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Biomedical subjects

M H Freedman

Publications and source records attributed to M H Freedman.

At least 145 records · Page 8Linked to original sources

'Recurrent' erythroblastopenia of childhood. An IgM-mediated RBC aplasia.

An anemia of childhood with reticulocytopenia and marrow RBC aplasia was found to be due to immune-mediated erythropoietic suppression. In vitro assays of marrow and peripheral blood erythroid progenitors indicated normal cell numbers that markedly declined when autologous serum or IgM was added to the cultures, but remained unchanged with autologous IgG or with autologous serum depleted of IgM. In contrast to "transient" erythroblastopenia of childhood, this anemia was recurrent, lasted longer, and seemed to be prednisone responsive.

Anemia, Aplastic↗

Transient erythroblastopenia of childhood: varied pathogenesis.

The mechanism of anemia in four patients with transient red cell aplasia of childhood ("erythroblastopenia") was studied at the time of diagnosis by assessing the colony growth of marrow erythroid progenitors in methylcellulose tissue cultures. Marrow from Patient 1 yielded high normal numbers of BFU-E colonies that were completely abolished on addition of autologous serum or IgG. Patient 2 had normal BFU-E growth that markedly declined when autologous serum or IgM was added to the cultures, but growth remained unchanged with added autologous IgG or peripheral blood mononuclear cells (PBMC). Marrow from Patient 3 yielded low CFU-E and BFU-E numbers with standard plating techniques, but colonies strikingly increased when marrow fractions from an albumin density gradient were cultured. PBMC from Patient 3 suppressed control marrow CFU-E and BFU-E, but serum had no effect. Patient 4 had normal CFU-E and BFU-E that increased with autologous serum and remained unchanged with autologous PBMC. We conclude that the red cell aplasia in Patients 1, 2, and 3 was due to suppressed erythropoiesis via IgG, IgM, and cell-mediated inhibition, respectively. In contrast, in Patient 4 no immune mechanism was demonstrated. Whereas transient red cell aplasia has a uniform clinical presentation, there are at least four pathogenetic mechanisms that can be detected in vitro.

Anemia, Aplastic↗

Autoerythrocyte sensitization.

We have seen six examples of autoerythrocyte sensitization in children that allow a definition of the disorder in the pediatric age group. The typical skin lesion is a painful, erythematous bruise that starts after minor trauma or surgery and often involves an area away from the injury site. The skin manifestations can be debilitating, and reappear unpredictably for an indefinite period. Somatic symptoms can be associated with the bruising. Usually the children have a disturbed psychological background. Characteristically, multiple detailed investigations are performed before the diagnosis is made. An intradermal injection of autologous red cells may or may not give a "positive" ecchymotic reaction. Pediatric patients seem to respond well to psychotherapy, which is usually the only effective form of treatment.

Adolescent↗

Ribonuclease inhibition of erythropoiesis in anemia of uremia.

The anemia of chronic renal failure was studied by assessing the effect of uremic serum on proliferation of human marrow erythroid stem cells into colonies in vitro. Of 50 sera tested, 46 inhibited "CFU-E" colony formation by a mean of 72%, and 42 inhibited "BFU-E" colonies by a mean of 53.5%, compared to normal sera. Analysis of the uremic sera revealed a striking increase of ribonuclease activity in every patient. Mean activity in the study group was 17,346 U/ml serum (range 6,700-36,250) compared to control mean of 1,047 +/- 247 U/ml. Purified ribonuclease added to marrow cultures in concentrations simulating uremic serum produced a dose-dependent decrease in CFU-E colonies suggesting that the substance has a role in the production of anemia of renal failure.

Adult↗

Anemia of chronic renal failure: inhibition of erythropoiesis by uremic serum.

The pathogenesis of anemia in patients with end-stage renal disease was studied by assessing the effect of uremic serum on the proliferation and maturation of erythroid progenitor cells, BFU-E and CFU-E, into colonies in vitro. Nucleated peripheral blood cells from 10 anemic patients produced normal or increased numbers of BFU-E colonies in response to added erythropoietin when cultured in control serum, but declined a mean of 63% when autologous uremic serum was substituted. Uremic sera from 90 patients cultured with normal human marrow produced a mean decrease in BFU-E colony growth of 72%, and of CFU-E colony growth of 82%, compared to control serum. Neither hemodialysis nor peritoneal dialysis was effective in removing the inhibitor. We conclude that patients with uremia have adequate circulating erythroid progenitors that respond to erythropoietin normally when removed from the uremic environment, and that uremic serum is toxic and inhibitory to erythropoiesis. This may be an important mechanism in the anemia of chronic renal failure.

Anemia↗

Diamond-Blackfan syndrome. I. Erythropoiesis in prednisone responsive and resistant disease.

