DNA sequence changes in the 5'-flanking region of G gamma-globin genes in a black with beta S and a non-deletional form of G gamma-beta+ HPFH.
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Base Sequence↗
Biomedical subjects
E Schwartz
Publications and source records attributed to E Schwartz.
The xerocytosis of Hb SC disease.
Patients with Hb SC disease were found to have microcytic and hyperchromic red cell indices despite mild reticulocytosis. Iron deficiency anemia was ruled out by the finding of normal serum ferritin levels. In order to determine whether the microcytosis was due to coexistent alpha-thalassemia, restriction endonuclease mapping was performed on genomic DNA extracted from peripheral blood leukocytes. Patients with Hb SC disease had microcytic indices despite the presence of a full complement of four alpha-genes (alpha alpha/alpha alpha), suggesting that the microcytosis may be due to cellular dehydration (or xerocytosis), since the mean corpuscular hemoglobin concentration in Hb SC disease patients was significantly higher than in controls. This possibility was investigated further by the determination of RBC cation content. RBC Na levels were similar in SC and normal red cells. Hb SC RBCs, however, had significantly reduced K levels. These findings show that RBC cation content, and thus cell water, is decreased in Hb SC disease. The decreased RBC K level in the presence of normal cellular Na concentration suggests selective K loss that is not due to inhibition of the Na K pump. Ouabain-insensitive K+ efflux was increased to four times normal in SC cells. Cell dehydration was confirmed by the demonstration of increased high-density RBCs on discontinuous Stractan density gradients and by osmotic gradient ektacytometry. Cellular dehydration and its sequelae were worse in CC erythrocytes and milder in AC cells than in Hb SC red cells. Taken together, these data indicate that in Hb SC disease the RBCs are severely dehydrated and typically microcytic and hyperchromic. Hb SC RBCs seem to be dehydrated due to selective K loss. These findings suggest a functional interrelationship between Hb SC, the red cell membrane, and cation regulation.
Adenosine Triphosphatases↗
Cloning and characterization of platelet factor 4 cDNA derived from a human erythroleukemic cell line.
We report the isolation of a platelet factor 4 (PF4) cDNA clone from a lambda gt11 expression cDNA library which was derived from a human erythroleukemic (HEL) cell line. The sequence of the DNA insert includes the 3'-untranslated region, the entire amino acid coding region for the mature PF4 protein, and a 5' region containing coding information for an additional 18 amino acids. In addition, supplemental genomic DNA sequencing shows that the full-length leader sequence is 30 amino acids long plus an initial methionine and codes for a hydrophobic signal-like sequence which is probably involved in transmembrane transport. A single species mRNA of approximately 800 nucleotides was detected on blots of HEL cell poly(A) + RNA using a labeled PF4 cDNA probe. The human PF4 leader sequence shares some DNA, but no amino acid, homology with the 15 amino acids at the N-terminus of mature bovine PF4, suggesting rapid divergence in this region of PF4 between these two species. Sequence comparison of the coding regions of mature PF4 and gamma IP-10, a protein induced in a variety of cells following treatment with gamma-interferon, shows a corrected divergence of 76%. The divergence of a common ancestor protein into PF4 and gamma IP-10 may have accompanied the development of sophisticated immune and coagulation systems in vertebrates. The availability of cDNA and genomic DNA information for these genes in other species will be useful in studying the evolution of the coagulation and immune systems.
Amino Acid Sequence↗
Anterior shoulder instability.
Current concepts for the diagnosis and treatment of anterior dislocation and subluxation, including classification of injuries, are presented. The pathophysiology, clinical and radiologic examination, and treatment protocols are discussed.
Arthroscopy↗
Posterior shoulder instability.
The incidence, basic pathophysiology, and clinical and radiologic examination in posterior instability of the shoulder are discussed. Conservative treatment protocols and surgical procedures are presented.
Humans↗
Thalassemia syndromes. Recent advances.
