Showing papers by "Icahn School of Medicine at Mount Sinai published in 1993"

An Epidemiological Study of Disorders in Late Childhood and Adolescence—I. Age‐ and Gender‐Specific Prevalence

Abstract: Developmental aspects of psychiatric disorders may be inferred from patterns of age differences in prevalence. Age-specific prevalences are provided for nine disorders in a general population sample of ages 10-20. Age and gender patterns for several disorders suggest developmental stage-associated risks. These include oppositional disorder in both genders and conduct disorder and major depression in girls. Major depression shows a pattern suggestive of a role for the onset of puberty. The prevalence of one or more disorders did not differ by age or gender. However, the pattern of specific diagnoses varied greatly by both age and gender.

Blood levels of organochlorine residues and risk of breast cancer.

Abstract: Background Organochlorines such as DDT [2,2-bis(p-chlorophenyl)-1,1,1-trichloroethane] and PCBs (polychlorinated biphenyls), which have been used extensively as insecticides and as fluid insulators of electrical components, respectively, are known to be persistent environmental contaminants and animal carcinogens. These agents have been found in human tissue due to their inefficient metabolism and their solubility in lipids, which lead to lifelong sequestration in adipose tissue. Their association with human cancer occurrence, however, has been explored only marginally, with most studies having 20 or fewer cases. Purpose This blinded study was designed to determine whether exposure to PCBs and to DDE [1,1-dichloro-2,2-bis(p-chlorophenyl) ethylene], the major metabolite of DDT, is associated with breast cancer risk in women. Methods We analyzed sera from the stored blood specimens of 14,290 participants enrolled between 1985 and 1991 in the New York University Women's Health Study, a prospective cohort study of hormones, diet, and cancer. Cohort members who developed breast cancer were included as case patients in our nested case-control study. DDE and PCBs were measured by gas chromatography in the sera of 58 women with a diagnosis of breast cancer 1-6 months after they entered the cohort and in 171 matched control subjects from the same study population who did not develop cancer. Results Mean levels of DDE and PCBs were higher for breast cancer case patients than for control subjects, but paired differences were statistically significant only for DDE (P = .031). After adjustment for first-degree family history of breast cancer, lifetime lactation, and age at first full-term pregnancy, conditional logistic regression analysis showed a fourfold increase in relative risk of breast cancer for an elevation of serum DDE concentrations from 2.0 ng/mL (10th percentile) to 19.1 ng/mL (90th percentile). For PCBs, the relative risk for a change in serum levels from 3.9 ng/mL (10th percentile) to 10.6 ng/mL (90th percentile) was less than twofold, a nonsignificant association that was further reduced after adjustment for DDE. Conclusion In this population of New York City women, breast cancer was strongly associated with DDE in serum but not with PCBs. Implications These findings suggest that environmental chemical contamination with organochlorine residues may be an important etiologic factor in breast cancer. Given the widespread dissemination of organochlorine insecticides in the environment and the food chain, the implications are far-reaching for public health intervention worldwide.

A novel, erythroid cell-specific murine transcription factor that binds to the CACCC element and is related to the Krüppel family of nuclear proteins.

Abstract: We describe a novel erythroid cell-specific cDNA (EKLF [erythroid Kruppel-like factor]) isolated by enriching for genes expressed in a mouse erythroleukemia cell line but not expressed in a mouse monocyte-macrophage cell line. The complete cDNA sequence is predicted to encode a protein of approximately 38,000 Da that contains a proline-rich amino domain and three TFIIIA-like zinc fingers within the carboxy domain. Additional sequence analyses reveal that the EKLF zinc fingers are most homologous to the Kruppel family of transcription factors and also allow us to predict potential DNA-binding target sites for the EKLF protein. On the basis of this prediction, we show that EKLF is able to bind the sequence CCA CAC CCT, an essential element of the beta-globin promoter. Its tissue distribution establishes that the EKLF transcript is expressed only in bone marrow and spleen, the two hematopoietic organs of the mouse, and analysis of murine cell lines indicates that EKLF expression is limited to erythroid and mast cell lines. Cotransfection assays establish that EKLF transcriptionally activates a target promoter that contains its DNA-binding site. The tissue expression pattern of EKLF, in conjunction with its function as a transcriptional activator, strongly suggests that the EKLF protein may be intimately involved in establishment and/or maintenance of the erythroid cell phenotype.

tinman and bagpipe: two homeo box genes that determine cell fates in the dorsal mesoderm of Drosophila.

