Showing papers by "Icahn School of Medicine at Mount Sinai published in 1983"

Amplified DNA with limited homology to myc cellular oncogene is shared by human neuroblastoma cell lines and a neuroblastoma tumour.

Abstract: Amplified cellular genes in mammalian cells frequently manifest themselves as double minute chromosomes (DMs) and homogeneously staining regions of chromosomes (HSRs). With few exceptions both karyotypic abnormalities appear to be confined to tumour cells. All vertebrates possess a set of cellular genes homologous to the transforming genes of RNA tumour viruses, and there is circumstantial evidence that these cellular oncogenes are involved in tumorigenesis. We have recently shown that DMs and HSRs in cells of the mouse adrenocortical tumour Y1 and an HSR in the human colon carcinoma COLO320 contain amplified copies of the cellular oncogenes c-Ki-ras and c-myc, respectively. Both DMs and HSRs are found with remarkable frequency in cells of human neuroblastomas. We show here that a DNA domain detectable by partial homology to the myc oncogene is amplified up to 140-fold in cell lines derived from different human neuroblastomas and in a neuroblastoma tumour, but not in other tumour cells showing cytological evidence for gene amplification. By in situ hybridization we found that HSRs are the chromosomal sites of the amplified DNA. The frequency with which this amplification appears in cells from neuroblastomas and its apparent specificity raise the possibility that one or more of the genes contained within the amplified domain contribute to tumorigenesis.

Bias in Treatment Assignment in Controlled Clinical Trials

Abstract: Controlled clinical trials of the treatment of acute myocardial infarction offer a unique opportunity for the study of the potential influence on outcome of bias in treatment assignment. A group of 145 papers was divided into those in which the randomization process was blinded (57 papers), those in which it may have been unblinded (45 papers), and those in which the controls were selected by a nonrandom process (43 papers). At least one prognostic variable was maldistributed (P less than 0.05) in 14.0 per cent of the blinded-randomization studies, in 26.7 per cent of the unblinded-randomization studies, and in 58.1 per cent of the nonrandomized studies. Differences in case-fatality rates between treatment and control groups (P less than 0.05) were found in 8.8 per cent of the blinded-randomization studies, 24.4 per cent of the unblinded-randomization studies, and 58.1 per cent of the nonrandomized studies. These data emphasize the importance of keeping those who recruit patients for clinical trials from suspecting which treatment will be assigned to the patient under consideration.

Stress-induced suppression of immunity in adrenalectomized rats.

Abstract: Stress-induced suppression of lymphocyte stimulation by phytohemagglutinin was demonstrated in Isolated lymphocytes and in cultures of whole blood from adrenalectomized rats. The results demonstrate that corticosteroid independent mechanisms participate in the suppression of lymphocyte function by stressors. Stress-induced lymphopenia, however, was found to be adrenal dependent, indicating that the modulation of immunity by stress is complex and multidetermined.

Depressed hepatic glutathione and increased diene conjugates in alcoholic liver disease. Evidence of lipid peroxidation.

Abstract: The role of lipid peroxidation in the pathogenesis of alcoholic liver disease has been a subject of controversy. In order to study this question we measured hepatic glutathione and diene conjugates in liver biopsies from 16 alcoholics with different stages of liver injury and 8 nonalcoholics with liver disease. Patients with alcoholic liver disease were found to have decreased hepatic glutathione compared to patients with liver disease unrelated to alcohol (22.1 +/- 2.5 vs 33.5 +/- 4.6 nmol/mg protein, P less than 0.05). The decrease in glutathione was accompanied by an increase in diene conjugates in hepatic lipids (3.37 +/- 0.14 vs 2.26 +/- 0.21 OD at 232 nm/mg lipid, P less than 0.001). The changes were present in all stages of alcoholic liver damage including fatty liver but unrelated to nutritional status in these patients. They support the concept that lipid peroxidation may be an important mechanism in the pathogenesis of alcoholic liver disease.