Laboratory and clinical investigators in the past several years have provided many advancements in the understanding of the thalassemia syndromes and in the care of affected patients. The diversity of genetic defects causing thalassemia has been extensively explored, with major benefits to our knowledge of normal globin gene function and of the consequences of specific mutations. In addition, the use of molecular biology methods in these studies has provided major advances in population genetics, gene transfer, and prenatal diagnosis of thalassemia. In the clinical area, guidelines for transfusion, splenectomy, prevention of postsplenectomy infection, and effective iron chelation have been considerably improved, and bone marrow transplantation is now available as an alternative means of treatment. Despite these advances, a great deal remains to be done in the areas of understanding the developmental regulation of globin gene expression, effective gene transfer, oral chelation therapy, safer blood products, and other important areas that will benefit patients afflicted with thalassemia.
Bone Marrow Transplantation↗
The nature of sensorimotor adaptation to altered G-levels: evidence from mass discrimination.
Mass discrimination is impaired under zero G compared to 1 G. This is partly due to loss of weight information (a reduction in z-axis pressure stimulation), and probably also to incomplete adaptation to the reduced G-level. Maladaptation to an increased G-level postflight causes objects to feel too heavy and weight discrimination to be impaired. Video tapes of hand movements while shaking test objects were made before, during, and after the D-1 Spacelab mission. Movements were faster inflight than preflight, slowed down postflight and returned to baseline by about the third day. Corresponding changes in movement amplitude also occurred. Errors of weight or mass perception during the maladaptation phase may be due to both inadequate monitoring of command signals and to inappropriate scaling of afferent signals. High-acceleration shaking was found to improve mass discrimination but impair weight discrimination.
Adaptation, Physiological↗
Cardiovascular disease risk factors in combat veterans after traumatic leg amputations.
Traumatic leg amputation, but not arm amputation, in World War II combat veterans has been associated with subsequent increased ischemic heart disease mortality. In a pilot project we examined a group of 19 high-risk Vietnam War veterans with bilateral above-knee amputations in comparison with a control group with unilateral below-elbow amputations. Nine of the 19 above-knee amputees were hypertensive (p = 0.05) and obese by hydrostatic weighing (p less than 0.001). Obesity was strongly associated with hypertension, decreased glucose tolerance, and marked hyperinsulinemia. Cigarette smoking, blood lipid abnormalities, and decreased cardiovascular fitness were not implicated as significant risk factors. Long-term risks of amputation may be related to metabolic and hemodynamic sequelae of excessive maturity-onset weight gain in young men immobilized by loss of lower limbs.
Adult↗
Molecular biologic diagnosis of the hemoglobinopathies.
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DNA↗
Mass discrimination in weightlessness improves with arm movements of higher acceleration.
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Arm↗
Acute and subchronic toxicity of a nonsulfhydryl angiotensin-converting enzyme inhibitor.
Acute and 1-month toxicity studies with SCH 31846, a nonsulfhydryl anti-hypertensive agent which acts by inhibiting angiotensin-converting enzyme, were initiated to evaluate its toxicity. The oral LD50s in mice and rats were approximately 1.8 and 2.5 g/kg, respectively, while the iv LD50 was approximately 450 mg/kg in mice and 150 mg/kg in rats. Signs of acute toxicity in rats and mice included salivation, hypoactivity, ataxia, prostration, and convulsions. In a 1-month dog study at oral doses of 25, 75, or 150 mg/kg, there was a dose-related increase in emesis between 1 and 2 hr after dosing. Absorption studies showed peak blood concentrations occurring in dogs between 0.3 and 1 hr after dosing. No other noteworthy antemortem changes were observed. In a 1-month rat study at oral doses of 30, 180, or 600 mg/kg, the hematocrit and hemoglobin values of the 600 mg/kg-dosed female rats were slightly but significantly (p less than 0.05) decreased and the blood urea nitrogen was slightly but significantly (p less than 0.05) increased in all SCH 31846-dosed male rats and the 600 mg/kg-dosed female rats. Absorption studies in male rats at doses of 30, 180, and 600 mg/kg indicate that SCH 31846 is well absorbed in rats. The 150 mg/kg-dosed dogs and the 180- and 600 mg/kg-dosed rats had a slight increase in the number of renin-containing granules in the renal juxtaglomerular cells. No other compound-related microscopic changes were observed. These data are similar to data reported for Captopril and suggest that in the dog and rat the toxicity of ACE inhibitors is not dependent upon the presence or absence of a sulfhydryl group.