Abstract: Whereas the mechanisms of early Drosophila mesoderm formation have been studied in much detail, the subsequent processes determining regional identities within the mesoderm remain largely unknown. Here, we describe two homeo box genes, tinman (tin) and bagpipe (bap), which spatially subdivide the mesoderm and determine cell fates in the dorsal mesoderm. These two genes are components of a cascade of genetic interactions that result in the spatial restriction of tin mRNA to the dorsal mesoderm and in the activation of bap in segmental clusters of cells in this region. A subset of cells from those clusters segregate to form visceral mesoderm that differentiates into gut musculature. This indicates that the visceral mesoderm is derived from metamerically repeated primordia. In embryos mutant for bap, visceral mesoderm formation is strongly disrupted. Most cells of the visceral mesoderm fail to differentiate properly, and a portion of them are transformed into body wall musculature and gonadal mesoderm. In tin mutant embryos, bap expression is not activated in the dorsal mesoderm. Probably as a consequence, neither visceral mesoderm nor midgut musculature are formed in these mutants, and the absence of visceral mesoderm results in strong disruptions of endoderm migration and midgut morphogenesis. In addition to visceral mesoderm development, tin is required for the formation of the heart from dorsal mesoderm and for the specification of founder cells for particular body wall muscles.

Heat shock protein 70-associated peptides elicit specific cancer immunity.

Abstract: Vaccination of mice with heat shock protein 70 (hsp70) preparations derived from the Meth A sarcoma, but not from normal tissues, renders the mice immune to a substantial challenge with Meth A sarcoma. The immunogenicity is dose dependent and tumor specific. Treatment of an antigenically active hsp70 preparation with ATP followed by removal of low-molecular weight material leaves hsp70 intact, as judged by SDS-PAGE but results in loss of antigenicity, as judged by tumor rejection assays. Separation of this low-molecular weight material on a C18 reverse-phase column shows a diverse array of peptides with molecular mass between 1,000 and 5,000 daltons. Our data indicate that antigenicity of hsp70 preparations derives, not from hsp70 per se, but from associated peptides. These observations may suggest a novel method of using the peptide-binding property of hsp70 for specific vaccination against cancer and infectious diseases.

Withdrawal of digoxin from patients with chronic heart failure treated with angiotensin-converting-enzyme inhibitors.

Abstract: Background. Although digoxin is effective in the treatment of patients with chronic heart failure who are receiving diuretic agents, it is not clear whether the drug has a role when patients are receiving angiotensin-converting-enzyme inhibitors, as is often the case in current practice. Methods. We studied 178 patients with New York Heart Association class II or III heart failure and left ventricular ejection fractions of 35 percent or less in normal sinus rhythm who were clinically stable while receiving digoxin, diuretics, and an angiotensin-converting-enzyme inhibitor (captopril or enalapril). The patients were randomly assigned in a double-blind fashion either to continue receiving digoxin (85 patients) or to be switched to placebo (93 patients) for 12 weeks

The Ly-49 and NKR-P1 gene families encoding lectin-like receptors on natural killer cells: the NK gene complex.

Abstract: Natural killer cells lyse tumor and virally infected cells in a specific manner that has not been molecularly characterized. Target cell expression of major histocompatibility complex (MHC) class I molecules is correlated with target cell resistance to natural killing. A mechanism to explain this observation is that NK cells may display two types of recognition and activation molecules that have opposing functions when bound to target cell ligands. One type of surface receptor such as the NKR-P1 molecule may activate NK activity whereas the other, represented by the mouse Ly-49 molecule, may engage target cell MHC molecules and inhibit cytotoxicity by transducing "negative" signals. NKR-P1 and Ly-49 are structurally related, and they are encoded by genetically linked loci in a chromosomal region, termed the NK gene complex (NKC), on distal mouse chromosome 6. Target cell susceptibility to natural killing may be dependent upon specific ligand-receptor interaction with these activating or inhibitory NKC-encoded molecules.

