

Abstract: We compare the way two models of consciousness treat subjective timing. According to the standard “Cartesian Theater” model, there is a place in the brain where “it all comes together,” and the discriminations in all modalities are somehow put into registration and “presented” for subjective judgment. The timing of the events in this theater determines subjective order. According to the alternative “Multiple Drafts” model, discriminations are distributed in both space and time in the brain. These events do have temporal properties, but those properties do not determine subjective order because there is no single, definitive “stream of consciousness,” only a parallel stream of conflicting and continuously revised contents. Four puzzling phenomena that resist explanation by the Cartesian model are analyzed: (1) a gradual apparent motion phenomenon involving abrupt color change (Kolers & von Grunau 1976), (2) an illusion of an evenly spaced series of “hops” produced by two or more widely spaced series of taps delivered to the skin (Geldard & Sherrick's “cutaneous rabbit” [1972]), (3) backwards referral in time, and (4) subjective delay of consciousness of intention (both reported in this journal by LIbet 1985a; 1987; 1989a). The unexamined assumptions that have always made the Cartesian Theater so attractive are exposed and dismantled. The Multiple Drafts model provides a better account of the puzzling phenomena, avoiding the scientific and metaphysical extravagances of the Cartesian Theater: The temporal order of subjective events is a product of the brain's interpretational processes, not a direct reflection of events making up those processes.

Clinical and metabolic efficacy of glutamine-supplemented parenteral nutrition after bone marrow transplantation. A randomized, double-blind, controlled study.

Abstract: Objective To determine whether glutamine-supplemented parenteral nutrition improves nitrogen retention and reduces hospital morbidity compared with standard parenteral nutrition after bone marrow transplantation. Design Double-blind, randomized, controlled clinical trial. Setting University teaching hospital. Patients Forty-five adults receiving allogeneic bone marrow transplants for hematologic malignancies. Intervention Parenteral nutrition was initiated the day after bone marrow transplantation (day 1). The experimental solution was supplemented with L-glutamine (0.57 g/kg body weight per day) and provided estimated requirements for energy and protein. The control solution was a standard, glutamine-free, isonitrogenous, isocaloric formula. Measurements Nitrogen balance was determined between days 4 and 11 in the initial 23 patients. The incidence of clinical infection and microbial colonization, time until bone marrow engraftment, indices of clinical care, and other data related to hospital morbidity were recorded for all patients. Results The glutamine-supplemented patients (n = 24) were clinically similar to the controls (n = 21) at entry. Nutrient intake was similar in both groups; however, nitrogen balance was improved in the glutamine-supplemented patients relative to the controls (-1.4 +/- 0.5 g/d compared with -4.2 +/- 1.2; P = 0.002). Fewer experimental patients developed clinical infection (three compared with nine in the control group; P = 0.041), and the incidence of microbial colonization was also significantly reduced. Hospital stay was shortened in patients receiving glutamine supplementation (29 +/- 1 d compared with 36 +/- 2 d; P = 0.017). Conclusion Patients receiving glutamine-supplemented parenteral nutrition after bone marrow transplantation had improved nitrogen balance, a diminished incidence of clinical infection, lower rates of microbial colonization, and shortened hospital stay compared with patients receiving standard parenteral nutrition. These effects occurred despite no differences between groups in the incidence of fever, antibiotic requirements, or time to neutrophil engraftment.

Familial lipoprotein disorders in patients with premature coronary artery disease.

Abstract: The prevalence of familial lipoprotein disorders was assessed in 102 kindreds with — total of 603 subjects in whom the proband had angiographically documented significant (>50% narrowing) coronary artery disease. Kindreds were classified as abnormal if the proband and at least one first degree relative had fasting triglyceride, low density lipoprotein (LDL) cholesterol, apolipoprotein (apo) B, or lipoprotein (a) values >90th percentile or their high density lipoprotein (HDL) cholesterol or apoA-I value were <10th percentile of age and gender adjusted control values. The following prevalence of familial disorders was noted: Lp(a) excess 18.6%, dyslipidemia (elevated triglycerides and low HDL cholesterol) 14.7%, combined hyperlipidemia (11.7% with low HDL cholesterol) 13.7%, hyperapobetalipoproteinemia 5%, hypoalphalipoproteinemia 4%, and hypercholesterolemia 3%.

Survival of Lactobacillus species (strain GG) in human gastrointestinal tract.

