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Global Cns Gene Transfer For A Childhood Neurogenetic Enzyme Deficiency: Canavan Disease., Paola Leone, Christopher G Janson, Scott J Mcphee, Matthew J During

Department of Neurosurgery Faculty Papers

The neurogenetic prototypic disease on which we chose to test our gene therapy strategy is Canavan disease (CD). CD is an autosomal recessive leukodystrophy associated with spongiform degeneration of the brain. At present the disease is uniformly fatal in affected probands. CD is characterized by mutations in the aspartoacylase (ASPA) gene, resulting in loss of enzyme activity. In this review, recent evidence is summarized on the etiology and possible treatments for CD. In particular, we discuss two gene delivery systems representing recent advances in both viral and liposome technology: a novel cationic liposome-polymer-DNA (LPD) complex, DCChol/DOPE-protamine, as well as recombinant …

Radiculopathy And Myelopathy At Segments Adjacent To The Site Of A Previous Anterior Cervical Arthrodesis., Alan S. Hilibrand, Gregory D. Carlson, M A Palumbo, P K Jones, H H Bohlman

Rothman Institute Papers

BACKGROUND: We studied the incidence, prevalence, and radiographic progression of symptomatic adjacent-segment disease, which we defined as the development of new radiculopathy or myelopathy referable to a motion segment adjacent to the site of a previous anterior arthrodesis of the cervical spine.

METHODS: A consecutive series of 374 patients who had a total of 409 anterior cervical arthrodeses for the treatment of cervical spondylosis with radiculopathy or myelopathy, or both, were followed for a maximum of twenty-one years after the operation. The annual incidence of symptomatic adjacent-segment disease was defined as the percentage of patients who had been disease-free at …

The Effects Of Free Fatty Acids On Gluconeogenesis And Glycogenolysis In Normal Subjects, X Chen, N Iqbal, G Boden

Rowan-Virtua School of Osteopathic Medicine Departmental Research

We have quantitatively determined gluconeogenesis (GNG) from all precursors, using a novel method employing 2H20 to address the question of whether changes in plasma free fatty acids (FFA) affect GNG in healthy, nonobese subjects. In the first study (n = 6), plasma FFA were lowered at 16 to 20 hours with nicotinic acid (NA) and were then allowed to rise at 20 to 24 hours (FFA rebound after administration of NA). FFA decreased from 387 microM at 16 hours to 43 microM at 20 hours, and then rebounded to 1,823 microM at 24 hours. GNG decreased from 58.1% at 16 …

Aneuploidy Frequencies In Semen Fractions From Ten Oligoasthenoteratozoospermic Patients Donating Sperm For Intracytoplasmic Sperm Injection, Jerome Pfeffer, Myung-Geol Pang, Stanton F. Hoegerman, Christopher J. Osgood, M. W. Stacey, Jacob Mayer, Sergio Oehninger, William G. Kearns

Biological Sciences Faculty Publications

Objective: To determine aneuploidy frequencies in pellet and swim-up semen fractions from 10 infertile men with severe oligoasthenoteratozoospermia (OAT) who were donating sperm for intracytoplasmic sperm injection and to determine whether the swim-up isolation method would successfully separate aneuploid from haploid sperm.

Design: Prospective study.

Setting: Infertility clinic and molecular genetics laboratory.

Patient(s): Ten patients with severe OAT.

Intervention(s): Cytogenetic analyses by fluorescence in situ hybridization to determine aneuploidy frequencies for chromosomes 1, 13, 18, 21, X, and Y in sperm from swim-up and pellet fractions.