Prevalence and Natural History of Cryptorchidism

Abstract: Objective. A prospective hospital-based cohort study was conducted to determine the prevalence rates of cryptorchidism at birth, 3 months, and 1 year of age. Design. A total of 6935 consecutive male neonates delivered at Mount Sinai Hospital in New York City between October 1987 and October 1990 were examined at birth for cryptorchidism. Standardized examination and classification criteria were used. Infants classified as cryptorchid at birth were reexamined at 3 months and 1 year after the expected date of delivery. Results. Of 6935 neonates assessed at birth, 255(3.7%) were found to be cryptorchid at birth. The rates were significantly elevated for low birth weight, preterm, small-for-gestational age, and twin neonates. The overall rate had declined to 1.0% by the 3-month assessment and 1.1% at the 1-year assessment. Although the rates at the 1-year assessment tended to be higher for low birth weight and preterm infants, no significant group differences were observed. Conclusions. Since the prevalence rates in this study are similar to those reported several decades ago, these data provide no evidence that the rate of cryptorchidism has increased either at birth or by 1 year of age. Furthermore, most testes that descend spontaneously do so within the first 3 months after the expected date of delivery.

Nosocomial outbreak due to Enterococcus faecium highly resistant to vancomycin, penicillin, and gentamicin.

Abstract: In October 1990, Enterococcus faecium that was highly resistant to glycopeptides, penicillins, and aminoglycosides was isolated from the peritoneal dialysis fluid from a patient in an intensive care unit. Over the following 6 months, multiresistant E. faecium organisms were isolated from cultures of blood, urine, or surgical wound specimens from eight additional patients. Surveillance cultures of groin and/or rectal swabs were positive for eight of 37 patients and four of 62 employees at risk. Restriction endonuclease digestion of chromosomal DNA from outbreak isolates was consistent with dissemination of a single strain throughout the intensive care unit. Strict infection control interventions contained the outbreak after several weeks. Review of patient charts suggested that renal insufficiency, length of hospital stay, duration of antibiotic treatment, and prior treatment with vancomycin were risks for infection due to multiresistant E. faecium. The emergence of multiple-drug-resistant enterococci presents serious infection control and therapeutic dilemmas.

Genomic organization of the sequence coding for fibrillin, the defective gene product in Marfan syndrome

Abstract: Marfan syndrome results from mutations in an extracellular matrix glycoprotein, fibrillin. Previous studies have characterized approximately 6.9-kb of the estimated 10-kb fibrillin transcript. We have now completed the primary structure of fibrillin, elucidated the exon/intron organization of the gene and derived a physical map of the genetic locus. Pre-fibrillin consists of 2,871 amino acids which, excluding the signal peptide, are arranged into five structurally distinct regions. The largest of these regions comprises about 75% of the entire protein and consists of numerous repeated cysteine-rich sequences homologous to the peptide motifs of the epidermal growth factor (EGF) and transforming growth factor-beta binding protein (TGF-bp). Forty-three of the forty-six EGF-like repeats contain a calcium binding consensus sequence (EGF-CB) conceivably mediating protein-protein interactions. Fibrillin exhibits a few additional cysteine-rich modules that are apparently unique to this macromolecule and may represent evolutionary variants of the EGF-CB and TGF-bp motifs. Almost all of the cysteine-rich repeats are encoded by single exons; consequently, the fibrillin gene is relatively large (approximately 110-kb) and highly fragmented (65 exons). This study provides the first comprehensive analysis of the fibrillin gene and relevant information for the full characterization of Marfan syndrome mutations.

Evidence for the presence of five distinct proteolytic components in the pituitary multicatalytic proteinase complex. Properties of two components cleaving bonds on the carboxyl side of branched chain and small neutral amino acids.