Abstract: A newly isolated strain of a species ofLactobacillus of human origin, designated GG (Lactobacillus GG), has been studied to determine its ability to survive in the human gastrointestinal tract. When fed to 76 volunteers as a frozen concentrate or as a fermented preparation in milk or whey,Lactobacillus GG was recovered in the feces of all subjects receiving the fermented milk or whey and in 86% receiving the frozen concentrate when a single fecal specimen was cultured. The organism was also present in the feces of subjects concurrently receiving ampicillin. After terminating feeding of the organism,Lactobacillus GG persisted in the feces of 87% of volunteers four days later and in 33% of subjects seven days later.Lactobacillus GG lowered fecal bacterial β-glucuronidase activity by approximately 80% in volunteers given the organism for four weeks. These studies demonstrate thatLactobacillus GG can survive and temporarily colonize the human gastrointestinal tract and can affect the metabolic activity of the resident microflora.

Variations in Resource Utilization Among Medical Specialties and Systems of Care: Results From the Medical Outcomes Study

Abstract: Objective. —To examine whether specialty and system of care exert independent effects on resource utilization. Study Design. —Cross-sectional analysis of just over 20 000 patients (≥18 years of age) who visited providers' offices during 9-day periods in 1986. Patient- and physician-provided information was obtained by self-administered questionnaires. Setting. —Offices of 349 physicians practicing family medicine, internal medicine, endocrinology, and cardiology within health maintenance organizations, large multispecialty groups, and solo practices or small single-specialty group practices in three major US cities. Outcome Measures. —Indicators of the intensity of resource utilization were examined among four medical specialties (family practice, general internal medicine, cardiology, and endocrinology) and five systems of care (health maintenance organization, multispecialty group—fee-for-service, multispecialty group—prepaid; solo practice and single-specialty group—fee-for-service, and solo practice and single-specialty group—prepaid) before and after controlling for the mix of patients seen in these offices. The indicators of resource utilization were hospitalizations, annual office visits, prescription drugs, and common tests and procedures, with rates estimated on both a per-visit and per-year basis. Results. —Variation in patient mix was a major determinant of the large variations in resource use. However, increased utilization was also independently related to specialty (cardiology and endocrinology), fee-for-service payment plan, and solo and single-specialty group practice arrangements. After adjusting for patient mix, solo practice/single-specialty groups—fee-for-service had 41% more hospitalizations than health maintenance organizations. General internists had utilization rates somewhat greater than family physicians on some indicators. Conclusion. —Although variations in patient mix should be a major determinant of variations in resource use, the independent effects of specialty training, payment system, and practice organization on utilization rates need further explication. The 2- and 4-year outcomes now being analyzed will provide information critical to interpretation of the variations reported herein. ( JAMA . 1992;267:1624-1630)

Active efflux mechanisms for antimicrobial resistance.

Abstract: Bacteria have inventive and versatile ways to resist antibiotics and other toxic elements (6). The earliest characterized mechanisms were those which inactivated the drug or altered its target in the cell. When decreased drug uptake accompanied resistance, decreased permeability or decreased binding was the initially proposed explanation (31, 40, 61). Active efflux as a mechanism to explain decreased accumulation came later. The early studies of transport in bacteria focused on how substances, particularly nutrients, get into the cells (75). In the 1970s, investigations widened to identify how certain substances came out of cells. Initially, those studies of efflux dealt with simple cations (Na+, K+, Ca2+) which were extruded by an energy-dependent process linked to the proton motive force (PMF) or ATP (2, 4, 5, 27, 37, 101). This transport occurred via cation-specific export proteins which were characterized by a number of laboratories (2, 4, 5, 27, 37, 79). Later, resistance to an organic compound, the antibiotic tetracycline, was linked to the energy-dependent efflux of tetracyclines in gram-negative bacteria (52). Today, active efflux systems, which are responsible for resistance to a variety of structurally unrelated antibiotics and toxic compounds, are being recognized more frequently in increasing numbers of environmental and clinical isolates (Table 1).

Expression cloning and characterization of the canine parietal cell gastrin receptor.

Abstract: Gastrin is an important stimulant of acid secretion by gastric parietal cells and is structurally related to the peptide hormone cholecystokinin (CCK) The pharmacologic properties of the parietal cell gastrin receptor are very similar to the predominant CCK receptor in the brain, CCK-B Neither the gastrin nor the CCK-B receptor have been cloned thus far, making it difficult to resolve whether these two receptors are distinct We have isolated a clone encoding the canine gastrin receptor by screening a parietal cell cDNA expression library using a radioligand-binding strategy Nucleotide sequence analysis revealed an open reading frame encoding a 453-amino acid protein with seven putative hydrophobic transmembrane domains and significant homology with members of the beta-adrenergic family of G protein-coupled receptors The expressed recombinant receptor shows the same binding specificity for gastrin/CCK agonists and antagonists as the canine parietal cell receptor Gastrin-stimulated phosphatidylinositol hydrolysis and intracellular Ca2+ mobilization in COS-7 cells expressing the cloned receptor suggest second-messenger signaling through phospholipase C Affinity labeling of the expressed receptor in COS-7 cells revealed a protein identical in size to the native parietal cell receptor Gastrin receptor transcripts were identified by high-stringency RNA blot analysis in both parietal cells and cerebral cortex, suggesting that the gastrin and CCK-B receptors are either highly homologous or identical

High-speed optical coherence domain reflectometry.

