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Biomedical subjects

E Schwartz

Publications and source records attributed to E Schwartz.

At least 235 records · Page 13Linked to original sources
PubMed1988

Chromosomal localization of the genes for the vitronectin and fibronectin receptors alpha subunits and for platelet glycoproteins IIb and IIIa.

The integrins, a family of related membrane receptors involved in cell-cell and cell-matrix interactions, are heterodimeric complexes of alpha and beta subunits. To begin to understand the evolution of these complexes, we studied the genomic organization of several alpha and beta integrin subunits. Using both somatic cell hybrids and an in situ hybridization technique, we have determined the chromosomal location of the genes for the alpha subunits of the vitronectin receptor (VNR alpha), the fibronectin receptor (FNR alpha), and for the alpha subunit of the platelet glycoprotein IIb/IIIa complex, GPIIb. In addition, we have determined the chromosomal location of the gene for the beta subunit of the GPIIb/IIIa heterodimer, GPIIIa. Our studies indicate that the alpha subunits do not localize to a single locus, but that each is found on a different chromosome. The gene for VNR alpha is located on chromosome 2, the gene for FNR alpha is on chromosome 12q11----13, and the gene for GPIIb is on chromosome 17q21----23. In contrast to the chromosomal dispersion of the alpha subunits, the genes for GPIIb and GPIIIa are physically close, with the gene for GPIIIa also located on chromosome 17q21----23. These studies indicate that the genes for the alpha subunits of the integrin family have been dispersed during evolution while GPIIb and GPIIIa are in close physical proximity. This physical proximity of GPIIb and GPIIIa may be involved in the concurrent expression of these proteins by megakaryocytes, and may result in linkage disequilibrium between these two genes, which would limit the use of restriction length polymorphisms in linkage studies of GPIIb/IIIa abnormalities in small kindreds.

Animals↗
PubMed1988

Overview of the beta thalassemias: genetic and clinical aspects.

There has been much progress in basic studies of the beta-thalassemia disorders in recent years, as well as in the practical aspects of prenatal diagnosis and clinical management. Alterations in a single or a few nucleotides account for most of the types of beta-thalassemia syndromes that have been characterized, and a variety of deletions have been found associated with beta O thalassemia, delta beta thalassemia, gamma delta beta thalassemia, and hereditary persistence of fetal hemoglobin (HPFH). Studies of nondeletional types of HPFH have revealed several single base changes 5' to the G gamma and A gamma genes, suggesting that these regions may be of major importance in the switchover from fetal to adult hemoglobin synthesis and in the relative production of the G gamma and A gamma globin chains during development. Evaluation of restriction enzyme polymorphisms and the assignment of haplotypes in the beta-like globin region of chromosome 11 have allowed delineation of the origin and distribution of thalassemia mutations, and have provided an important means for prenatal diagnosis. These studies have accumulated much new information about the function and expression of eukaryotic genes, and have served as a model for the investigation of human genetic disorders. The clinical management of patients with Cooley's anemia has benefited greatly from changes in transfusion practice, clear guidelines for splenectomy, and the availability of effective chelation therapy for iron overload. Current basic and clinical studies may lead to new approaches to management, treatment and eventual cures for this disease, including safe bone marrow transplantation, oral chelation treatment, and gene therapy.

Fetal Hemoglobin↗
PubMed1988

Non-random association of the Rsa I polymorphic site 5' to the beta-globin gene with major sickle cell haplotypes.

There are three main African haplotypes associated with the sickle mutation on chromosome 11. We have examined an Rsa I polymorphism 550 bp 5' to the beta-globin gene to study the degree of linkage disequilibrium between this Rsa I site and the three haplotypes. This Rsa I site is contained within the 10.3 kb or less area of randomization separating the 5'- and 3'-haplotype clusters. The beta S-containing chromosomes of the Benin and Senegal haplotypes are not cut, while those of the Central African Republic are cleaved by Rsa I at this site. Possible explanations of these findings are discussed.

Anemia, Sickle Cell↗
PubMed1988

A single-base change at position -175 in the 5'-flanking region of the G gamma-globin gene from a black with G gamma-beta+ HPFH.