Abstract: Initial studies on the specificity of the multicatalytic proteinase complex (MPC; EC 3.4.99.46) led to the identification of three distinct proteolytic components designated as trypsin-like, chymotrypsin-like, and peptidylglutamyl-peptide hydrolyzing, all sensitive to inactivation by 3,4-dichloroisocoumarin (DCI), a general serine proteinase inhibitor. The three components cleave the peptidyl-arylamide bonds in the model synthetic substrates, Z-(D)-Ala-Leu-Arg-2-naphthylamide, Z-Gly-Gly-Leu-p-nitroanilide, and Z-Leu-Leu-Glu-2-naphthylamide, respectively. We report here evidence for the presence in the MPC of two additional distinct components, neither of them capable of cleaving the three model substrates. One of these components cleaves the Leu-Gly and the Leu-Ala bonds in the substrates Cbz-Gly-Pro-Ala-Leu-Gly-p-aminobenzoate and Cbz-Gly-Pro-Ala-Leu-Ala-p-aminobenzoate, respectively, and is activated by treatment of the MPC with DCI, N-ethylmaleimide, Mg2+, Ca2+, and low concentrations of sodium dodecyl sulfate and fatty acids. This component is apparently identical with the previously identified DCI-resistant component of the MPC that cleaves preferentially bonds on the carboxyl side of branched chain amino acids in natural peptides including neurotensin and proinsulin [Cardozo, C., Vinitsky, A., Hidalgo, M. C., Michaud, C., & Orlowski, M. (1992) Biochemistry 31, 7373-7380]. It is probably also identical with the component proposed to be the main factor responsible for the caseinolytic activity [Pereira, M. E., Nguyen, T., Wagner, B. J., Margolis, J. W., Yu, B., & Wilk, S. (1992a) J. Biol. Chem. 267, 7949-7955]. The designation "branched chain amino acid preferring" (BrAAP) is proposed for this component. The second component cleaves peptide bonds between the small neutral amino acids Ala-Gly and Gly-Gly in the substrates Cbz-Gly-Pro-Ala-Ala-Gly-p-aminobenzoate and Cbz-Gly-Pro-Ala-Gly-Gly-p-aminobenzoate, respectively. This component is sensitive to inactivation by DCI, N-ethylmaleimide, and organic mercurials, but unlike the BrAAP it is significantly activated neither by Mg2+ or Ca2+ nor by fatty acids or sodium dodecyl sulfate. The designation "small neutral amino acid preferring" (SNAAP) is proposed for this component. Both components are sensitive to inhibition by the peptidyl-aldehydes N-acetyl-Leu-Leu-norleucinal (Ac-LLnL-CHO; calpain inhibitor I) and N-acetyl-Leu-Leu-methioninal (Ac-LLM-CHO; calpain inhibitor II) but are resistant to inhibition by Z-LLF-CHO, a potent inhibitor of the chymotrypsin-like activity.(ABSTRACT TRUNCATED AT 400 WORDS)

Infection, Thyroid Disease, and Autoimmunity

Abstract: The etiology of the AITDs remains unclear but it is now generally believed that both genetic and environmental factors contribute to their development Some recent findings have begun to directly and indirectly implicate the possibility of infectious agents in the pathogenesis of AITD, and these data serve as the basis for this review Classical AITD (ie Graves' disease and Hashimoto's thyroiditis) has been shown to be associated with a variety of infectious agents (eg Yersinia enterocolitica, retroviruses) while infections of the thyroid gland (eg subacute thyroiditis, congenital rubella) have been shown to be associated with thyroid autoimmune phenomena However, the causative role of infectious agents in AITD has not been definitively demonstrated in humans although AITD can be induced in experimental animals by certain viral infections Infectious agents may induce thyroid autoimmunity by a variety of diverse mechanisms, such as inducing modifications of self-antigens, mimicking self-molecules, inducing polyclonal T cell activation (for example by superantigens), altering the idiotypic network, forming immune complexes, and inducing expression of MHC molecules on thyroid epithelial cells While indirect data suggesting involvement of the infecting organisms in the pathogenesis of human AITD is abundant, only a limited number of studies have employed direct approaches Such a direct approach would involve isolation or molecular identification of the potentially infecting organisms from the thyroid gland and the subsequent induction of AITD in an experimental model

Tumor rejection antigen gp96/grp94 is an ATPase: implications for protein folding and antigen presentation.

