Showing papers by "Icahn School of Medicine at Mount Sinai published in 1991"

Effect of Oral Milrinone on Mortality in Severe Chronic Heart Failure

Abstract: Background. Milrinone, a phosphodiesterase inhibitor, enhances cardiac contractility by increasing intracellular levels of cyclic AMP, but the long-term effect of this type of positive inotropic agent on the survival of patients with chronic heart failure has not been determined. Methods. We randomly assigned 1088 patients with severe chronic heart failure (New York Heart Association class III or IV) and advanced left ventricular dysfunction to double-blind treatment with 40 mg of oral milrinone daily (561 patients) or placebo (527 patients). In addition, all patients received conventional therapy with digoxin, diuretics, and a converting-enzyme inhibitor throughout the trial. The median period of follow-up was 6.1 months (range, 1 day to 20 months). Results. As compared with placebo, milrinone therapy was associated with a 28 percent increase in mortality from all causes (95 percent confidence interval, 1 to 61 percent; P = 0.038) and a 34 percent increase in cardiovascular mortality (95 percent...

Sex Differences in the Management of Coronary Artery Disease

Abstract: Background. Despite the fact that coronary artery disease is the leading cause of death among women, previous studies have suggested that physicians are less likely to pursue an aggressive approach to coronary artery disease in women than in men. To define this issue further, we compared the care previously received by men and women who were enrolled in a large postinfarction intervention trial. Methods. We assessed the nature and severity of anginal symptoms and the use of antianginal and anti-ischemic interventions before enrollment in the 1842 men and 389 women with left ventricular ejection fractions ≤40 percent after an acute myocardial infarction who were randomized in the Survival and Ventricular Enlargement trial. Results. Before their index infarction, women were as likely as men to have had angina and to have been treated with antianginal drugs. However, despite reports by women of symptoms consistent with greater functional disability from angina, fewer women had undergone cardiac catheterizati...

Detection of Abnormal Memory Decline in Mild Cases of Alzheimer's Disease Using CERAD Neuropsychological Measures

Abstract: • The present study was designed to determine which of the memory tasks included in the CERAD ( C onsortium to E stablish a R egistry for A lzheimer's D isease) neuropsychological battery best differentiate patients with early Alzheimer's disease from cognitively normal elderly control subjects and also best distinguish between the various levels of severity of the dementia process. A sample of CERAD patients with Alzheimer's disease was stratified by disease severity into those with mild, moderate, or severe dementia and matched with control subjects for sex, age, and education. Using multivariate procedures and cutting scores, the efficacy of each memory measure in distinguishing between these groups and control subjects was determined. The test for delayed recall was found to be the best overall discriminatory measure. The other tests of memory, ie, immediate recall, intrusion errors, and recognition memory, had poor overall discriminability. None of the CERAD memory measures were found to be particularly powerful in staging the severity of dementia. These findings suggest that tests for delayed recall may be particularly useful in the early detection of Alzheimer's disease and should be considered in screening batteries for dementia in community surveys.

Fetal fibronectin in cervical and vaginal secretions as a predictor of preterm delivery.

Abstract: Background. Preterm delivery is the leading cause of neonatal mortality in the United States, but efforts to address the problem are hampered by the inability to predict accurately which pregnancies are at risk. We postulated that damage to the fetal membranes may release fetal fibronectin into the cervix and vagina, giving rise to a biochemical marker for preterm delivery. Methods. We measured fetal-fibronectin concentrations in cervical and vaginal secretions, amniotic fluid, and maternal plasma with a sensitive immunoassay using the monoclonal antibody FDC-6. Immunohistochemical studies were used to determine the distribution of fetal fibronectin in the placenta and amniochorionic membranes and to ascertain its cell of origin. Results. Women with uncomplicated pregnancies (n = 163) who delivered at term rarely had cervicovaginal fetal-fibronectin concentrations above 0.05 μg per milliliter between 21 and 37 weeks of gestation (11 of 267 cervical samples [4 percent] and 9 of 267 vaginal samples...