Main Outcome Measure(s): Gametic aneuploidy was scored in sperm fractions separated by the swim-up …

Isolation Of Lautropia Mirabilis From Oral Cavities Of Human Immunodeficiency Virus-Infected Children, S. N. Rossmann, P. H. Wilson, J. Hicks, B. Carter, S. G. Cron, C. Simon, C. M. Flaitz, G. J. Demmler, W. T. Shearer, M. W. Kline

Faculty, Staff and Student Publications

Lautropia mirabilis, a pleomorphic, motile, gram-negative coccus, has been isolated from the oral cavities of 32 of 60 (53.3%) children infected with human immunodeficiency virus (HIV) and 3 of 25 (12.0%) HIV-uninfected controls; the association of L. mirabilis isolation with HIV infection is significant (P < 0.001). All children in the study, both HIV-infected children and controls, were born to HIV-infected mothers. The presence of this bacterium was not associated with clinical disease in these children. The HIV-infected children with L. mirabilis did not differ from the HIV-infected children without L. mirabilis in immunological status, clinical status, or systemic medications. The role of HIV infection itself or concomitant factors in the establishment of L. mirabilis in the oral cavity remains to be elucidated.

The Baculovirus Anti-Apoptotic P35 Protein Promotes Transformation Of Mouse Embryo Fibroblasts., M Resnicoff, B. Valentinis, D. Herbert, D. Abraham, P D. Friesen, E. S. Alnemri, R Baserga

Department of Microbiology and Immunology Faculty Papers

The baculovirus p35 protein is a potent inhibitor of programmed cell death induced by a variety of stimuli in insects, nematodes, and mammalian cell lines. The broad ability of p35 in preventing apoptosis has led us to investigate its effect on mouse embryo fibroblasts in vitro and in vivo. For this purpose, we have used R- cells (3T3-like fibroblasts derived from mouse embryos with a targeted disruption of the insulin-like growth factor I receptor (IGF-IR) genes) and R508 cells (derived from R- and with 15 x 10(3) IGF-IRs per cell). Both cell lines grow normally in monolayer, but they do …

Antisense Inhibition Of Silica-Induced Tumor Necrosis Factor In Alveolar Macrophages, Yon Rojanasakul, David N. Weissman, Xianglin Shi, Vincent Castranova, Joseph K. H. Ma, Weiwen Liang

Faculty & Staff Scholarship

No abstract provided.

Computed Tomography In Staging Of Patients With Melanoma Metastatic To The Regional Nodes., T M Johnson, D J Fader, A E Chang, Alan M. Yahanda Md, Facs, J W Smith, K R Hamlet, V K Sondak

PCI Publications and Projects

BACKGROUND: This study addresses the yield and clinical impact of computed tomography (CT) imaging in otherwise asymptomatic patients with stage III melanoma metastatic to the regional nodes.

METHODS: The database from the University of Michigan Mutlidisciplinary Melanoma Clinic was reviewed and identified 127 asymptomatic patients with stage III melanoma (regional nodal disease) who received CT scans of the head, chest, abdomen, and/or pelvis. Scans were confirmed as true positive, false positive, and normal.

RESULTS: Four hundred twenty-six head and body CT scans were performed at the time of presentation of stage III disease. Twenty patients had a true-positive CT scan …

Scanning Electron Microscopy Of The Accessory Sex Glands Of The Adult Male Rat, R. Wahlqvist, E. Dahl, K. J. Tveter

Scanning Microscopy

This study describes the morphology of the accessory sex glands of the adult male rat as observed by scanning electron microscopy (SEM). The purpose was to obtain a systematic and comparative SEM description of these glands and to evaluate different preparation techniques. A common morphological feature is polyhedral delineation of the cells, which exhibited a variable convexity of their apical surface. The cell apices were more or less studded with microvilli. Nevertheless, it was possible to distinguish the glands by their surface morphology. In the ventral prostate, there was a considerable heterogeneity in cell surface appearance. The lateral lobe bad …

Pancreatic Expression Of Interleukin-4 Abrogates Insulitis And Autoimmune Diabetes In Nonobese Diabetic (Nod) Mice., Regula Mueller, Troy Krahl, Nora Sarvetnick