Abstract: Immunization of mice with gp96/grp94 heat shock proteins (HSPs) elicits tumor-specific cellular immunity to the tumors from which gp96 is isolated. However, the cDNA sequence of gp96 is identical among tumors and normal tissues. This raises the question regarding the structural basis of the specific immunogenicity of gp96. As HSPs bind a wide array of molecules including peptides, we have proposed that gp96 may not be immunogenic per se, but may chaperone antigenic peptides. Furthermore, gp96 is localized predominantly in the lumen of the endoplasmic reticulum (ER) suggesting that it may act as a peptide acceptor and as accessory to peptide loading of MHC class I molecules. We demonstrate here that gp96 molecules contain ATP-binding cassettes, bind ATP and possess an Mg(2+)-dependent ATPase activity. Gp96 preparations are also observed to contain tightly bound peptides, which can be eluted by acid extraction. These properties of gp96 are consistent with its proposed roles in chaperoning antigenic peptides and in facilitating MHC class I--peptide assembly in the ER lumen. We present a model to explain how interaction of gp96 with MHC class I may result in transfer of peptides to the latter.

Molecular and functional diversity of mammalian Gs-stimulated adenylyl cyclases.

Abstract: Receptor-regulated adenylyl cyclase in mammalian systems is among the best-studied of the cell surface signaling pathways that utilize G-proteins as transducers. In addition to the multiplicity of receptors and Gs proteins that function in this pathway, recent studies have shown that substantial molecular diversity exists in the effector as well. Full-length cDNAs encoding six different G-protein-regulated adenylyl cyclases have been isolated, and partial sequences identifying two more are known. These eight mammalian adenylyl cyclases can be grouped into five distinct families. The different types share some common properties such as stimulation by Gs and the diterpene forskolin. They show very distinct patterns of regulation by the beta gamma-subunits of G-proteins and protein kinases such as protein kinase C. The different types also appear to be localized in a tissue-specific manner. This diversity of regulatory features indicates that the effector can play an important role in determining the routing of signals to the cAMP pathway. The tissue and cell type-specific localization of the individual forms suggests that effectors such as adenylyl cyclase could be potential targets for a new generation of cell and tissue-specific drugs.

Priming with recombinant influenza virus followed by administration of recombinant vaccinia virus induces CD8+ T-cell-mediated protective immunity against malaria

Abstract: Live vectors expressing foreign antigens have been used to induce immunity against several pathogens. However, for the virulent rodent malaria parasite Plasmodium yoelii, the use of recombinant vaccinia virus, pseudorabies virus, or Salmonella, expressing the circumsporozoite protein of this parasite, failed to induce protection. We generated a recombinant influenza virus expressing an epitope from the circumsporozoite protein of P. yoelii known to be recognized by CD8+ T cells and demonstrated that this vector induced class I major histocompatibility complex-restricted cytotoxic T cells against this foreign epitope. Immunization of mice with this recombinant influenza virus, followed by a recombinant vaccinia virus expressing the entire circumsporozoite protein, induced protective immunity against sporozoite-induced malaria. The sequence of immunization appears to be crucial, since a primer injection with recombinant vaccinia virus, followed by a booster injection with recombinant influenza virus, failed to induce protection. The protection induced by immunization with these recombinant viruses is mostly mediated by CD8+ T cells, as treatment of mice with anti-CD8 monoclonal antibody abolishes the anti-malarial immunity. The use of different live vectors for primer and booster injections has a synergistic effect on the immune response and might represent an effective general strategy for eliciting protective immune responses to key antigens of microbial pathogens.

Bioactivation of halogenated hydrocarbons by cytochrome P4502E1.