Hereditary persistence of fetal hemoglobin (HPFH) is a human hemoglobinopathy characterized by the continued expression of fetal globins during adult life. Both deletional and nondeletional forms have been described. A number of single-base changes in the immediate 5'-flanking region of the fetal G gamma and A gamma have been reported associated with nondeletional forms of HPFH. We now present the nucleotide sequence of a G gamma-globin gene from an American black with G gamma-beta + HPFH. The immediate 5'-flanking region of this G gamma gene has a T-to-C change at -175, C at -158, and a normal C at -202. Additional changes were found in IVS2 and in the immediate 3'-flanking region, some of which may represent gene-conversion events. The sequence change at -175 probably represents a second mutation associated with the G gamma-beta + HPFH phenotype in blacks. This base change alters an octamer sequence known to be of importance in the normal expression of several other genes.

Base Sequence↗
PubMed1988

Rheologic predictors of the severity of the painful sickle cell crisis.

Deformable sickle erythrocytes have been reported by Mohandas and Evans to be more adherent to vascular endothelium than rigid irreversibly sickled cells (ISC). To define the clinical implications of this finding we have determined genetic, hematological, clinical, and rheological characteristics of sickle erythrocytes obtained from 65 patients with sickle cell anemia and fetal hemoglobin (Hb F) levels less than 15%. The alpha-globin gene number had a significant effect on the hematological parameters, the percentage of dense cells, ISC number, and HB A2 levels. The presence or absence of alpha thalassemia, however, had no effect on the frequency and severity of the sickle cell painful crisis (r = 0.06, P greater than .05). RBC deformability, determined by an ektacytometer, showed great heterogeneity among patients with three or four alpha-globin genes. Linear regression analyses of the data showed significant positive correlation of the frequency and severity of the painful crisis with RBC deformability (r = 0.49, P less than .001), and negative correlations with the percentage of dense cells (r = -0.37, P = .002), and the percentage of ISC (r = -0.46, P less than .001). We propose that the more deformable the sickle RBC are, the greater their adherence to vascular endothelium, and the more they cause vaso-occlusive crises, RBC deformability and the percentage of dense cells (or ISC) seem to have a predictive value of the frequency and severity of painful crises in sickle cell anemia.

Adolescent↗
PubMed1987

DNA methylation in hereditary persistence of fetal hemoglobin (HPFH-2).

Recent studies show that the region of DNA brought into close proximity to the fetal gamma-globin genes in deletional forms of hereditary persistence of fetal hemoglobin (HPFH) is selectively hypomethylated (and presumably active) in normal erythroid tissue. This region is normally located approximately 100 kilobases (kb) 3' to the fetal genes. The continued expression of fetal hemoglobin in adult life in these forms of HPFH has been ascribed to the effect of this erythroid-specific region in altering local chromosomal structure and allowing transcription. Because transcriptional activity is often associated with hypomethylation, we have examined the methylation status of the gamma-globin genes and the truncated psi beta gene on the HPFH chromosome to determine whether juxtaposition of this erythroid-specific region results in a generalized hypomethylation of the globin gene region upstream of the deletion breakpoint. Genomic DNA purified from nucleated red blood cells (nRBC) from a patient with HPFH-2/beta O thalassemia was digested with Msp I or Hpa II, and the methylation pattern determined on the HPFH chromosome by using secondary cleavage with restriction enzymes which span the deletion breakpoint. These studies show that in nRBC the HPFH-2 chromosome is hypomethylated in the 3'-juxtaposed region (3'JR) and in the region of the gamma-globin genes. In contrast, Msp I sites near the truncated psi beta-globin gene remain methylated, suggesting that only a subset of CpG sites upstream from the 3'JR become hypomethylated in HPFH-2. This subset of sites corresponds to those which are normally hypomethylated when fetal genes are active. The continued high level of fetal globin expression is, therefore, not associated with a generalized hypomethylation upstream from the deletion junction.

DNA↗
PubMed1987

Structure of the platelet membrane glycoprotein IIb. Homology to the alpha subunits of the vitronectin and fibronectin membrane receptors.