Journal Articles: Regenerative Medicine

Diabetes in nonobese diabetic (NOD) mice is a T cell-dependent autoimmune disease. The destructive activities of autoreactive T cells have been shown to be tightly regulated by effector molecules. In particular, T helper (Th) 1 cytokines have been linked to diabetes pathogenesis, whereas Th2 cytokines and the cells that release them have been postulated to be protective from disease. To test this hypothesis, we generated transgenic NOD mice that express interleukin (IL) 4 in their pancreatic beta cells under the control of the human insulin promoter. We found that transgenic NOD-IL-4 mice, both females and males, were completely protected from …

Cloning Of The Mammalian Type Ii Iodothyronine Deiodinase. A Selenoprotein Differentially Expressed And Regulated In Human And Rat Brain And Other Tissues., Walburga Croteau, Jennifer C. Davey, Valerie Anne Galton, Donald L. St Germain

Dartmouth Scholarship

The deiodination of thyroid hormones in extrathyroidal tissues plays an important role in modulating thyroid hormone action. The type II deiodinase (DII) converts thyroxine to the active hormone 3,5,3'-triiodothyronine, and in the rat is expressed in the brain, pituitary gland, and brown adipose tissue (BAT). Complementary DNAs (cDNAs) for the types I and III deiodinases (DI and DIII, respectively) have been isolated and shown to code for selenoproteins. However, information concerning the structure of the mammalian DII remains limited, and the pattern of its expression in human tissues is undefined. We report herein the identification and characterization of rat and …

Il-10 Is Necessary And Sufficient For Autoimmune Diabetes In Conjunction With Nod Mhc Homozygosity., Myung-Shik Lee, Regula Mueller, Linda S. Wicker, Laurence B. Peterson, Nora Sarvetnick

Journal Articles: Regenerative Medicine

Contrary to expectations based on in vitro experiments, we previously found that pancreatic IL-10 did not inhibit autoimmune diabetes but accelerated it in an MHC-dependent manner. Therefore, the ability of IL-10 to overcome the absence of all non-MHC diabetes susceptibility (Idd) alleles was studied in transgenic mice expressing pancreatic IL-10 backcrossed to B10.H2g7 congenic mice, which have no Idd alleles other than NOD MHC (H2g7). IL-10 transgenic backcross 1 (BC1) mice with H2g7/g7 haplotype developed clear-cut insulitis and diabetes, but neither transgenic mice with the H2g/b haplotype nor nontransgenic BC1 mice did so. Further implicating IL-10 in autoimmune diabetes, anti-IL-10 …

A Polymorphism Of A Platelet Glycoprotein Receptor As An Inherited Risk Factor For Coronary Thrombosis., Ethan J. Weiss, Paul F. Bray, Matthew Tayback, Steven P. Schulman, Thomas S. Kickler, Lewis C. Becker, James L. Weiss, Gary Gerstenblith, Pascal J. Goldschmidt-Clermont

Cardeza Foundation for Hematologic Research

BACKGROUND: Platelet glycoprotein IIb/IIIa is a membrane receptor for fibrinogen and von Willebrand factor, and it has an important role in platelet aggregation. It is known to be involved in the pathogenesis of acute coronary syndromes. Previously, we found a high frequency of a particular polymorphism, PlA2, of the gene encoding glycoprotein IIIa in kindreds with a high prevalence of premature myocardial infarction.

METHODS: To investigate the relation between the PlA2 polymorphism and acute coronary syndromes, we conducted a case-control study of 71 case patients with myocardial infarction or unstable angina and 68 inpatient controls without known heart disease. The …

Feminism For Men: Legal Ideology And The Construction Of Maleness, Nancy Levit

Faculty Works

It may seem a little odd to suggest that feminist theory has overlooked men. Yet, in several important respects, apart from the role of culprit, men have been largely omitted from feminism. Feminist legal theorists have paid mild attention to the "Can men be feminists?" question but this issue is usually relegated to footnotes. The negative effect gender role stereotypes have on men is typically subsidiary to the main focus of feminist legal literature, which has concentrated on documenting the patterns of subordination of women and on questions of feminist ideology.