Linkage of Marfan syndrome and a phenotypically related disorder to two different fibrillin genes

Abstract: Marfan syndrome (MFS), one of the most common genetic disorders of connective tissue, is characterized by skeletal, cardiovascular and ocular abnormalities. The incidence of the disease is about 1 in 20,000, with life expectancy severely reduced because of cardiovascular complications. As the underlying defect is unknown, MFS diagnosis is based solely on clinical criteria. Certain phenotypic features of MFS are also shared by other conditions, which may be genetically distinct entities although part of a clinical continuum. Immunohistochemical studies have implicated fibrillin, a major component of elastin-associated microfibrils, in MFS aetiology. Genetic linkage analysis with random probes has independently localized the MFS locus to chromosome 15. Here we report that these two experimental approaches converge with the cloning and mapping of the fibrillin gene to chromosome 15q15-21, and with the establishment of linkage to MFS. We also isolated a second fibrillin gene and mapped it to chromosome 5q23-31. We linked this novel gene to a condition, congenital contractural arachnodactyly, that shares some of the features of MFS. Thus, the cosegregation of two related genes with two related syndromes implies that fibrillin mutations are likely to be responsible for different MFS phenotypes.

A psychobiological perspective on the personality disorders.

Abstract: A preliminary but growing body of evidence supports the existence of genetic and biological substrates of personality, suggesting the utility of a psychobiological perspective on the personality disorders. The investigation of biological correlates of personality disorders can provide an empirical base to explore the relationship between biological predispositions and psychological function. The authors propose a psychobiological model based on dimensions of cognitive/perceptual organization, impulsivity/aggression, affective instability, and anxiety/inhibition. These dimensions span the DSM-III-R axis I and axis II disorders. The authors review phenomenological, genetic, and biological evidence in relation to each of these dimensions. Although such an approach remains heuristic, this model provides a promising vantage point from which to generate investigation of the development and treatment of the personality disorders.

DNA probes: applications of the principles of nucleic acid hybridization.

Abstract: Nucleic acid hybridization with a labeled probe is the only practical way to detect a complementary target sequence in a complex nucleic acid mixture. The first section of this article covers quantitative aspects of nucleic acid hybridization thermodynamics and kinetics. The probes considered are oligonucleotides or polynucleotides, DNA or RNA, single- or double-stranded, and natural or modified, either in the nucleotide bases or in the backbone. The hybridization products are duplexes or triplexes formed with targets in solution or on solid supports. Additional topics include hybridization acceleration and reactions involving branch migration. The second section deals with synthesis or biosynthesis and detection of labeled probes, with a discussion of their sensitivity and specificity limits. Direct labeling is illustrated with radioactive probes. The discussion of indirect labels begins with biotinylated probes as prototypes. Reporter groups considered include radioactive, fluorescent, and chemiluminescent nucleotides, as well as enzymes with colorimetric, fluorescent, and luminescent substrates.

Substituted judgment: how accurate are proxy predictions?

Abstract: Substituted judgment has been proposed as a method of promoting the autonomy of the mentally incapacitated patient, but little is known about the accuracy of surrogate decision makers in reflecting the true wishes of patients. In this study, surrogate decision makers' views (those of primary care providers and close family members) were compared with the decisions of currently competent chronically ill elderly patients, using a hypothetic cardiopulmonary resuscitation scenario under circumstances of current health and progressive dementia. Concordance between patients and their surrogates was evaluated by assessing percent agreement, kappa coefficient (for concordance beyond chance), and directionality of discrepant responses. Most patient respondents chose to be resuscitated in both scenarios. Although patients predicted that both their physicians (90%) and family members (87%) would accurately represent their wishes, neither family members nor physicians, in fact, were able to adequately predict patients' wishes in both scenarios (kappa less than or equal to 0.3 in all scenarios; percent agreement range, 59% to 88%). Few patients had ever discussed their resuscitation preferences with either their family member (16%) or their physician (7%). These results cast doubt on the usefulness of a strict substituted judgment standard as an approach to medical decision making for patients with diminished mental capacity.

Unsuspected osteomyelitis in diabetic foot ulcers. Diagnosis and monitoring by leukocyte scanning with indium in 111 oxyquinoline