The platelet membrane glycoprotein IIb X IIIa heterodimer complex (GPIIb X IIIa) is the platelet receptor for adhesive proteins, containing binding sites for fibrinogen, von Willebrand factor, and fibronectin on activated platelets. GPIIb X IIIa also appears to be a member of a family of membrane adhesive protein receptors that plays a major role in cell-cell and cell-matrix interactions. GPIb is the larger component of this platelet receptor and is composed of two disulfide-linked subunits. In this report we describe the analysis of cDNA clones for human GPIIb that were isolated from a lambda gt11 expression library prepared using RNA from HEL cells. A total of 3.3 kilobases of cDNA was sequence, revealing a continuous open reading frame encoding both GPIIb subunits. The cDNA encodes 1039 amino acids: 137 constituting the smaller subunit, 871 constituting the larger subunit, and 30 constituting an NH2-terminal signal peptide. No homology was found between the larger and smaller subunits. The smaller subunit contains a 26-residue hydrophobic sequence near its COOH terminus that represents a potential transmembrane domain. Four stretches of 12 amino acids present in the larger subunit are homologous to the calcium binding sites of calmodulin and troponin C. Northern blot analysis using HEL cell RNA indicated that the mature mRNA coding for GPIIb is 4.1 kilobases in size. A comparison of the GPIIb coding region with available cDNA sequences of the alpha-chains of the vitronectin and fibronectin receptors revealed 41% DNA homology and 74% and 63% amino acid homology, respectively. Our data establish the amino acid sequence for the human platelet glycoprotein IIb and provide additional evidence for the existence of a family of cellular adhesion protein receptors.

Amino Acid Sequence↗
PubMed1987

Shedding of GD2 ganglioside by human neuroblastoma.

Substantial concentrations of the cell-surface glycosphingolipid, the disialoganglioside GD2, are uniformly present in human neuroblastoma tumors. This ganglioside can also be detected in the plasma of patients with neuroblastoma by direct thin-layer chromatographic analysis. Among 32 neuroblastoma patients in all clinical stages studied prior to the initiation of treatment, 27 (84%) showed measurably elevated plasma concentrations of GD2 (greater than or equal to 50 pmol/ml). The mean level (545 +/- 108 pmol/ml) was more than 50 times the normal plasma GD2 concentration of less than or equal to 10 pmol/ml. Circulating GD2 was not detected in the plasma of patients with the related, more differentiated tumors, ganglioneuroblastoma and ganglioneuroma, indicating an association of the shedding of this ganglioside with the undifferentiated phenotype. Circulating GD2 diminished in patients in response to therapy, and reappeared in patients whose disease recurred. The results suggest that the sequential determination of circulating GD2 will be of value in monitoring individual patients with neuroblastoma.

Antibodies, Monoclonal↗
PubMed1987

Abrogation of bone marrow allograft resistance in mice by increased total body irradiation correlates with eradication of host clonable T cells and alloreactive cytotoxic precursors.

Host-vs-graft activity presents a major obstacle for transplantation of T cell-depleted bone marrow in HLA-mismatched patients. In a primate model, conditioned exactly like leukemia patients, it was shown that residual host clonable T cells, as well as alloreactive cytotoxic precursors, were present in peripheral blood and spleen after completion of cytoreduction. We have now extended this study in a mouse model for allogeneic bone marrow transplantation. C3H/HeJ mice were treated by 9 Gy total body irradiation (TBI), and 24 hr later their spleen cells were cultured in the presence of T cell growth factor and phytohemagglutinin according to the limit dilution procedure. After 7 days of culture the average frequency of clonable cells was 2.5 X 10(-3) compared with 37 X 10(-3) in the spleens of normal mice. The T cell derivation of the growing cells was ascertained by complement-mediated cytotoxicity with anti-Thy-1 as well as with anti-Lyt-2 and anti-Ly-3T4. In parallel, we found that the initial engraftment rate of bone marrow allograft in mice given 9 Gy TBI was lower than that found in recipients of syngeneic marrow. The initial engraftment rate was measured by the number of colony-forming units in the spleen and by splenic uptake of 125IUdR. A slight increase in TBI from 9 Gy to 11 Gy markedly reduced the difference in the number of spleen colony-forming units or the IUdR uptake between recipients of allogeneic and syngeneic bone marrow. This increase in TBI also coincided with eradication of detectable clonable T cells. Moreover, in mice transplanted with T cell-depleted bone marrow after 9 Gy TBI, we also demonstrate that cytotoxicity against donor-type target cells is present in the spleen 10 to 14 days posttransplantation, whereas in mice treated by 11 Gy TBI such alloreactivity could not be detected. These results suggest that resistance to T cell-depleted allogeneic bone marrow in irradiated mice closely correlates with the frequencies of residual host clonable T cells detectable by conventional immunologic assays.