The primary purpose of this article is to suggest …

Infant Physiological Responses To Noxious Stimuli Of Circumcision With Anesthesia And Analgesia, Traci Lynn Olson

Theses and Dissertations

No abstract provided.

Production Of Interleukin 10 By Islet Cells Accelerates Immune-Mediated Destruction Of Beta Cells In Nonobese Diabetic Mice., Lise Wogensen, Myung-Shik Lee, Nora Sarvetnick

Journal Articles: Regenerative Medicine

The T helper type 2 (Th2) cell product interleukin 10 (IL-10) inhibits the proliferation and function of Th1 lymphocytes and macrophages (M phi). The nonobese diabetic mouse strain (NOD/Shi) develops a M phi and T cell-dependent autoimmune diabetes that closely resembles human insulin-dependent diabetes mellitus (IDDM). The objective of the present study was to explore the consequences of localized production of IL-10 on diabetes development in NOD/Shi mice. Surprisingly, local production of IL-10 accelerated the onset and increased the prevalence of diabetes, since diabetes developed at 5-10 wk of age in 92% of IL-10 positive I-A beta g7/g7, I-E- mice …

Elevated Expression Of Type Vii Collagen In The Skin Of Patients With Systemic Sclerosis. Regulation By Transforming Growth Factor-Beta., Lidia Rudnicka, John Varga, Angela M. Christiano, Renato V. Iozzo, Sergio A. Jimenez, Jouni Uitto

Department of Dermatology and Cutaneous Biology Faculty Papers

A hallmark of systemic sclerosis (SSc) is the development of tissue fibrosis. Excessive production of several connective tissue components normally present in the dermis, including type I, III, V, and VI collagens as well as fibronectin and proteoglycans, is a consistent finding in the skin of SSc patients. Type VII collagen is a major constituent of anchoring fibrils, present in the skin at the dermal-epidermal basement membrane zone. TGF-beta has been shown to upregulate the expression of the type VII collagen gene. In this study, we assessed the expression of type VII collagen and TGF-beta in the skin of patients …

The Random Inactivation Of The X Chromosome Carrying The Defective Gene Responsible For X-Linked Hyper Igm Syndrome (X-Him) In Female Carriers Of Higm1, D Hollenbaugh, L H. Wu, H D. Ochs, S Nonoyama

Dartmouth Scholarship

No abstract provided.

E-Cadherin Mediates Adherens Junction Organization Through Protein Kinase C, Jani E. Lewis, Pamela J. Jensen, Keith R. Johnson, Margaret J. Wheelock

Biology

Cultured human keratinocytes maintained in 30 μM Ca2+ do not form adherens junctions; however, when the extracellular Ca2+ concentration is raised to 1 mM, adherens junctions form very rapidly. The formation of a junction involves the coordinate organization of intracellular and extracellular components. Cadherins have been shown to mediate this coordinate organization. In this report we show that E-cadherin organizes the various junctional components by signalling through protein kinase C.

Sequencing Of Cdna From 50 Unrelated Patients Reveals That Mutations In The Triple-Helical Domain Of Type Iii Procollagen Are An Infrequent Cause Of Aortic Aneurysms., Gerard Tromp, Yuli Wu, Darwin J. Prockop, Swarna L. Madhatheri, Caren Kleinert, James J. Earley, Jiapiao Zhuang, Orjan Norrgård, R. Clement Darling, William M. Abbott, C. William Cole, Pekka Jaakkola, Markku Ryynanen, William H. Pearce, James S.T. Yao, Kari Majamaa, Stanton N. Smullens, Zoran Gatalica, Robert E. Ferrell, Sergio A. Jimenez, Charles E. Jackson, Virginia V. Michels, Michael Kaye, Helena Kuivaniemi