Administration, Oral↗
Pulmonary function abnormalities in homozygous beta-thalassemia.
Pulmonary function tests were performed on 19 patients with homozygous beta-thalassemia ranging in age from 10 to 29 years. These included patients who had and had not received transfusions. None of the 19 subjects had completely normal pulmonary function. Residual volume (in 16 of 19 patients), ratio of residual volume to total lung capacity (12 of 19), and airway resistance (16 of 19) were abnormally increased; maximum expiratory flow (15 of 19) and peak flow (10 of 19) were abnormally reduced. Single-breath carbon monoxide diffusion was normal in 16 of 19. These results indicate that mild to moderate small airway obstruction and hyperinflation are common in thalassemia and that patient age, transfusion history, and iron accumulation are not important factors in the genesis of these pulmonary abnormalities.
Adolescent↗
Refractory shock secondary to copper sulfate ingestion.
Presented is the case of a 62-year-old man with refractory shock secondary to copper sulfate ingestion. The patient's history was complicated by the presence of peptic ulcer disease, myocardial disease, and a known abdominal aortic aneurysm. Despite the presence of such characteristic signs and symptoms as hemorrhagic gastroenteritis, hemolytic anemia, and refractory hypotension, the diagnosis of copper sulfate ingestion was delayed for several days after ingestion, when the family first volunteered that the patient had vomited blue-green material the day before his admission to the hospital. This delay contributed significantly to the patient's ultimate demise.
Copper↗
Delay of UV-induced eye lens protein damage in guinea pigs by dietary ascorbate.
Large accumulations of postsynthetically oxidized proteins are observed in the aged and cataractous eye lens. Ascorbate has previously been used to delay photooxidative damage in vitro. The goals of this study were to confirm that dietary ascorbate can be used to enhance lens ascorbate levels and to determine if lenses with enhanced ascorbate can better withstand photooxidative stress in the form of ultraviolet (UV) light exposure. Guinea pigs were placed on high dietary ascorbate (HDA), 50 mg/day, and low dietary ascorbate (LDA), 2 mg/day, for 21 weeks. Lenses from HDA animals were found to contain 3.3 times more ascorbate than LDA animals. Prior to irradiation, SDS-PAGE protein profiles and exopeptidase activity in HDA and LDA lens soluble proteins were indistinguishable. However upon exposure to UV light, more protein damage (e.g., high-molecular-weight aggregates and enhanced loss of exopeptidase activity) was seen in lens preparations from LDA as compared to HDA animals. These results suggest that ascorbate protects lens components against cataract-like and age-related postsynthetic changes in vivo. As in previous tests on lens preparations, attenuated exopeptidase activity was observed before protein aggregation.
Animals↗
Demonstration of clonable alloreactive host T cells in a primate model for bone marrow transplantation.
The phenomenon of marrow rejection following supralethal radiochemotherapy was explained in the past mainly by non-T-cell mechanisms known to be resistant to high-dose irradiation. In the present study a low but significant number of radiochemoresistant-clonable T cells was found in the peripheral blood and spleen of Rhesus monkeys following the cytoreductive protocol used for treatment of leukemia patients prior to bone marrow transplantation. More than 95% of the clonable cells are concentrated in the spleen 5 days after transplant. The cells possess immune memory as demonstrated by the generation of alloreactive-specific cytotoxicity. The present findings suggest that host-versus-graft activity may be mediated by alloreactive T cells. It is hoped that elimination of such cells prior to bone marrow transplantation will increase the engraftment rate of HLA-nonidentical marrow in leukemia patients.