Abstract: Numerous halogenated hydrocarbons of the alkane, alkene, and alkyne classes are metabolized by P450 enzymes to products that elicit cytotoxic and/or carcinogenic effects. Such halogenated hydrocarbons include anesthetics (e.g., halothane and enflurane) and industrial solvents (e.g., carbon tetrachloride, chloroform, and vinylidine chloride). Formation of reaction intermediates from these compounds occurs via P450-promoted dehalogenation, reduction, or reductive oxygenation, with certain hydrocarbons undergoing all three reaction types. Of the multiple forms of P450 present in liver microsomes, P4502E1 has been identified as the primary catalyst of hydrocarbon bioactivation in animals and, most likely, in humans as well. As hepatic concentrations of this P450 enzyme are highly inducible by ethanol and similar agents, prior exposure to 2E1-inducing compounds can play a pivotal role in halogenated hydrocarbon toxicity. Considering that metabolism governs the cytotoxicity and carcinogenicity of halogenated hydrocarbons, an understanding of the mechanism(s) underlying 2E1 induction in man becomes all the more important.

Zidovudine treatment of the AIDS dementia complex: Results of a placebo-controlled trial

Abstract: The efficacy of two doses of zidovudine was examined for the treatment of the acquired immunodeficiency syndrome (AIDS) dementia complex in a randomized, double-blinded, placebo-controlled trial conducted at nine study centers. For the initial 16 weeks, 40 subjects with mild to moderate AIDS dementia complex were randomized to one of three treatment arms: 400 mg of zidovudine five times daily, 200 mg of zidovudine five times daily, or placebo five times daily. After week 16, patients initially randomized to the placebo group were rerandomized to one of the two zidovudine treatment arms. The primary efficacy end point was improvement in performance on a battery of seven neuropsychological tests; the secondary end point was improvement on a protocol neurological evaluation directed at the cardinal features of the AIDS dementia complex. For the initial 16-week period, average z scores based on the neuropsychological test battery revealed a significant improvement in the combined treatment groups compared to the placebo group; however, when the two treatment groups were compared separately to the placebo group, only the group receiving the higher zidovudine dose exhibited significant improvement. After rerandomization of the placebo patients to one of the two treatment arms at week 16, this group also showed significant improvement in the average neuropsychological z score by week 32. These results extend previous observations that indicate a therapeutic benefit of zidovudine for the treatment of AIDS dementia complex.

Toxic and Protective Effects of l‐DOPA on Mesencephalic Cell Cultures

Abstract: The autoxidation of L-DOPA or dopamine (DA) and the metabolism of DA by monoamine oxidase generate a spectrum of toxic species, namely, hydrogen peroxide, oxy radicals, semiquinones, and quinones. When primary dissociated cultures of rat mesencephalon were incubated with L-DOPA (200 microM) for 48 h, the number of tyrosine hydroxylase-positive neurons (DA neurons) was reduced to 69.7% of control values, accompanied by a decrease in [3H]DA uptake to 42.3% of control values; the remaining DA neurons exhibited reduced neurite length and overall deterioration. Lack of simultaneous change in the number of neurons stained with neuron-specific enolase indicated that toxicity was relatively specific for DA neurons. At the same time, the level of GSH, a major cellular antioxidant, rose to 125.2% of control values. Thus, exposure of mesencephalic cultures to L-DOPA results in both damaging and antioxidant actions. Ascorbate (200 microM), an antioxidant, prevented the rise in GSH. The effect of ascorbate on GSH points to an oxidative signal to initiate the rise in GSH content. On the other hand, neither inhibition of monoamine oxidase with pargyline nor addition of superoxide dismutase or catalase to the culture medium prevented the rise in GSH level or the loss in [3H]DA uptake. The latter results tend to exclude the products of monoamine oxidase activity or the presence of hydrogen peroxide or superoxide in the medium as responsible agents for the rise in GSH or neuronal toxicity. In cultures treated with L-buthionine sulfoximine (L-BSO), an inhibitor of GSH synthesis, L-DOPA prevented cell death by L-BSO.