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J W Adamson

Publications and source records attributed to J W Adamson.

At least 145 records · Page 8Linked to original sources
PubMed1981

Megakaryocytopoiesis in the mouse: response to varying platelet demand.

The response of murine megakaryocytopoiesis was studied under conditions of varying platelet demand. Twenty-four hours after mice were given a single injection of rabbit anti-platelet serum, megakaryocyte number and volume were increased, becoming maximal at 65 and 40 hr, respectively. Total body megakaryocytic colony-forming unit (CFU-M) numbers did not change until 90 hr, when a 35% increase in the experimental group was noted. The percentage of CFU-M in DNA synthesis in the experimental group was 38 +/-2% at 24 hr, 49 +/- 1% at 40 hr, and returned to normal (11 +/- 3%) at 90 hr. When mice were made thrombocytotic by platelet transfusions, both megakaryocyte number and volume were decreased compared to controls, while no difference was noted in the number and percentage of CFU-M in DNA synthesis. Finally, experiments were performed to examine the effect of platelet transfusions on regenerating marrow. Experimental mice were given platelet transfusions while control animals received platelet buffer solution. At sacrifice the number and volume of megakaryocytes in the experimental group (platelet count 2.568 X 10(6)/microliters) were less than controls (platelet count 0.363 X 10(6)/microliters), while the number and percentage of CFU-M in DNA synthesis were similar in both groups. These results demonstrate that CFU-M are not immediately responsive to acute changes in platelet demand. The data suggest that megakaryocytopoiesis is structured on at least two levels which are independently regulated.

Animals↗
PubMed1981

Chronic myelogenous leukemia: in vitro studies of hematopoietic regulation in a patient undergoing intensive chemotherapy.

A patient heterozygous for the X-linked enzyme glucose-6-phosphate dehydrogenase and with Philadelphia chromosome-positive chronic myelogenous leukemia (CML) was treated with combination chemotherapy and had a partial loss of Philadelphia chromosome accompanied by partial restoration of nonclonal hematopoiesis as determined by glucose-6-phosphate dehydrogenase. Studies of in vitro hematopoiesis were performed after chemotherapy to evaluate the influences of neoplastic stem cells on normal cells and to determine whether there were physical and cell kinetic differences between leukemic stem cells and their normal counterparts. The data revealed the following: (a) The frequencies of normal committed granulocytic stem cells (CFU-C) and erythroid stem cells (BFU-E) in blood did not differ from the frequencies in marrow. (b) Normal late erythroid progenitors (CFU-E) were found at a significantly lower frequency that the more primitive BFU-E. Calculations indicated that not only was there a decrease in CFU-E production by normal BFU-E, but there was also abnormal clonal expansion of CML BFU-E (CFU-E:BFU-E ratio for normal progenitors was 1.1, whereas for the CML clone it was 11.5). (c) No increase in frequency of normal CFU-C was found after marrow cells were exposed to high specific activity tritiated thymidine. (d) Normal CFU-C and those from the CML clone were not separable on the basis of density. (e) The frequency of normal BFU-E was consistently greater than that of CFU-C, suggesting that regulatory differences influence the commitment of normal progenitors to the two pathways.

Adult↗
PubMed1981

Polycythemia: mechanisms and management.

The principal function of erythrocytes is the transport of oxygen. Erythropoiesis proceeds at a rate consistent with the demand for oxygen-carrying capacity, and the major regulator of erythrocyte production is erythropoietin. Erythropoietin is produced primarily by the kidney under control of a tissue oxygenation sensor. The recently developed erythropoietin radioimmunoassay should provide a clinically useful tool. Erythrocytosis is a pathologic state characterized by an elevated erythrocyte mass, which may result from increased proliferation of erythroid progenitors due to an intrinsic cellular defect or in response to extrinsic signals. Secondary erythrocytosis results from either physiologically appropriate compensation for inadequate tissue oxygenation or from inappropriate stimulation of erythropoiesis. Erythrocytosis increases oxygen-carrying capacity of the blood, but at high hematocrit levels increased blood viscosity may result in decreased tissue oxygen delivery. Polycythemia vera is a hematopoietic stem cell disease of clonal origin. Initial results from the Polycythemia Rubra Study Group suggest that therapy with chlorambucil is associated with an unacceptably high risk for development of acute leukemia, and 32P is preferred for situations in which phlebotomy alone is insufficient.

Blood Gas Analysis↗
PubMed1981

Haemoglobin synthesis in human erythroid bursts during ontogeny: reproducibility and sensitivity to culture conditions.