Role of the flocculus and paraflocculus in optokinetic nystagmus and visual-vestibular interactions: Effects of lesions

Abstract: Optokinetic nystagmus (OKN), optokinetic after-nystagmus (OKAN), vestibular nystagmus and visual-vestibular interactions were studied in monkeys after surgical ablation of the flocculus and paraflocculus. After bilateral flocculectomy the initial rapid rise in slow phase eye velocity of horizontal and vertical OKN was severely attenuated, and maximum velocities fell to the preoperative saturation level of OKAN. There is generally little or no upward OKAN in the normal monkey, and upward OKN was lost after bilateral lesions. Unilateral flocculectomy affected the rapid rise in horizontal velocity to both sides. Consistent with the absence of a rapid response to steps of surround velocity, animals were unable to follow acceleration of the visual field with eye accelerations faster than about 3-5 degrees/s2. The slow rise in OKN slow phase velocity to a steady state level was prolonged after operation. However, rates of rise were approximately equal for the same initial retinal slips before and after operation. The similarity in the time course of OKN when adjusted for initial retinal slip, and in the gain, saturation level and time course of OKAN before and after flocculectomy indicates that the lesions had not significantly altered the coupling of the visual system to the velocity storage integrator or its associated time constant. When animals were rotated in a subject-stationary visual surround after flocculectomy, they could not suppress the initial jump in eye velocity at the onset of the step. Despite this, they could readily suppress the subsequent nystagmus. The time constant of decline in the conflict situations was almost as short as in the normal monkey and was in the range of the peripheral vestibular time constant. This suggests that although the animals were unable to suppress rapid changes in eye velocity due to activation of direct vestibulo-oculomotor pathways, they had retained their ability to discharge activity from the velocity storage mechanism. Consistent with this, animals had no difficulty in suppressing OKAN after flocculectomy. Visual-vestibular interactions utilizing the velocity storage mechanism were normal after flocculectomy, as was nystagmus induced by rotation about a vertical axis or about axes tilted from the vertical. Also unaffected were the discharge of nystagmus caused by tilting the head out of the plane of the response and visual suppression of nystagmus induced by off-vertical axis rotation. The flocculus does not appear to play an important role in mediating these responses. The data before and after flocculectomy were simulated by a model which is homeomorphic to that presented previously.(ABSTRACT TRUNCATED AT 400 WORDS)

A soluble metalloendopeptidase from rat brain

Abstract: A metalloendopeptidase, optimally active at a neutral pH, was purified from the soluble fraction of brain homogenates. The enzyme (molecular weight about 67000) is strongly inhibited by metal chelators such as EDTA and o-phenanthroline. An EDTA-treated enzyme can be reactivated by several divalent metal ions including Zn2+, Co2+, and Mn2+. The specificity and kinetic parameters of the enzyme were studied with a series of model synthetic substrates. The enzyme preferentially cleaves peptide bonds in which the carbonyl group is contributed by an aromatic amino acid residue in the P1 position. The lowest Km values and the highest Kcat/Km ratios were obtained with substrates having aromatic residues in the P′3 and P1 position or in the P′3 and both the P1 and P2 positions. Lower Kcat/Km ratios were obtained with substrates having arginine residues in position P1, and even lower values with those substrates having a glycine or aspartyl residue in this position. Introduction of a D-amino acid residue in either position P1 or P′1 renders the substrate totally resistant to hydrolysis. The specificity studies suggest that the active site of the metalloendopeptidase can accomodate at least five amino acid residues, with two of those residues binding on the N-terminal side and three binding on the C-terminal side of the hydrolyzed bond. Several biologically active peptides are cleaved by the enzyme at sites consistent with the specificity deduced from studies with model synthetic substrates.

Identification of three major synovial lining cell populations by monoclonal antibodies directed to Ia antigens and antigens associated with monocytes/macrophages and fibroblasts.

Abstract: Synovial lining cells obtained from patients with rheumatoid arthritis or non-inflammatory joint diseases were divisible into three populations according to the expression of surface antigens detected by various monoclonal antibodies. A population of cells designated type I was defined by the presence of Ia antigens. Fc receptors, five different monocyte lineage differentiation antigens, and the property of phagocytosis. The greatly increased amounts of both Ia antigens and certain monocyte lineage antigens distinguished these cells from blood monocytes. A second distinctive cell population was non-phagocytic, occasionally binucleate, and had abundant Ia antigens but lacked IgG Fc receptors, monocyte lineage antigens, B or T lymphocyte antigens, and fibroblast-associated antigens detected by reagents raised against synovial cells. This population, designated type II, accounted for approximately one-third of the synovial cells in patients with rheumatoid arthritis but few or no cells in the synovial lining of patients with non-inflammatory diseases. The Ia-positive synovial cells with a dendritic morphology were contained in this population. An additional population, designated type III, contained nearly all of the remaining cells and was defined by the presence of antigens expressed primarily on fibroblasts and by the absence of phagocytosis, demonstrable Ia antigens, and four antigens of the monocyte lineage. This population exhibited proliferative capacity, becoming the predominant cell in long-term cultures. The proportions of each population varied considerably from patient to patient.