Abstract: Objective. —The prevalence of osteomyelitis in diabetic foot ulcers is unknown. Early diagnosis of this infection is critical, as prompt antibiotic treatment decreases the rate of amputation. We therefore assessed the prevalence of osteomyelitis in 35 diabetic patients with 41 foot ulcers. We compared results of roentgenograms, leukocyte scans with indium In 111 oxyquinoline, and bone scans with the diagnostic criterion standards of bone histologic and culture findings. Leukocyte scans were repeated at 2- to 3-week intervals during antibiotic treatment. Design. —Cohort study. Setting. —Institutional and private, ambulatory and hospitalized patients. Patients. —Consecutive sample of 54 diabetic patients. Thirty-five patients with 41 foot ulcers were included. Results. — As determined by bone biopsy and culture, osteomyelitis was found to underlie 28 (68%) of 41 diabetic foot ulcers. Only nine (32%) of the 28 cases were diagnosed clinically by the referring physician. Underscoring the clinically silent nature of osteomyelitis in these ulcers, 19 (68%) of 28 occurred in outpatients, 19 (68%) of 28 occurred in ulcers not exposing bone, and 18 (64%) of 28 had no evidence of inflammation on physical examination. All patients with ulcers that exposed bone had osteomyelitis. Of the imaging tests, the leukocyte scan had the highest sensitivity, 89%. In patients with osteomyelitis, the leukocyte scan image intensity decreased by 16 to 34 days of antibiotic treatment and normalized by 36 to 54 days. Conclusion. —The majority of diabetic foot ulcers have an underlying osteomyelitis that is clinically unsuspected. Leukocyte scans are highly sensitive for diagnosing osteomyelitis in diabetic foot ulcers and may be useful for monitoring the efficacy of antibiotic treatment. We recommend that diabetic patients with foot ulcers that expose bone should be treated for osteomyelitis. Diabetic patients with foot ulcers that do not expose bone should undergo leukocyte scanning, which eliminates the risk of bone biopsy in diagnosing osteomyelitis and allows for the diagnosis and treatment of this well-known but often silent precursor of lower extremity amputation. ( JAMA . 1991;266:1246-1251)

Dispersion and repulsion contributions to the solvation energy: Refinements to a simple computational model in the continuum approximation

Abstract: A computational method for the evaluation of dispersion and repulsion contributions to the solvation energy is here presented in a formulation which makes use of a continuous distribution of the solvent, without introducing additional assumptions (e.g., local isotropy in the solvent distribution). The analysis is addressed to compare the relative importance of the various components of the dispersion energy (n = 6, 8, 10) and of the repulsion term, to compare several molecular indicators (molecular surface and volume, number of electrons) which may be put in relation to the dispersion-repulsion energy, and to define simplified computational strategies. The numerical examples refer to saturated hydrocarbons in water, treated with the homogeneous approximation of the distribution function which for this type of solution appears to be acceptable.

Depression, the Immune System, and Health and Illness: Findings in Search of Meaning

Abstract: During the past several decades many investigators have devoted their efforts to determining whether psychosocial factors, such as stress or depression, are associated with the onset, course, or outcome of physical illness. Considerable evidence suggests that both stressful life events and depressive disorders are associated with increased morbidity and mortality. 1 A large body of research in the last few years has considered the possibility that immunologic alterations may be associated with depressive disorders and depressive symptoms accompanying stressful life events. The related immunologic alterations have been viewed as a link between depression and stress and increased risk for immune-related disease states, such as cancer, autoimmune disorders, and infections, including human immunodeficiency virus (HIV). However, there has been a lack of substantial evidence supporting the association between depression or stress and increased morbidity or mortality due to disorders involving the immune system. In a series of articles recently published in

GEPOL: An improved description of molecular surfaces II. Computing the molecular area and volume

Abstract: The algorithm used by the program GEPOL for a finer description of molecular surface (for a fast calculation of molecular area and volume and for an efficient selection of sampling points) is presented in detail. Different types of surfaces such as van der Waals and Richard's molecular surfaces can be computed. As we described in the first article (J.L. Pascual-Ahuir and E. Silla, J. Comp. Chem., 11, 1047(1990)), GEPOL begins by building a set of spherical surfaces which fill the space which is not solvent accessible. In this second article, a triangular tessellation approach to select the parts of these spherical surfaces which form the molecular surface is described. By using a data coded generic pentakisdodecahedron, each spherical surface is divided in triangular tesserae. A simple method is used to eliminate all triangles found at the intersection volume of the spheres. The center coordinates and the surface of the remaining triangles are used in order to calculate the molecular area and volume and as starting point of the graphic representation of scalar and vector properties. We study the behavior of the method, presenting several examples of application. Special attention is given to the accuracy, spatial invariance and computer efficiency measured by CPU time. Some models of aligned spheres whose area and volume can be found exactly allow us to do a comparative study with a well-known method, analyzing their behavior in line with their respective graining parameters. A fragment of protein is used as an example of the application of the method for characterizing biomolecular surfaces. Aqueous solubility of organic compounds is studied as an example of the experimental property that depends on the molecular area obtaining a good correlation between the logarithm of the solubility and the area calculated using GEPOL.

Dendritic location of neural BC1 RNA.