Abstract: We describe a high-speed optical coherence domain reflectometer. Scan speeds of 40 mm/s are achieved with a dynamic range of >90 dB and a spatial resolution of 17 μm. Two applications are presented: the noninvasive measurement of anterior eye structure in a rabbit inυiυo and the characterization of reflections and interelement spacing in a multielement lens.

Escherichia coli cell-division gene ftsZ encodes a novel GTP-binding protein

Abstract: ESCHERICHIA COLI divides by forming a septum across the middle of the cell. The biochemical mechanism underlying this process is unknown. Genetic evidence suggests that of all the fts (filamentation temperature sensitive) genes1,2 involved in E. coli cell division, ftsZ plays a central role at the earliest known step of septation3–5. Here we show that FtsZ protein binds GTP in vitro using unusual sequence elements6–8. In contrast, such binding to the product of the conditional-lethal ftsZ84 allele is impaired. Purified FtsZ displays a Mg2+-dependent GTPase activity which is markedly reduced in the FtsZ84 protein. FtsZ copurifies with near stoichiometric amounts of noncovalently-bound GDP, implying the presence of a GTPase cycle in vivo, similar to that known for signal-transducing GTP-binding proteins8,9. We also show that a small fraction of FtsZ exists as a distinct membrane-associated species that binds GTP. The membrane association of FtsZ and the known ability of GTPases to act as molecular switches8,9 implicate FtsZ in a GTP-activated signal transduction pathway that may regulate the start of septation in E. coli.

Left ventricular diastolic dysfunction as a cause of congestive heart failure. Mechanisms and management.

Abstract: Objective To define the mechanisms underlying left ventricular diastolic dysfunction in patients with congestive heart failure and normal systolic function and to identify the patients at risk for this syndrome. Study selection Studies were selected that describe the clinical observations of congestive heart failure with normal systolic function and that provide experimental and clinical insights into the mechanisms responsible for ventricular diastolic dysfunction. Data synthesis Recent studies indicate that a large number of patients (up to 40% in some series) presenting with congestive heart failure have preserved left ventricular systolic function. The factors contributing to altered left ventricular diastolic function include fibrosis, hypertrophy, ischemia, and increased afterload. The latter three factors, alone or in combination, predispose to impaired left ventricular relaxation, an active energy-requiring process. Thus, decreased left ventricular diastolic distensibility (increased diastolic pressure at any level of diastolic volume) may arise not only from altered passive elastic properties stemming from fibrosis or increased muscle mass but also from derangements in the dynamics of ventricular relaxation. Results In patients with essential hypertension, all four of the above mechanisms may be operative. Considering the prevalence of hypertension in the general population, hypertension appears to be an important underlying factor in many patients with heart failure on the basis of diastolic mechanisms. In the patient presenting with dyspnea and elevated filling pressures, but with a nondilated, normally contracting ventricle, treatment with standard heart failure medications (such as digitalis, diuretics, and vasodilators) is often ineffective and may be deleterious. Such patients may respond more favorably to beta-blockers and calcium-channel blockers. Conclusions Diastolic dysfunction should be considered in the patient presenting with heart failure symptoms but with normal systolic function, particularly in hypertensive patients with left ventricular hypertrophy.

The KL-ONE family

Abstract: The knowledge representation system KL-ONE has been one of the most influential and imitated knowledge representation systems in the Artificial Intelligence community. Begun at Bolt Beranek and Newman in 1978, KL-ONE pioneered the development of taxonomic representations that can automatically classify and assimilate new concepts based on a criterion of terminological subsumption. This theme generated considerab interest in both the formal community and a large community of potential users. The KL-ONE community has since expanded to include many systems at many institutions and in many different countries. This paper introduces the KL-ONE family and discusses some of the main themes explored by KL-ONE and its successors. We give an overview of current research, describe some of the systems that have been developed, and outline some future research directions.

