Showing papers by "Johns Hopkins University School of Medicine published in 1985"

Hypomethylation of DNA from benign and malignant human colon neoplasms.

Abstract: The methylation state of DNA from human colon tissue displaying neoplastic growth was determined by means of restriction endonuclease analysis. When compared to DNA from adjacent normal tissue, DNA from both benign colon polyps and malignant carcinomas was substantially hypomethylated. With the use of probes for growth hormone, gamma-globin, alpha-chorionic gonadotropin, and gamma-crystallin, methylation changes were detected in all 23 neoplastic growths examined. Benign polyps were hypomethylated to a degree similar to that in malignant tissue. These results indicate that hypomethylation is a consistent biochemical characteristic of human colonic tumors and is an alteration in the DNA that precedes malignancy.

Identification of a family of human centromere proteins using autoimmune sera from patients with scleroderma.

Abstract: We have examined "preimmune" serum samples from a patient who progressively developed the symptoms of scleroderma CREST over a period of several years. During this period, anti-centromere antibodies (recognized by indirect immunofluorescence) appeared in the serum. Concomitant with the appearance of the anti-centromere antibodies, antibody species recognizing three chromosomal antigens in immunoblots of SDS polyacrylamide gels appeared in the patient's serum. These antigens migrate with electrophoretic mobilities corresponding to Mr = 17, 80, and 140 kilodaltons (kd). Affinity-eluted antibody fractions recognizing the antigens have been prepared from sera of three other patients. Indirect immunofluorescence labeling of mitotic cells using these antibody fractions demonstrates that the antigens are centromere components. We designate them CENP (CENtromere Protein) - A (17kd), CENP-B (80kd), and CENP-C (140kd). The three CENP antigens share antigenic determinants. Immunoblotting experiments show that these patients make antibody species recognizing at least three distinct epitopes on CENP-B and two on CENP-C. Sera from different patients contain different mixtures of the antibody species.

Assessment of stimulus preference and reinforcer value with profoundly retarded individuals.

Abstract: We evaluated a procedure for identifying potential reinforcers with profoundly retarded individuals. In Experiment 1, six persons were repeatedly exposed to 16 stimuli, and approach behaviors to each stimulus were used to identify preferred and nonpreferred stimuli. In Experiment 2, we examined the reinforcing properties of preferred and nonpreferred stimuli by delivering them contingently on the occurrence of arbitrarily selected responses. Results revealed that the preferred stimulus conditions typically produced higher rates of responding than did either the baseline or the nonpreferred stimulus conditions, suggesting that the procedure can be used to assess reinforcer value for individuals with limited behavioral repertoires.

The Meaning of Cognitive Impairment in the Elderly

Abstract: In order to determine the meaning of cognitive impairment in community dwelling elderly, 3,481 adults were interviewed in their homes using the Mini-Mental State Examination. Ninety-six per cent of the population aged 18-64 scored 23 or higher, whereas 80 per cent of the population 65 and over scored 23 or higher. Individuals with low scores were suffering from a variety of psychiatric disorders including dementia. Thirty-three per cent of the elderly population scoring in the range of 0-23 had no diagnosable DSM-III condition. Prevalence of dementia from all causes was 6.1 per cent of the population over age 65. Two per cent of the population over age 65 were diagnosed as having Alzheimer's disease.

Choline acetyltransferase activity in striatum of neonatal rats increased by nerve growth factor

Abstract: Some neurodegenerative disorders may be caused by abnormal synthesis or utilization of trophic molecules required to support neuronal survival. A test of this hypothesis requires that trophic agents specific for the affected neurons be identified. Cholinergic neurons in the corpus striatum of neonatal rats were found to respond to intracerebroventricular administration of nerve growth factor with prominent, dose-dependent, selective increases in choline acetyltransferase activity. Cholinergic neurons in the basal forebrain also respond to nerve growth factor in this way. These actions of nerve growth factor may indicate its involvement in the normal function of forebrain cholinergic neurons as well as in neurodegenerative disorders involving such cells.

Early Homo erectus skeleton from west Lake Turkana, Kenya

Abstract: The most complete early hominid skeleton ever found was discovered at Nariokotome III, west Lake Turkana, Kenya, and excavated in situ in sediments dated close to 1.6 Myr. The specimen, KNM-WT 15000, is a male Homo erectus that died at 12 ± 1 years of age, as judged by human standards, but was already 1.68 m tall. Although human-like in many respects, this specimen documents important anatomical differences between H. erectus and modern humans for the first time.

Monoclonal antibody studies of mammalian epithelial keratins: a review.