Stages of drug abuse in adolescence: Personality, peer, and family correlates.

Abstract: This article presents several models for exploring the interrelationship of sets of personality, peer, and family factors and ordered stages of drug use. Black (n = 403) and white (n = 529) first- and second-year high school students served as subjects. Results of the study indicate the following: (a) domains of personality, peer, and family are of importance in differentiati ng among the stages of drug use; (b) drug use by family and peers interacts with the socialization techniques of family and peers and with the personality attributes of the adolescents; (c) family and peer positive and negative reinforcement are differentially effective, depending on the adolescents' personality attributes. In addition, the data supported an independent model; that is, each of the three domains (personality, peer, and family) is associated with the adolescent's stage of drug use independent of the latter's relationship with the remaining two domains. An independent model also obtained in the following comparisons between successive stages: nonusers versus legal users, legal users versus marijuana users, and marijuana users versus other illicit drug users. A growing body of literature dealing with adolescents demonstrates the importance of domains of personality, peer, and family factors and their relation to adolescents' use of tobacco, alcohol, marijuana, and other illicit drugs (Brook, G9rdon, & Brook, 1980; Brook, Lukoff, & Whiteman, 1978; Brook, Whiteman, & Gordon, 1981a, 1981b; Huba, Wingard, & Bentler^ 1979; Jessor, Chase, & Donovan, 1980; for reviews see Jessor, 1979; Kandel, 1980; Lettieri, 1975; Lettieri, Sayers, & Pearson, 1980), A second theme in recent research in drug use has been the study of what Kandel calls stages of drug use. Kandel (1975) has proposed a model of drug use that includes the following stages: nonuse; use of legal drugs (i.e., tobacco and/or alcohol); use of marijuana; and use of illicit drugs other

Physiopathology of Cushing's Disease

Abstract: HARVEY CUSHING first described a patient with the disease bearing his name in 1912 (1). The patient manifested rapidly acquired central obesity, hypertrichosis, amenorrhea, and muscle weakness; on physical examination, “her round face was dusky and cyanoid,” supraclavicular and posterior cervical fat pads were present, and it was also noted that the skin was rough and dry, with considerable pigmentation, and with numerous ecchymoses and purplish striae. At that time, Cushing was uncertain as to whether the symptoms were attributable to pituitary “or adrenal, pineal, or ovarian influences,” involvement of these regions having previously been reported in association with similar clinical findings. There was apparently an even earlier report of a similar clinical syndrome by Osier in 1899 (2), which was described, however, as “An acute myxoedematous condition, with tachycardia, glycosuria, melaena, mania, and death” (the latter occurring within 6 months of onset). Between 1923 and 1926, in addition to other ...

Severe Acquired Immune Deficiency Syndrome in Male Homosexuals: Diminished Capacity to Make Interferon-a in Vitro Associated with Severe Opportunistic Infections

Abstract: Natural killer cell function, directed against either K562 tumor targets or herpes simplex virus type 1-infected fibroblasts, was often low in patients with acquired immune deficiency syndrome (AIDS) but failed to distinguish these patients from either male homosexual controls or patients with lymphadenopathy. Mononuclear cells from patients with AIDS and opportunistic infections generated diminished levels of interferon-a in response to herpes simplex virus type 1-infected fibroblasts. This deficiency discriminated patients with severe opportunistic infections from most individuals with either generalized lymphadenopathy or Kaposi's sarcoma only and from male homosexual control subjects. The deficiency in interferon-a generation may be the consequence of the opportunistic infections that these individuals have contracted or may be a direct manifestation of AIDS itself. Our studies of five homosexual men with ulcera

Isovolumetric sphering of erythrocytes for more accurate and precise cell volume measurement by flow cytometry.