Interleukin-1α and Interleukin-1 β in Preterm and Term Human Parturition

Abstract: Interleukin-1 (IL-1) has been implicated in the mechanism of human parturition in the setting of infection. The purpose of this study was to determine the effect of labor (term and preterm) and microbial invasion of the amniotic cavity on amniotic fluid (AF) concentrations IL-1 alpha and IL-1 beta. AF was retrieved by transabdominal amniocentesis from the following groups of women: midtrimester genetic amniocentesis (16 to 18 wk) (N = 15), preterm labor with intact membranes (21 to 36 wk) with or without infection (N = 72), preterm premature rupture of membranes (PROM) (N = 88), and term not in labor or in active labor with or without infection (N = 58). AF was cultured for aerobic and anaerobic bacteria as well as Mycoplasmas. IL-1 was measured with a commercially available immunoassay validated for AF (sensitivity: IL-1 alpha, 157 pg/ml; IL-1 beta, 50 pg/ml). All women at midtrimester had undetectable AF IL-1 alpha and IL-1 beta. Among women in preterm labor with positive AF cultures, IL-1 alpha and IL-1 beta were detectable in the AF in 86.6% (13/15) and 100% (15/15), respectively. In contrast, all women with negative AF cultures without labor (N = 36) had undetectable AF IL-1 alpha concentrations and 52.7% (19/36) had undetectable AF IL-1 beta concentrations. Histopathological chorioamnionitis was present in 92.8% (13/14) of patients who had positive AF cultures and detectable IL-1 in the AF. IL-1 was significantly higher in patients with preterm PROM, labor, and positive AF cultures than in the other subgroups of patients with preterm PROM.(ABSTRACT TRUNCATED AT 250 WORDS)

Expression of transforming growth factor-beta 1 is increased in human vascular restenosis lesions.

Abstract: Human atheromata obtained in vivo were used to test the hypothesis that transforming growth factor-beta 1 plays a role in the development of vascular restenosis. We analyzed 28 specimens from patients with primary atherosclerotic or restenotic lesions; 26 of these were obtained by directional atherectomy and 2 at the time of coronary bypass surgery. Seven control tissues included operatively excised segments of human internal mammary artery, myocardium, and unused portions of vein graft obtained intraoperatively. From these 35 specimens, 210 sections were examined using in situ hybridization. Measurement of silver grains/nucleus disclosed that expression of transforming growth factor-beta 1 mRNA was highest in restenotic tissues (P < 0.001 vs. primary atherosclerotic tissues) and lowest in nonatherosclerotic (control) tissues. In cultures of human vascular smooth muscle cells grown from explants of internal mammary artery, expression of mRNA for transforming growth factor-beta 1 was significantly greater in subconfluent than in confluent smooth muscle cells (P = 0.05). Transforming growth factor type-beta III receptor was expressed in cell cultures and undetectable in the tissue specimens. Sections taken adjacent to those studied by in situ hybridization were examined by immunohistochemistry using antibodies against transforming growth factor-beta 1 and alpha-actin (as a marker for smooth muscle cells) and disclosed transforming growth factor-beta 1 in smooth muscle cells present in these sections. These findings are consistent with the concept that transforming growth factor-beta 1 plays an important role in modulating repair of vascular injury, including restenosis, after balloon angioplasty.

Mechanism of action of biological antioxidants.

Abstract: More and more diseases have been proposed to have a radical or oxidant involvement. Although in most cases we do not know if this involvement is a cause or a result of the disease process, it is still valuable to learn about those compounds or enzymes that might block, inhibit, or prevent radical-initiated reactions. Therefore, it becomes increasingly important to understand which compounds can function as antioxidants, where they are located in the body, and what their mechanism of action might be. As we increase our knowledge in these areas, we will have a better opportunity to propose interventions that might suppress or even reverse some of the ravages of oxidant-based diseases in humans.

Molecular cloning of cDNAs encoding a guanine-nucleotide-releasing factor for Ras p21

Abstract: The stimulation of a variety of cell surface receptors promotes the accumulation of the active, GTP-bound form of Ras proteins in cells. This is a critical step in signal transduction because inhibition of Ras activation by anti-Ras antibodies or dominant inhibitory Ras mutants blocks many of the effects of these receptors on cellular function. To reach the active GTP-bound state, Ras proteins must first release bound GDP. This rate-limiting step in GTP binding is thought to be catalysed by a guanine-nucleotide-releasing factor (GRF). Here we report the cloning of complementary DNAs from a rat brain library that encode a approximately 140K GRF for Ras p21 (p140Ras-GRF). Its carboxy-terminal region is similar to that of CDC25, a GRF for Saccharomyces cerevisiae RAS. This portion of Ras-GRF accelerated the release of GDP from RasH and RasN p21 in vitro, but not from the related RalA, or CDC42Hs GTP-binding proteins. A region in the amino-terminal end of Ras-GRF is similar to both the human breakpoint cluster protein, Bcr, and the dbl oncogene product, a guanine-nucleotide-releasing factor for CDC42Hs. An understanding of Ras-GRF function will enhance our knowledge of the many signal transduction pathways mediated by Ras proteins.