Abstract: Significant progress has been made during the past decade with regard to the biochemistry and immunology of keratin filaments. The results indicate that keratin represents a family of more than 17 water-insoluble, cytoskeletal proteins,"2 that keratins are restricted to epithelia and their derivatives;d that different subsets of 210 keratins are expressed in different epithelia,1~2~7-12 that at least two keratin species are required for filament a~sembly,'".'~ and that keratin molecules consist of a central helical domain with two nonhelical end^.^^-^^ Despite these advances, however, it remains a puzzle as to why such a large number of keratin species have evolved to form tonofilaments, while other morphologically similar, intermediate-sized filaments are characterized by a much simpler protein composition with only one to three subunits (for reviews, see Lazaridesl' and other chapters in this volume). To address this fundamental question, we have prepared several monoclonal antikeratin antibodies2' and used them as a tool for studying keratin expression. In this

Peripheral-Type Benzodiazepine Receptors in Endocrine Organs: Autoradiographic Localization in Rat Pituitary, Adrenal, and Testis*

Abstract: We have used [3H]Ro5-4864, a ligand selective for peripheral-type benzodiazepine receptors, to identify and localize peripheral-type benzodiazepine receptors in endocrine organs. Autoradiographic studies reveal an uniform distribution of [3H]Ro5-4864 binding sites within the anterior, intermediate, and posterior lobes of the pituitary gland, with highest concentrations present in the posterior pituitary. In rat adrenal gland, specific binding sites for [3H]Ro5-4864 are found only in the adrenal cortex, with highest density in the zona glomerulosa and significantly lower concentrations in the zona fasciculata and zona reticularis. [3H]Ro5-4864-associated silver grains in the testis are intensely localized over the interstitial tissue; low concentrations of silver grains are present over the epithelium of the seminiferous tubules but are absent from the tubular lumen. These studies demonstrate a differential and discrete localization of peripheral-type benzodiazepine receptors in rat pituitary, adrenal, and testis.

Lentiviral Diseases of Sheep and Goats: Chronic Pneumonia Leukoencephalomyelitis and Arthritis

Abstract: This review describes the pathogenesis of a slowly progressive disease complex caused by naturally occurring nononcogenic retroviruses in sheep and goats. In nature, infections are usually clinically silent, but disease may manifest itself after prolonged incubation periods. Clinically, this is seen as dyspnea, progressive paralysis, and/or progressive arthritis. In all organs the basic lesion is inflammatory with infiltration and proliferation of lymphocytes, plasma cells, and macrophages. Other organ-specific pathologic changes such as primary demyelination in the central nervous system and degeneration of cartilaginous structures in joints accompany inflammation. The viruses infect tissue-specific macrophage populations in vivo. Viral replication in these cells is restricted to minimal levels but continues indefinitely in the animal as a result of either failure to induce specific neutralizing antibodies or antigenic drift when neutralizing antibodies develop. Consistent low-grade viral replication sets the pace for disease by providing continuous antigenic stimulation for the inflammatory cellular immune response or antibodies that localize in the target tissues. These cells and immune complexes may have adverse effects on indigenous cell populations.

DNA polymorphism and molecular pathology of the human globin gene clusters

Abstract: In the past few years there has been intensive study of the human globin genes. This study has provided important insights into normal gene structure and function and the nature of molecular defects leading to a set of inherited diseases. In turn, this information forms the basis for rational design of specific tests for prenatal diagnosis of particular forms of β-gene cluster in which recombination appears to be more frequent than in areas surrounding it. This will provide new insights into the evolution of a segment of the genome and aid in explaining how particular mutations are dispersed to numerous chromosome types. Second, study of additional β-thalassemia genes from human populations not previously studied will provide new gene defects, some of which may yield further clues about RNA transcription and processing. In addition, some (e.g., the coding region substitutions that affect RNA processing) may allow identification of new mechanisms of gene dysfunction. Third, we need further refinement of prenatal diagnostic tests so that early, accurate, and simplified assessment of pregnancies at risk can be accomplished widely, particularly in those geographic regions where β-thalassemia is especially prevalent.

Three related centromere proteins are absent from the inactive centromere of a stable isodicentric chromosome.

Abstract: We developed an aqueous spreading procedure that permits simultaneous analysis of human chromosomes by Q-banding and indirect immunofluorescence. Using this methodology and anticentromere antibodies from an autoimmune patient we compared the active and inactive centromeres of an isodicentric X chromosome. We show that a family of structurally related human centromere proteins (CENP-A, CENP-B, and CENP-C) is detectable only at the active centromere. These antigens therefore may be regarded both as morphological and functional markers for active centromeres.