Abstract: Typical mammalian erythrocytes are biconcave disks. Flow cytometric light-scattering measurements of red cell volume show large, orientation-dependent variations in signal size. To eliminate errors caused by shape factors, we sphere erythrocytes isovolumetrically on an Auto-Analyzer manifold (Technicon Instruments Corp., Tarrytown, N. Y.) using a carefully controlled ratio of concentrations of a salt of long chain sulfated fatty alcohol (e.g.), sodium dodecyl sulfate (SDS) to albumin in neutrally buffered isotonic saline, producing a suspension with at least 2 1/2 hours of stability with respect to cell volume, cell count and retention of hemoglobin. A two-step manifold modification of this procedure is preferred. It uses the endogeneous serum protein and a first SDS-saline reagent without added albumin at a low dilution, and further dilution with a second SDS-saline containing a very low concentration of glutaraldehyde. This bypasses a serious shelf life problem with the albumin-SDS reagent. Microhematocrit and Coulter electronic impedance measurements were correlated with light-scattering measurements on our own flow cytometer system of unsphered, sphered, and sphered and fixed samples. These reveal marked superiority over unsphered samples (e.g., reduced coefficients of variation of cell volume and improved correlation with microhematocrit) of the sphered and of the sphered and lightly fixed cells. The resulting tighter unimodal cell volume distributions also provide the following advantages: (1) The separation of signals of large platelets from that of the smallest red cells is substantially increased permitting better resolution of microcytic red cells in some abnormal bloods, and (2) bimodality of red cell volume distribution in abnormal bloods is more easily resolved.

Occupationally derived chemicals in breast milk

Abstract: Exogenously derived chemicals have been widely reported in breast milk. Chemicals typically found in occupational exposures, including trace metals, solvents, and halogenated hydrocarbons, are reviewed, in terms of milk partition factors, potential infant exposures, and possible infant health effects. In addition to ingestion of a chemical from breast milk, an infant incurs a neonatal body burden of a chemical due to transplacental migration from maternal blood. For trace metals, neonatal blood levels are similar to maternal blood levels. Partition of metals to milk is less efficient, but nevertheless can contribute significantly to an infant's body burden. For lipid-soluble pesticide residues and halogenated biphenyls, neonatal body burden is much less than that of the mother, but transfer to milk is efficient, due to the high proportion of milk fat. It is suggested that potential organic mercury toxicity can be estimated from concentration in maternal blood or milk. For other chemicals, available data are not sufficient to evaluate short- or long-term health effects. However, for many halogenated hydrocarbons, concentrations in normal human milk would permit infant exposure above guidelines for allowable daily intake set by the World Health organization.

Inhibition of Amino Acid Transport by cis-Diamminedichloroplatinum(II) Derivatives in L1210 Murine Leukemia Cells

Abstract: The uptake of cis-diamminedichloroplatinum(II) (cisplatin) has been studied in the L1210 murine lymphoid leukemia cell line. Labeled cisplatin and its aquated derivatives were resolved by high-performance liquid chromatography on a strong cationic exchange column. After 10 min of incubation of cisplatin with the cells, the major portion of the non-protein-bound platinum was in the form of cisplatin. However, a portion of this platinum was converted with time to a derivative which coeluted with the monoaquo derivative of cisplatin. With the appearance of this derivative, there was a concomitant inhibition of sodium-dependent amino acid transport as measured by the uptake of aminoisobutyric acid and methionine. Furthermore, the exposure of L1210 cells to a preparation of predominantly aquated product(s) of cisplatin inhibited amino acid uptake following a brief (2-min) incubation, whereas measurable inhibition of amino acid uptake by cisplatin required a longer preincubation period. This inhibition of aminoisobutyric acid and methionine was dependent on the concentration of platinum. Aminoisobutyric acid and methionine were shown to be concentrated in L1210 cells in the presence of sodium ions, and competition experiments suggest similar uptake systems. Since L1210 cells are methionine-auxotrophic leukemic cells, inhibition of essential amino acid transport by cisplatin may be a mechanism of cytotoxic action.

Combined Lipase Deficiency (cld): A Lethal Mutation on Chromosome 17 of the Mouse

Abstract: Two triglyceride lipases, lipoprotein lipase and hepatic triglyceride lipase, participate in the metabolism of plasma lipoproteins. A single recessive mutation, cld, on mouse chromosome 17 causes an apparent deficiency of both lipoprotein lipase and hepatic triglyceride lipase activities. Mice homozygous for this defect develop lethal hyperchylomicronemia within 2 days postpartum as a consequence of nursing. Plasma triglyceride values in affected mice often reach 20,000 milligrams per deciliter (100 times higher than that in normal littermates), and total lipase activity in plasma or tissues is 5 to 20 percent of that in controls.

Anatomical mapping of epidermal Langerhans cell densities in adults

Abstract: The densities of T6 antigen-bearing Langerhans cells in 112 biopsies of human skin from sixteen surgical out-patients and four cadavers were determined for eight anatomical regions. The regional mean densities (+/- s.e.m.) of epidermal Langerhans cells per mm2 were: head and neck, 489 +/- 27; chest, 466 +/- 22; back, 466 +/- 11; upper extremities, 458 +/- 25; lower extremities, 431 +/- 30; buttocks, 411 +/- 11; genitalia, 298 +/- 45; soles, 58 +/- 12. No statistically significant differences were found between any of these Langerhans cell densities except for that of the soles which was lower than those of all other regions (P less than 0.002). No significant differences were detected between the mean densities of patients and cadavers, Caucasians and Hispanics or males and females.