Department of Biochemistry and Molecular Biology Faculty Papers

Detailed DNA sequencing of the triple-helical domain of type III procollagen was carried out on cDNA prepared from 54 patients with aortic aneurysms. The 43 male and 11 female patients originated from 50 different families and five different nationalities. 43 patients had at least one additional blood relative who had aneurysms. Five overlapping asymmetric PCR products, covering all the coding sequences of the triple-helical domain of type III procollagen, were sequenced with 28 specific sequencing primers. Analysis of the sequencing gels revealed only two nucleotide changes that altered the structure of the protein. One was a substitution of threonine for …

How To Make A Blastocyst., A J Watson, G M Kidder, G A Schultz

Obstetrics & Gynaecology Publications

Several of the new reproductive technologies have been cultivated from our current understanding of the genetic programming and cellular processes that are involved in the major morphogenetic events of mammalian preimplantation development. Research directed at characterizing the patterns of gene expression during early development has shown that the embryo is initially under maternal control and later superseded by new transcriptional activity provided by the activation of the embryonic genome. Several embryonic transcripts encoding: (i) growth factors, (ii) cell junctions, (iii) plasma membrane ion transporters, and (iv) cell adhesion molecules have been identified as contributing directly to the progression of the …

Immunocytochemical And Histopathological Investigation Of The Hypothalamic-Pituitary-Testicular Axis Of The Primary Infertile Dark Mink (Mustela Vison), Baha M. Alak

Biology

This study was designed to investigate the hypothalamic-pituitary-testicular axis of the primary infertile dark male mink. The specific objectives were (1) to describe the morphology and localization of the neurons containing gonadotropin-releasing hormone (GnRH) and its precursor (proGnRH) within the preoptic-basal hypothalamus (POA-BH) of the sexually mature dark male mink, (2) to ascertain any differences in the number or the distribution of GnRH- and proGnRH-containing neurons between the fertile and infertile dark male mink, (3) to determine if GnRH and proGnRH are produced in insufficient amounts by the hypothalami of primary infertile dark male mink, and (4) to describe the …

Association Of Circulating Receptor Fc Gamma Riii-Positive Monocytes In Aids Patients With Elevated Levels Of Transforming Growth Factor-Beta, J B. Allen, H L. Wong, P M. Guyre, G L. Simon

Dartmouth Scholarship

No abstract provided.

Aldosterone Stimulates K Secretion Across Mammalian Colon Independent Of Na Absorption, Gerhard Rechkemmer, Dan R. Halm

Neuroscience, Cell Biology & Physiology Faculty Publications

K transport across guinea pig (Cavia porcellus) distal colon was measured in vitro using isotopically determined unidirectional fluxes. Aldosterone stimulated electrogenic Na absorption, as measured by amiloride-sensitive short-circuit current (I_sc), and reduced net K absorption from +2.5 ± 0.2 µEq/cm² per hr to +0.8 ± 0.3 µEq/cm² per hr (mean ± SEM). Amiloride addition to the mucosal solution did not enhance net K absorption, as expected if inhibiting active Na absorption would reduce active K secretion as in the distal nephron. The amiloride-insensitive I_sc was -1.0 ± 0.2 µEq/cm² per hr (mean ± SEM) …

The Epidermal Growth Factor Receptor From Prostate Cells Is Dephosphorylated By A Prostate-Specific Phosphotyrosyl Phosphatase., Ming-Fong Lin, Gail M. Clinton

Journal Articles: Biochemistry & Molecular Biology

Human prostatic acid phosphatase (PAcP) has been found to have phosphotyrosyl-protein phosphatase activity (H. C. Li, J. Chernoff, L. B. Chen, and A. Kirschonbaun, Eur. J. Biochem. 138:45-51, 1984; M.-F. Lin and G. M. Clinton, Biochem. J. 235:351-357, 1986) and has been suggested to negatively regulate phosphotyrosine levels, at least in part, by inhibition of tyrosine protein kinase activity (M.-F. Lin and G. M. Clinton, Adv. Protein Phosphatases 4:199-228, 1987; M.-F. Lin, C. L. Lee, and G. M. Clinton, Mol. Cell. Biol. 6:4753-4757, 1986). We investigated the molecular interaction of PAcP with a specific tyrosine kinase, the epidermal growth factor …