Japanese encephalitis: immunocytochemical studies of viral antigen and inflammatory cells in fatal cases.

Abstract: The distribution of virus and the composition of the mononuclear inflammatory response were studied in the brains of 7 children who died with Japanese encephalitis. Viral antigen was localized to neurons, with greatest involvement in the thalamus and brainstem. Quantitation of perivascular inflammatory responses showed a preponderance of T cells, but only 7 to 30% of these cells were T suppressor/cytotoxic cells. Inflammatory cells invading the parenchyma were predominantly macrophages with small numbers of T cells. B cells remained localized to perivascular cuffs. Viral antigen was progressively cleared in patients with survival of 6 days or more.

Abnormalities of the nucleus basalis in Down's syndrome.

Abstract: One of the most striking manifestations of Down's syndrome is profound mental retardation Furthermore, after 35 years of age, many patients with Down's syndrome develop clinical and pathological features of Alzheimer's disease Since brains of patients with Alzheimer's disease show significant loss of neurons in the nucleus basalis of Meynert (nbM), we sought to establish normal standards of nbM neurons in persons with Down's syndrome and to determine whether reductions in the number of neurons occur with increasing age The number and size of neurons in the nbM were measured in selected sagittal sections from 5 patients with Down's syndrome and 5 age-matched controls The patients (age range, 16 to 56 years) had 29% fewer nbM neurons than controls, and the oldest patient had the lowest cell count of all subjects The size of nbM neurons did not differ significantly between the two groups Our results show that the nbM contains fewer neurons in young persons with Down's syndrome than in normal controls and suggest that the number of these nerve cells may be further reduced in older persons with Down's syndrome

Synapsin I is a spectrin-binding protein immunologically related to erythrocyte protein 4.1.

Abstract: The membrane-associated cytoskeleton is considered to be the apparatus by which cells regulate the properties of their plasma membranes, although recent evidence has indicated additional roles for the proteins of this structure, including an involvement in intracellular transport and exocytosis (see refs 1-3 for review). Of the membrane skeletal proteins, to date only spectrin (fodrin) and ankyrin have been purified and characterized from non-erythroid sources. Protein 4.1 in the red cell is a spectrin-binding protein that enhances the binding of spectrin to actin and can apparently bind to at least one transmembrane protein Immunoreactive forms of 4.1 have been detected in several cell types, including brain. Here we report the purification of brain 4.1 on the basis of its cross-reactivity with erythrocyte 4.1 and spectrin-binding activity. We further show that brain 4.1 is identical to the synaptic vesicle protein, synapsin I, one of the brain's major substrates for cyclic AMP and Ca2+-calmodulin-dependent kinases. Spectrin and synapsin are present in brain homogenates in an approximately 1:1 molar ratio. Although synapsin I has been implicated in synaptic transmission, no activity has been previously ascribed to it.

The incidence of systemic lupus erythematosus in baltimore, maryland, 1970–1977

Abstract: The incidence of systemic lupus erythematosus, based on first hospital discharge diagnosis, in Baltimore, Maryland for the years 1970 through 1977 was determined for individual sex-race groups and the total population. Age-specific incidence rates were consistently highest among black females and lowest among white males: rates for white females exceeded those for black males through age 54, but then declined for ages greater than or equal to 55. Mean age at diagnosis was significantly lower for black females versus white females (35.5 versus 41.7 years, P = 0.005) and for all females versus all males (37.2 versus 44.2 years, P = 0.012). There were no temporal trends noted in yearly age-adjusted incidence rates during the 8-year study period. The overall population incidence of systemic lupus erythematosus was 4.6 per 100,000 per year, representing a twofold increase over a comparable study done in New York City 15 years ago.

Epileptic seizure disorders. Developments in diagnosis and therapy.

Abstract: There has been considerable progress in various segments of epileptology over the past two to three decades. The diagnostic sector has benefited from more advanced and sophisticated EEG-related techniques. The advent of computerized tomography has expedited the clinical evaluation of epileptic patients and new high-technology methods have been introduced. A new type of diagnostic subdivision (based on age-determined epileptic conditions and certain epileptic syndromes) is of great practical significance because of its prognostic implications (distinction of basically benign and severe forms of epileptic seizure disorders). The therapeutic sector has been stimulated by the introduction of new antiepileptic medications and particularly by profound insights into metabolic and pharmacokinetic characteristics of anticonvulsants; this has resulted in the introduction of techniques for serum level determinations. There have been new developments in the field of neurosurgical treatment of epileptic seizure disorders.