Abstract: In nerve cells, a specialized protein synthetic machinery is thought to operate in local compartments of dendrites, in particular beneath synaptic junctions, and thereby to facilitate swift adjustments of the postsynaptic protein repertoire in situ. This notion has been supported by the identification of polyribosomes and selected mRNAs in those compartments. In this study, we report the discovery of a specific RNA polymerase III transcript in dendrites. This RNA, a noncoding, 152-nucleotide-long, single-gene transcript known as BC1 RNA, is expressed almost exclusively in the nervous system. In adult rats as well as in immature rats in late developmental stages, BC1 RNA has been located in the dendrites and somata of a subset of neurons in the central and peripheral nervous system. The colocalization of BC1 RNA with dendritic mRNAs and polyribosomes may indicate a role--possibly within the functional unit of a high molecular mass ribonucleoprotein particle--in specific pre- or posttranslational processes in postsynaptic compartments of neurons.

In vivo paracrine interaction between urokinase and its receptor: effect on tumor cell invasion.

Abstract: Numerous studies have linked the production of increased levels of urokinase type plasminogen activator (uPA) with the malignant phenotype. It has also been shown that a specific cell surface receptor can bind uPA through a domain distinct and distant from the proteolytic domain. In an in vivo model of invasion, consisting of experimentally modified chorioallantoic membrane (CAM) of a chick embryo, only cells that concurrently expressed both uPA and a receptor for uPA, and in which the receptor was saturated with uPA, were efficient in invasion. To test whether uPA produced by one cell can, in a paracrine fashion, affect the invasive capacity of a receptor-expressing cell, we transfected LB6 mouse cells with human uPA (LB6[uPA]), or human uPA-receptor cDNA (LB6[uPAR]). LB6(uPA) cells released into the medium 1-2 Ploug units of human uPA per 10(6) cells in 24 h. The LB6(uPAR) cells expressed on their surface approximately 12,000 high affinity (Kd 1.7 x 10(-10) M uPA binding sites per cell. Unlabeled LB6(uPA) and 125-IUdR-labeled LB6(uPAR) cells were coinoculated onto experimentally wounded and resealed CAMs and their invasion was compared to that of homologous mixtures of labeled and unlabeled LB6(uPAR) or LB6(uPA) cells. Concurrent presence of both cell types in the CAMs resulted in a 1.8-fold increase of invasion of the uPA-receptor expressing cells. A four-fold stimulation of invasion was observed when cells were cocultured in vitro, prior to in vivo inoculation. Enhancement of invasion was prevented in both sets of experiments by treatment with specific antihuman uPA antibodies, indicating that uPA was the main mediator of the invasion-enhancing, paracrine effect on the receptor-expressing cells.

Stress-induced proteins in immune response to cancer.

Abstract: Chemically induced tumors of inbred mice elicit immunity in animals in which the tumors are induced and in other animals of the same inbred stock. The immunity is specific for each tumor: even two tumors induced in one animal with the same carcinogen are not cross-reactive. Immunity to cancer has since been observed in the case of sarcomas and carcinomas induced by a number of chemical and physical carcinogens and in several species, including mice, rats, and guinea pigs. The nature of molecules which mediate immunity to tumors is a central question in cancer immunology. A small number of such molecules have been biochemically defined. Of these, some are viral antigens expressed in tumor cells, while the relationship of some others to viral antigens is unclear. A surprising majority of nonviral tumor antigens have turned out to bear homology with stress-induced proteins. Four families of such molecules are discussed: the gp96 (hsp100) and p84/86 (hsp90) antigens of chemically induced mouse sarcomas, hsp70 antigens of tumors obtained by transfection of normal rat fetal fibroblasts with an H-ras oncogene, and the albuminoid antigens of murine melanomas and a rat histiocytoma. (Albumin-like antigens are included among the stress-induced proteins because albumin, though constitutively expressed in adult tissues, is heat shock inducible in fetal liver.) Each of these antigens is a moderately abundant protein, present not only in tumors but also in normal tissues. Administration of each of these antigen preparations from the tumor, but not from normal tissue, renders the animal immune to challenge with live cells of the tumor from which the antigens are prepared. And yet, no structural differences in the antigens have been observed between normal tissues and tumors. It is suggested that these stress-induced proteins may not be tumor antigens per se, but may be carriers of immunogenic moieties such as short peptides. The stress-induced proteins may therefore serve either as antigen-presenting molecules like the MHC-encoded molecules or as accessory molecules in the presentation of antigens by MHC molecules. The ability of stress-induced proteins to bind to a variety of molecules, including peptides, is consistent with this possibility.

Evidence of limited variability of antigen receptors on intrathyroidal T cells in autoimmune thyroid disease.