Electromagnetic fields induced by Helmholtz aiding coils inside saline-filled boundaries.

Abstract: The use of Helmholtz aiding coils to induce small electromagnetic (EM) fields in living tissue for both medical and research purposes has become quite common. While much progress has been made in showing that these induced EM signals can cause a variety of effects in tissues and individual cells, a satisfactory explanation of how the effects occur or how the EM signals couple to the tissue has not yet emerged. To address the latter problem adequately, it becomes necessary to know the spatial distribution of the induced fields inside a given set of boundaries. This paper examines the situation used for much in vitro research where a cylindrical culture dish is filled with a conducting solution and placed between the Helmholtz coils. Two cases are considered. The first assumes that the coils are above and below the culture dish (the planes of the coils are parallel with the top and bottom of the dish); the second assumes that the planes of the coils are parallel with the sides of the dish. A closed form solution is obtained for both cases, and it is shown that the induced EM field distribution is markedly different for the two cases.

The ultrastructural localization of serotonin immunoreactivity in myelinated and unmyelinated axons within the medial forebrain bundle of rat and monkey.

Abstract: Myelinated and unmyelinated serotonin-containing axons were demonstrated in the medial forebrain bundle of rats and monkeys with an antibody against serotonin (5-HT) conjugated to hemocyanin. The level of 5-HT in the brain was increased by pretreatment of animals with pargyline and L-tryptophan. The addition of nickel salts to the diaminobenzidine-peroxidase reaction mixture increased the intensity of the reaction product. Specific 5-HT immunoreactivity was observed to be localized to membrane-enclosed and membrane-attached compartments. 5-HT immunoreactivity was seen predominantly in unmyelinated axons (0.2 to 1.25 micron in diameter) surrounded by unlabeled processes. More than half of these 5-HT-immunoreactive fibers were in apposition with unreactive myelinated axons in the hypothalamus of both the rat (55%) and the monkey (54%). These appositions may provide the anatomical substrate for the observations that sprouting serotonergic fibers in the adult brain use myelinated axons for contact guidance. In addition to the unmyelinated fibers, intensely labeled myelinated axons (1.0 to 2.1 micron) were seen in the medial forebrain bundle of both rats and monkeys. The percentage of 5-HT-immunoreactive myelinated axons appeared greater in the monkey than in the rat (25.4% versus 0.7% of the total number of 5-HT-immunoreactive fibers, respectively). the observation of an increased number of myelinated 5-HT-immunoreactive axons in the monkey hypothalamus as compared to the rat supports the general hypothesis of a trend toward increased myelination during evolution.

Indications for left ventricular aneurysmectomy.

Abstract: MORE THAN 25 years ago, C.P. Bailey performed the first successful left ventricular aneurysmectomy in a human being.' Since then, with cardiopulmonary bypass and improved surgical techniques, aneurysmectomy has become an established procedure available to patients with ventricular aneurysms and severe symptoms. In this paper we review the available literature concerned with elective left ventricular aneurysmectomy in the setting of chronic ischemic heart disease. We compare theoretical models and predictions with the empirical observations made by previous investigators and suggest an approach to the symptomatic patient with a left ventricular aneurysm.

Cocaine-induced rotation: sex-dependent differences between left- and right-sided rats.

Abstract: Cocaine elicited dose-related rotation (circling) in naive rats. The maximum effect was greater than observed previously with other drugs. Overall, females were more sensitive to cocaine than males. However, right-biased females were more sensitive than left-biased females, whereas left-biased males were more sensitive than right-biased males. The results suggest that sex-dependent differences in brain asymmetry may be an important determinant of cocaine sensitivity.

Improvement of muscle function in acid maltase deficiency by high‐protein therapy

Abstract: Progressive muscle weakness in acid maltase deficiency (AMD) is associated with intralysosomal accumulation of glycogen and altered myofibrillar morphology. A rapid fall in circulating branched chain amino acids after protein ingestion in a child with AMD suggested that increased net muscle protein catabolism may play a part in the pathogenesis of this condition. To reduce this muscle catabolism, the patient was treated with a high-protein diet for 12 months. This has reversed the weakness and wasting, with improvement in muscle function, exercise tolerance, and growth.