We studied the in vitro proliferative characteristics of marrow erythroid progenitors, colony forming unit-erythroid (CFU-E) and burst forming unit-erythroid (BFU-E), in two infants with Diamond-Blackfan syndrome before and during prednisone treatment. Patient 1, had a brisk erythropoietic response to prednisone and the anemia improved; Patient 2 was steroid-unresponsive. Marrow from Patient 1 yielded linear increases in numbers of colonies in erythropoietin dose-response studies, and the magnitude of response was much greater while on prednisone compared to pretreatment. Cultures of stem cell rich fractions of marrow from Patient 1 separated by unit gravity sedimentation (STA-PUT) revealed moderately reduced CFU-E and BFU-E numbers before prednisone, but normal colony numbers during treatment. Patient 2 differed because CFU-E and BFU-E were almost absent at all erythropoietin doses before and during therapy. Even stem cell rich marrow fraction initially yielded very low colony numbers which did not increase significantly while on prednisone. These findings suggest that in Patient 1 there were adequate numbers of progenitors that were able to differentiate normally only in the presence of prednisone. In Patient 2 the erythropoietic failure in vivo and in vitro was unaffected by prednisone.

Anemia, Aplastic↗

Diamond-Blackfan syndrome. II. In vitro corticosteroid effect on erythropoiesis.

To study the action of corticosteroids on erythroid precursors, (burst forming unit-erythroid and colony forming unit-erythroid) in Diamond-Blackfan Syndrome (DBS), marrow from a newly diagnosed untreated infant was studied in vitro with prednisone and dexamethasone. This patient subsequently proved to be steroid responsive. Colony numbers increased linearly in an erythropoietin (EPO) dose response study. There was marked enhancement of colony numbers at all EPO doses after adding either prednisone (10(-6) M) or dexamethasone (10(-9) M) to the cultures. The data indicate that corticosteroids augment erythropoiesis at both early (BFU-E) and late (CFU-E) stages of development in DBS. In contrast, marrow from a second infant with DBS, clinically steroid resistant, failed to respond to steroids in vitro.

Anemia, Aplastic↗

Erythropoietic inhibitors in uremic serum.

The anemia of chronic renal failure was studied by assessing the inhibitory effect of uremic serum on the proliferation of normal human marrow erythroid progenitor cells (CFU-E and BFU-E) using an in vitro colony assay. Of 10 uremic patients studied, sera from 9 inhibited CFU-E colony growth by 29-100%, sera from 8 inhibited BFU-E colony growth by 23-94%, and sera from all inhibited either CFU-E or BFU-E. The sera were fractionated by Sephacryl gel filtration and the fractions were added to the marrow cultures. Almost all the suppressive activity against erythroid colony growth was detected in fractions with mol. wts of from 47,000 to greater than 150,000 daltons and this indicates the presence of several high mol. wt inhibitors. Serum fractionation by Sephacryl gel was useful in confirming the presence of uremic inhibitors of erythropoiesis, and in concentrating them to a degree that will allow detailed characterisation studies.

Adult↗

Hematopoiesis in the human spleen.

To assess the capacity of the human spleen to function as a hematopoietic organ, spleen mononuclear cells from patients undergoing splenectomy were cultured to assay CFU-E, BFU-E, and CFU-C. Although the peripheral blood from cases of hereditary spherocytosis, Gaucher disease, Thalassemia major, and idiopathic thrombocytopenic purpura yielded 3-20 BFU-E/5 X 10(5) cells plated and 1-7 CFU-C/5 X 10(5), suspensions of spleen cells failed to grow colonies. Histologically these spleens did not show extramedullary hematopoiesis. In contrast, peripheral blood from a patient with osteopetrosis (marble bone disease) yielded 130 BFU-E/5 X 10(5), 40 CFU-E/5 X 10(5), and 9 CFU-C/5 X 10(5). The spleen had extensive extramedullary hematopoiesis on microscopy and grew 180 BFU-E/10(5), 210 CFU-E/10(5), and 25 CFU-C/10(5). We conclude that spleens from patients without extramedullary hematopoiesis do not contain committed hematopoietic progenitors in spite of normal precursors in the blood. In osteopetrosis the spleen contained stem cells in a concentration comparable to bone marrow, and the embryonic role of the spleen in blood formation appeared to continue in postnatal life.

Colony-Forming Units Assay↗

Lithium therapy of children with chronic neutropenia.