Patterns of haemoglobin (Hb) synthesis were analysed in erythroid bursts grown in vitro from human fetal, umbilical cord and adult blood to determine the reproducibility of the system and its sensitivity to various alterations in culture conditions. The proportion of Hb F synthesis in duplicate plates from the same sample showed little variation but when an individual was studied under the same conditions but at different times, far more variability was observed. We have confirmed that the synthesis of Hb F and Hb A in the cultures is asynchronous, relatively more Hb F being synthesized earlier in the maturation of the colony. Hence factors affecting colony maturation are likely to change the apparent pattern of Hb synthesis. Removal of adherent cells prior to plating resulted in the presence of more mature colonies and lower levels of Hb F synthesis at any fixed time in culture. Furthermore, the overall ratio of gamma:beta chain synthesis measured in the whole plate was dependent on the proportion of large, immature multicluster bursts present. The significance of measurements of Hb synthesis in erythroid bursts can be assessed only if all of these factors are recognized and taken into account.

Adult↗
PubMed1981

Acute nonlymphocytic leukemia: heterogeneity of stem cell origin.

Four patients with acute nonlymphocytic leukemia who were heterozygous for the X-chromosome-linked enzyme glucose-6-phosphate dehydrogenase (G6PD) were studied to determine the numbers and types of progenitor cells in which the disease arose. Both forms of enzyme were found in normal tissues, but the malignant blast cells showed only one G6PD, indicating that the disease was clonal at the time of testing. The observations that normal erythroid cells were present in two young patients at diagnosis and relapse indicate that the clone suppressed expression of normal granulopoiesis but did not prevent normal erythroid differentiation. In contrast to this situation, in two elderly patients, the disease involved stem cells multipotent for granulocytes, red cells, and platelets. These results indicate that acute nonlymphocytic leukemia is heterogeneous. In some patients, the disease is expressed in cells with differentiation restricted to the granulocyte-monocyte pathway; in others, it involves stem cells capable of differentiating to granulocytes-monocytes, platelets, and erythrocytes. This heterogeneity may reflect differences in causation and could have prognostic and therapeutic importance.

Acute Disease↗
PubMed1981

Autosomal Dominant familial erythrocytosis due to autonomous erythropoietin production.

A family is described in which four members spanning three consecutive generations have erythrocytosis associated with a normal hemoglobin oxygen affinity. When bone marrow from one affected family member was cultured in vitro, erythroid colonies formed only when erythropoietin was added to the culture. Serum erythropoietin, measured by radioimmunoassay, was significantly elevated above normal in each of the affected family members. Bioassayable erythropoietin was detected in the urine of two of the three affected family members. In two of the affected family members, erythropoietin was measured in serum by radioimmunoassay and in urine by bioassay before and for 4 days following an isovolemic phlebotomy, which reduced the red cell mass by 20%. Neither serum nor urinary erythropoietin levels changes following phlebotomy. The erythrocytosis in this family appears to be secondary to inappropriately increased erythropoietin production unassociated with a decrease in the blood oxygen-carrying capacity. This is the first instance in which autonomous erythropoietin production appears to be inherited on an autosomal dominant basis.

Adolescent↗
PubMed1980

Megakaryocytopoiesis in culture: modulation by cholinergic mechanisms.

Treatment of murine bone marrow cultures with the cholinergic agonist carbamylcholine enhanced megakaryocytic colony growth by as much as 65%. In contrast, adrenergic agonists had no such effect. Addition to cultures of dibutyryl cyclic GMP (db-cGMP) also enhanced megakaryocytic colonies up to 50%, whereas dibutyryl cyclic AMP (db-cAMP) had no effect. Sodium nitroprusside and sodium nitrite, putative guanyl cyclase activators, also enhanced colony numbers, as did imidazole, a postulated cGMP phosphodiesterase inhibitor. Preincubation of marrow for two hours with carbamylcholine resulted both an increase in colony numbers (58%) and percent of progenitors in DNA synthesis (48%, compared to 14% for controls) as determined by tritiated thymidine suicide studies. Treatment of mice with the acetylcholinesterase inhibitor neostigmine resulted in an increase in CFU-M/humerus (62%) and percent in DNA synthesis (45%). These data indicate that 1) cholinergic, but not adrenergic, agonists modulate megakaryocytopoiesis in culture; 2) this effect may be mediated by cyclic GMP; and 3) only a brief period of exposure of marrow cells to agonist results in enhancement of megakaryocytic colonies.

Adrenergic alpha-Agonists↗
PubMed1980

Physiologic studies in normal and uremic sheep: I. The experimental model.