Characterization Of Wolbachia Postica Which Causes Hybrid Incompatibility In Alfalfa Weevil, Sy-Jye Christine Leu

Biology

The rickettsia Wolbachia postica is the cause of hybrid incompatibility between males of the western alfalfa weevil and females of eastern or Egyptian weevils. Studies were carried out to obtain information about the biochemical and immunological characteristics of this microorganism. Because of the similarity between rickettsia and mycoplasma under the electron microscope, hybridization of DNA from this microorganism with a mycoplasma-specific gene probe confirmed a previous observation that this microorganism is a rickettsia. A rapid and accurate diagnostic assay for the infection of alfalfa weevils by wolbachia has been accomplished by the production of a polyclonal antibody against Wolbachia postica …

Parentage Analysis With Genetic Markers In Natural Populations I The Expected Proportion Of Offspring With Unambiguous Paternity, R Chakraborty, T R Meagher, P E Smouse

Faculty, Staff and Student Publications

Recent studies indicate that polymorphic genetic markers are potentially helpful in resolving genealogical relationships among individuals in a natural population. Genetic data provide opportunities for paternity exclusion when genotypic incompatibilities are observed among individuals, and the present investigation examines the resolving power of genetic markers in unambiguous positive determination of paternity. Under the assumption that the mother for each offspring in a population is unambiguously known, an analytical expression for the fraction of males excluded from paternity is derived for the case where males and females may be derived from two different gene pools. This theoretical formulation can also be …

Regulation By Adrenal Corticosteroids Of Sodium And Potassium Transport In Loop Of Henle And Distal Tubule Of Rat Kidney., Bruce A. Stanton

Dartmouth Scholarship

Studies were conducted to examine the effects of adrenalectomy (ADX) and selective, physiological adrenal corticosteroid replacement on sodium and potassium transport by the superficial loop of Henle and distal tubule of rat kidney in vivo. In the loop of Henle, ADX inhibited sodium reabsorption by 33%. Whereas dexamethasone had no effect on reabsorption, aldosterone increased sodium transport to control levels. Thus, physiological levels of mineralocorticoids, but not glucocorticoids, control a fraction of sodium reabsorption in the loop of Henle. ADX also inhibited potassium reabsorption in the loop of Henle. Both dexamethasone and aldosterone reversed the inhibition, although only aldosterone increased …

Tyrosyl Kinase Activity Is Inversely Related To Prostatic Acid Phosphatase Activity In Two Human Prostate Carcinoma Cell Lines., Ming-Fong Lin, Ching-Li Lee, Gail M. Clinton

Journal Articles: Biochemistry & Molecular Biology

Alterations in prostatic acid phosphatase (PAcP), a phosphotyrosyl phosphatase, corresponded to changes in overall tyrosyl kinase activity. PAcP added to extracts of prostate carcinoma cells with a low endogenous level of PAcP activity and elevated tyrosyl kinase activity decreased the tyrosyl kinase activity. On the other hand, when PAcP activity was decreased by the addition of androgens to cells, there was a corresponding increase in tyrosyl kinase activity.

Heterogeneity Of Clonogenic Cells In Acute Myeloblastic Leukemia., Kert D. Sabbath, Edward D. Ball, Peter Larcom, Roger B. Davis, James D. Griffin

Dartmouth Scholarship

The expression of differentiation-associated surface antigens by the clonogenic leukemic cells from 20 patients with acute myeloblastic leukemia (AML) was studied with a panel of seven cytotoxic monoclonal antibodies (anti-Ia, -MY9, -PM-81, -AML-2-23, -Mol, -Mo2, and -MY3). The surface antigen phenotypes of the clonogenic cells were compared with the phenotypes of the whole leukemic cell population, and with the phenotypes of normal hematopoietic progenitor cells. In each case the clonogenic leukemic cells were found within a distinct subpopulation that was less "differentiated" than the total cell population. Clonogenic leukemic cells from different patients could be divided into three phenotype groups. …