Abstract: Background. Patients with autoimmune thyroid diseases, including Graves' disease and Hashimoto's disease, have marked lymphocytic infiltration in their thyroid glands. We examined the gene for the variable regions of the α-chain of the human T-cell receptor (the Vα gene) in intrathyroidal T cells to determine whether the infiltration is a secondary heterogeneous immune response or a more restricted, and therefore primary and presumably pathogenetic, reaction to thyroid autoantigens. Methods. We used the polymerase chain reaction to detect small numbers of T cells expressing the variable region of the Vα gene. Different oligonucleotides were used to amplify complementary DNA for the 18 known families of the Vα gene in intrathyroidal T cells from 9 patients with autoimmune thyroid disease. We compared the findings with the results in patients with nonautoimmune thyroid disease as well as those in normal subjects. Results. We found marked restriction in the expression of T-cell–receptor Vα genes by ...

Effect of exercise training on insulin sensitivity and glucose metabolism in lean, obese, and diabetic men.

Abstract: To clarify the impact of vigorous physical training on in vivo insulin action and glucose metabolism independent of the intervening effects of concomitant changes in body weight and composition and...

EGF enhances the survival of dopamine neurons in rat embryonic mesencephalon primary cell culture.

Abstract: Epidermal growth factor (EGF) immunoreactive material has been demonstrated to be present in the basal ganglia. In this study, we investigated the effect of EGF on cells cultured from 16-day embryonic rat mesencephalon, which included dopamine neurons that project to the striatum in vivo. EGF receptors were detected in untreated cultures by [125I]-EGF binding. Treatment of the cultures with EGF resulted in up to 50-fold increases in neuronal high-affinity dopamine uptake. Scatchard analysis of uptake kinetics and counting of tyrosine hydroxylase-immunoreactive cells suggest that the effect of EGF on uptake is due to increased survival and maturation of dopaminergic neurons. By contrast, the high-affinity uptake for serotonin was increased only threefold over its controls. There was no significant effect on high-affinity gamma-aminobutyric acid (GABA) uptake. These results suggest that EGF is acting as a neurotrophic agent preferential for dopaminergic neurons in E16 mesencephalic cultures. Immunocytochemistry for glial fibrillary acidic protein demonstrated an increase in astroglia with EGF treatment. Fluorodeoxyuridine, an agent that is toxic to proliferating cells was able to eliminate the effect of EGF on dopamine uptake, suggesting that EGF may be increasing dopaminergic cell survival largely through a population of dividing cells.

The polyadenylation signal of influenza virus RNA involves a stretch of uridines followed by the RNA duplex of the panhandle structure.

Abstract: Appropriate RNAs are transcribed and amplified and proteins are expressed after transfection into cells of in vitro-reconstituted RNA-protein complexes and infection with influenza virus as the helper. This system permits us to study the signals involved in transcription of influenza virus RNAs. For the analysis we used a plasmid-derived RNA containing the reporter gene for chloramphenicol acetyltransferase (CAT) flanked by the noncoding sequences of the NS RNA segment of influenza A/WSN/33 virus. Mutations were then introduced into both the 5' and 3' ends, and the resulting RNAs were studied to determine their transcription in vitro and their CAT expression activity in the RNA-protein transfection system. The results reveal that a stretch of uninterrupted uridines at the 5' end of the negative-strand RNA is essential for mRNA synthesis. Also, a double-stranded RNA "panhandle" structure generated by the 5'- and 3'-terminal nucleotides appears to be required for polyadenylation, since opening up of these base pairs diminished mRNA synthesis and eliminated expression of CAT activity by the mutant RNAs. Finally, it was shown that this double-stranded RNA structural requirement is not sequence specific, since a synthetic GC clamp can replace the virus-coded RNA duplex. The data suggest that the viral RNA polymerase adds poly(A) by a slippage (stuttering) mechanism which occurs when it hits the double-stranded RNA barrier next to the stretch of uridines.

High-efficiency formation of influenza virus transfectants.

Abstract: cDNA-derived RNAs were introduced into the genomes of influenza viruses by using an improved ribonucleoprotein (RNP) transfection protocol. Up to 10(5) viral transfectants with a novel neuraminidase gene could be obtained by using a 35-mm dish (10(6) cells) for RNP transfection. In addition to genes coding for surface proteins (hemagglutinin and neuraminidase), we also exchanged a gene coding for nonsurface proteins. The cDNA-derived influenza A/PR/8/34 virus NS gene was introduced into a temperature-sensitive mutant with a defect in this gene. We suggest that the term influenza virus transfectant be used for those viruses which are made by RNP transfection with cDNA-derived RNA.