We treated five children with chronic neutropenia using lithium carbonate and studied the effect in vivo on granulopoiesis. Granulocyte precursors (CFU-C) from blood and marrow, and colony-stimulating activity (CSA) from peripheral blood leukocytes, were assayed in a methylcellulose tissue culture system. Three patterns of response to lithium were seen. In patients with aplastic anemia (one acquired and two Fanconi's aplastic anemia) despite increased colony-stimulating activity, CFU-C numbers remained very low and the neutropenia persisted. In a patient with Kostmann neutropenia colony-stimulating activity, and blood and marrow CFU-C numbers increased, but the agranulocytosis was unchanged. An impressive therapeutic effect was seen in one patient with idiopathic neutropenia with low colony-stimulating activity who responded to lithium with an increase in colony-stimulating activity and CFU-C resulting in persisting normal neutrophil counts. Lithium appears useful in treating a select group of neutropenic patients in whom colony-stimulating activity production is responsive to lithium, and the granulocytic progenitor compartment is capable of producing mature neutrophils.

Adolescent↗

Differentiation of murine marrow megakaryocyte progenitors (CFUm): humoral control in vitro.

Differentiation of mouse marrow megakaryocyte progenitors (CFUm) was studied in vitro by a colony assay using a plasma clot system. Erythropoietin (EPO) from sheep plasma (6 units/mg protein) in doses from 1 to 5 units/ml induced a linear increase in CFUm to a maximum of 20 colonies/10(5) cells plated. Human urinary EPO also induced a dose-responsive increase in CFUm, but the maximum was 9 colonies/10(5) with 2.0 units/ml of EPO and there was a decrease in colonies above that concentration. Thrombocytopoiesis-stimulating factor (TSF) derived from human embryonic kidney culture supernatant fluids induced a dose-responsive increase in CFUm in concentrations from 0.01 to 0.32 mg protein/ml in the absence of added EPO. TSF did not support the growth in vitro of erythroid colonies from mouse marrow (CFUe and BFUe) indicating the absence of EPO activity. In these studies sheep EPO appeared more effective in supporting CFUe growth than human EPO. TSF also had a stimulatory function in megakaryocyte differentiation at a precursor level. Multiple humoral factors play a role in megakaryocytopoiesis in vitro.

Animals↗

Ribonuclease activity in renal failure. Evidence for toxicity.

Ribonuclease isolated from human urine is a glucoprotein of molecular weight 33,000. The purified enzyme inhibits: (1) the stimulation of 3H-thymidine uptake into lymphocytes by phytohemagglutinin, pokeweed, and concanavalin A; (2) the growth of pancreatic fibroblastoid cells in in vitro cell culture, and (3) the growth of colonies in bone marrow cell cultures. Ribonuclease levels in the uremic patient vary from 9,500 to 35,000 U/ml (normal 1,041 +/- 247). Serum ribonuclease levels are unaffected by dialytic procedures. It is suggested that the ribonuclease glycoprotein may represent a large number of nondialyzable high molecular weight uremic 'toxins'.

Acute Kidney Injury↗

Lipid fluidity and membrane protein monitoring using 1,6-diphenyl-1,3,5-hexatriene.

Experiments have been designed to challenge the use of stedy-state fluorescence polarizaiton with 1,6-diphenyl-1,3,5-hexatriene as an evaluator of the fluidity of cell plasma membranes. We used paraffinic systems, of defined structure and composition (liquid paraffin, soap bilayers and phospholipid liposomes--with and without incorporated proteins), to demonstrate that corresponding polarizaiton values cannot be interpreted in terms of the overall fluidity of the labeled medium. In homogeneous structured paraffinic media (lipid bilayers), knowledge of the location of the probe is essential for a consistent interpretation of the observed fluorescence polarization. Due to the highly polarizable electronic structure of the diphenylhexatriene molecule, the presence of heterogeneities with potential sites for interaction (e.g., C18-coated Si particles, albumin molecules, etc.) can lead to relatively high polarization values, even in isotropic media. In cellular systems, translocation experiments from labeled cells to added proteins show a rather localized peripheral distribution of the probe as well as its high affinity for hydrophobic sites of proteins. This and other arguments presented here suggest that although cellular polarization values represent an intricate average over all labeled hydrophobic regions of the cell (phospholipid bilayers, membrane proteins, etc.), these values might reflect, to a large extent, interactions of the probe with proteins from the inner periphery of the cell.

Animals↗

Membrane associated proteins and malignancy: an experimental hypothesis.

Normal human lymphocytes and human tumor cell lines were labeled with an apolar fluorescent probe (1, 6-diphenyl-1, 3, 5-hexatriene), and fluoresence polarization (P) values were determined. The arguments presented in this study suggest that although P values represent an intricate average of all labeled hydrophobic regions of the cell (phospholipid bilayers, membrane proteins and enzymes, etc.), to a large extent, interactions of the probe with membrane proteins are of primary importance. The lower P values obtained with the tumor cell lines, compared with the normal lymphocytes, were interpreted as indicating alterations in either the structure or concentration of a membrane associated protein(s).

Animals↗