Animals↗
Immunochemistry of elastotic material in sun-damaged skin.
The nature of elastotic material in sun-damaged human skin was investigated by indirect immunofluorescence. Antibodies were used against the following components of the dermis: type I and type VI collagens, aminopropeptide of type I and type III procollagens, fibronectin, elastin, microfibrillar proteins, and basement membrane represented by the 7S domain of type IV collagen, laminin, and nidogen. The elastotic material exhibited marked fluorescence for elastin and microfibrillar proteins which codistributed with fibronectin. The presence of type I and VI collagens and procollagen type III were demonstrated to a lesser extent within the elastotic material. These results suggest that solar elastosis is primarily derived from elastic fibers and not from preexisting or newly synthesized collagens.
Antibodies↗
Insulin as a potential factor influencing blood pressure in amputees.
War-injured, bilateral above-knee amputees are known to be at increased risk for cardiovascular mortality. To evaluate possible risk factors, we compared blood pressures and plasma glucose and insulin responses to orally administered glucose in 19 above-knee amputees from the Vietnam War (mean age, 36 +/- 1 years) with those of 12 age-matched unilateral below-elbow amputees. Body composition by densitometry and maximal oxygen consumption during arm or leg exercise were also determined. Nine of 19 leg amputees were hypertensive compared with one of 12 arm amputees. Their 3-hour average insulin responses were markedly increased (260 +/- 60 microU/ml) compared with those of normotensive leg (125 +/- 24 microU/ml) and arm amputees (101 +/- 20 microU/ml), and their mean body fat content (37.2%) also was elevated compared with that in both of these groups (23.2 and 22.6%, respectively). A unique finding was that both insulin response and body fat content were strongly and independently correlated with diastolic blood pressure (r = 0.55, p less than 0.01, and r = 0.62, p less than 0.01, respectively). We conclude that insulin may be a major factor in blood pressure regulation in the maturity-onset obesity that develops following traumatic leg amputation in young, healthy men.
Adult↗
Association of elastin with oxytalan fibers of the dermis and with extracellular microfibrils of cultured skin fibroblasts.
The formation of a mature elastic fiber is thought to proceed by the deposition of elastin on pre-existing microfibrils (10-12 nm in diameter). Immunohistochemical evidence has suggested that in developing tissues such as aorta and ligamentum nuchae, small amounts of elastin are associated with microfibrils but are not detected at the light microscopic and ultrastructural levels. Dermal tissue contains a complex elastic fiber system consisting of three types of fibers--oxytalan, elaunin, and elastic--which are believed to differ in their relative contents of microfibrils and elastin. According to ultrastructural analysis, oxytalan fibers contain only microfibrils, elaunin fibers contain small quantities of amorphous elastin, and elastic fibers are predominantly elastin. Using indirect immunofluorescence techniques, we demonstrate in this study that nonamorphous elastin is associated with the oxytalan fibers. Frozen sections of normal skin were incubated with antibodies directed against human aortic alpha elastin and against microfibrillar proteins isolated from cultured calf aortic smooth muscle cells. The antibodies to the microfibrillar proteins and elastin reacted strongly with the oxytalan fibers of the upper dermis. Oxytalan fibers therefore are composed of both microfibrils and small amounts of elastin. Elastin was demonstrated extracellularly in human skin fibroblasts in vitro by indirect immunofluorescence. The extracellular association of nonamorphous elastin and microfibrils on similar fibrils was visualized by immunoelectron microscopy. Treatment of these cultures with sodium dodecyl sulfate/mercaptoethanol (SDS/ME) solubilized tropoelastin and other proteins that reacted with the antibodies to the microfibrillar proteins. It was concluded that the association of the microfibrils with nonamorphous elastin in intact dermis and cultured human skin fibroblasts may represent the initial step in elastogenesis.
Animals↗