Animals↗
PubMed1987

Proportionate mortality ratio analysis of automobile mechanics and gasoline service station workers in New Hampshire.

A proportionate mortality ratio (PMR) analysis of all deaths recorded from 1975 to 1985 among New Hampshire white male residents (age 20 years or older) was performed using death certificate information. Among automobile mechanics, the analysis revealed increases in mortality from leukemia (PMR = 178, N = 6); cancers of the oral cavity (PMR = 163, N = 4), lung (PMR = 112, N = 36), bladder (PMR = 169, N = 5), rectum (PMR = 182, N = 4), and lymphatic tissues (PMR = 200, N = 6); and cirrhosis of the liver (PMR = 140, N = 13) and suicide (PMR = 177, N = 22; p less than 0.05). Workers in the gasoline service station industry experienced a leukemia mortality excess (PMR = 328, N = 3; p less than 0.05) as well as increases in deaths from suicide (PMR = 162, N = 4), emphysema (PMR = 245, N = 4), and mental and psychoneurotic conditions (PMR = 394, N = 3). These workers are potentially exposed to a variety of substances including gasoline vapor, benzene, solvents, lubricating oils and greases, and asbestos (from brake and clutch repair) as well as welding fumes and car and truck exhaust. Despite limitations regarding the small number of deaths and methodologic constraints, the results of this analysis suggest that one or more of the exposures experienced by these workers poses a significant carcinogenic risk. More definitive epidemiologic studies are required to determine if the leukemia excess is associated with exposure to benzene, gasoline, or other workplace substances.

Adult↗
PubMed1987

Rickettsiosis-associated hyponatremia.

Two patients with hyponatremia (130 mEq/l and 122 mEq/l, respectively), and rickettsial disease are described. The causes of hyponatremia were attributed to rickettsial vasculitis and increased capillary permeability in the first patient and to the syndrome of inappropriate anti-diuretic hormone (ADH) secretion in the second patient. The differentiation between the mechanisms was established by measurement of urinary sodium excretion which was low in the first patient (7 mEq/l) and high in the second patient (60 mEq/l), and levels of ADH that were inappropriately high in the second patient (7-9 pg/ml) in the presence of low plasma osmolality. The differentiation between these causes of hyponatremia has important therapeutic implications.

Adolescent↗
PubMed1987

Human platelet factor 4 gene is mapped to 4q12----q21.

The gene for human platelet factor 4 has been mapped to the q12----q21 region of chromosome 4 by in situ hybridization. Hybridization of the same probe to leukemic cells carrying a t(4;11)(q21;q23) showed that the human platelet factor 4 gene is proximal to the breakpoint on chromosome 4.

Chromosome Banding↗
PubMed1987

Familial bilateral paralysis of diaphragm. Adult onset.

At age 50 two homozygote twin brothers developed bilateral paralysis of the diaphragm. No infectious, metabolic, degenerative or proliferative disorders of the neuromuscular system and no thoracic diseases which could explain this lesion were detected during four years of follow-up. It appears thus to be an isolated lesion of genetic origin. To the best of our knowledge, no similar cases have been reported in literature.

Diaphragm↗
PubMed1987

Use of court records for supplementing occupational disease surveillance.

To conduct surveillance of occupationally related health events, the New Hampshire Division of Public Health Services analyzes death certificates and workers' compensation claims. In an effort to bolster these limited data sources, a previously unrecognized data-set comprised of court records was explored. Court records obtained from the Federal District Court proved to be a readily accessible and detailed source of information for identifying suspected cases of asbestos-related disease and potential sources of asbestos exposure.

Asbestosis↗
PubMed1987

Riboflavin metabolism in the hypothyroid human adult.

It had been shown that thyroxine regulates the conversion of riboflavin to riboflavin mononucleotide and flavin adenine dinucleotide (FAD) in laboratory animals. In the hypothyroid rat, the flavin adenine dinucleotide level of the liver decreases to levels observed in riboflavin deficiency. We have shown that in six hypothyroid human adults, the activity of erythrocyte glutathione reductase, an accessible FAD-containing enzyme, is decreased to levels observed during riboflavin deficiency. Thyroxine therapy resulted in normal levels of this enzyme while the subjects were on a controlled dietary regimen. This demonstrates that thyroid hormone regulates the enzymatic conversion of riboflavin to its active coenzyme forms in the human adult.

Aged↗