A model of chronic renal failure was created in nine adult sheep by two-stage, subtotal nephrectomy. Carotid-jugular cannulas provided clot-free access for 72 to 274 days without exit-site infections. All sheep became uremic and anemic. Median survival, while uremic, was 145 days (72 to 327 days), although three were sacrificed. Five required dialysis within the first week of uremia, and median survival on dialysis was 70 days (41 to 177 days). Sheep that maintained adequate nutrition survived the longest on dialysis. Mean creatinine and BUN levels in the stable uremic and dialyzed sheep were 4.8/95 and 7.8/59 mg/dl, respectively. The other serum chemistries remained unchanged (mean values) from normal, although one sheep died of hypercalcemia (17.8 mg/dl). Renal blood flow correlated to GFR in both normal and uremic states. GFR fell more than serum creatinine rose, suggesting extrarenal excretion of creatinine.

Animals↗
PubMed1980

Physiologic studies in normal and uremic sheep. II. Changes in erythropoiesis and oxygen transport.

Red cell production and survival, cardiac output (CO), renal blood flow (RBF), serum erythropoietin (ESF), oxygen (O2) consumption, 2,3-diphosphoglycerate (2,3-DPG), P50, and circulating hemoglobin (HbC) were measured in normal sheep and in animals made chronically uremic and anemic by subtotal nephrectomy. The erythropoiesis characterizing uremic anemia was hypoproliferative as quantitated by ferrokinetics, but was still subject to normal feedback control in that erythropoiesis in normal and uremic animals increased with phlebotomy and was suppressed with transfusion. ESF levels were only measurable when the hematocrit fell below 25 in normal animals and were undetected in most stable uremics (hematocrit, 18 to 10%). HbC correlated with ESF. CO increased linearly with progressive anemia in normal and uremic states but, despite this increase, relative RBF decreased; the percent of the CO going to the kidney fell with severe anemia. Venous O2 extraction increased linearly in normal and uremic states as anemia progressed, resulting in no difference in O2 utilization between the study states. There were no correlations between 2,3-DPG, P50, or hematocrit, under any conditions. These results confirm the mechanism of anemia in chronic renal failure and demonstrate that the O2 delivery ESF erythroid marrow feedback mechanism persists in the uremic state over a wide range of hematocrits.

Animals↗
PubMed1980

Congenital erythrocytosis: a new form associated with an erythropoietin-dependent mechanism.

Three patients with probable congenital erythrocytosis were studied to determine the role of erythropoietin (ESF) in their disease. In addition, haemoglobin function was measured and ESF excretion determined in response to reduction in the haemoglobin concentration. In two cases ESF excretion was clearly elevated above normal, and in the third excretion was normal even at an elevated PCV. In all, phlebotomy of 15--20% of the blood volume led tomore than doubling in ESF excretion. This occurred in the presence of normal molecular haemoglobin function. Studies of the renal vasculature were normal. These results suggest a new form of congenital erythrocytosis associated with increased ESF production which is reciprocally related to the oxygen carrying capacity of the blood, but in the absence of any demonstrable abnormality in oxygen transport. These findings suggest an inherited defect, likely residing in the renal sensor responsible for the production of ESF. This defect is possible due to impaired recognition of available oxygen or else a decrease in oxygen supply at the subcellular level.

Adolescent↗
PubMed1980

Polycythemia vera. Physical separation of normal and neoplastic committed granulocyte-macrophage progenitors.

In previous studies of two patients with polycythemia vera (PV) who were heterozygous at the X-linked locus for glucose-6-phosphate dehydrogenase (G6PD), only A type enzyme was found in nonlymphoid blood cells. However, some erythroid and granulocytic colonies grown in vitro were type B and therefore arose from presumably normal progenitors. One patient had enough type B colonies (8%) that studies of the physical characteristics of normal and PV clonal colony-forming cells could be undertaken. When marrow cells were separated by velocity sedimentation at unit gravity, most PV clonal granulocyte-macrophage progenitors (CFU-C) (type A G6PD) sedimented between 6.4 and 7.2 mm/h, whereas most residual normal, type B CFU-C sedimented less than or equal to 5.9 mm/h (P = 0.04)., When blood cells were separated over a discontinuous buoyant density gradient, PV clonal CFU-C equilibrated at densities < 1.065 g/ml, whereas residual normal CFU-C were found greater than or equal to 1.065 g/ml (P < 0.01). PV clonal and residual normal erythroid burst-forming progenitors were not separable by either method. Thus PV clonal CFU-C are larger and less dense cells than are residual normal CFU-C.

Erythrocytes↗
PubMed1980

Polycythemia vera. Further in vitro studies of hematopoietic regulation.

Further in vitro studies of hematopoietic regulation were carried out in two patients with polycythemia vera who were also heterozygotes (Gd(B)/Gd(A)) for glucose-6-phosphate-dehydrogenase (G-6-PD). While only G-6-PD type A was detectable in circulating erythrocytes, granulocytes and platelets, cultures of peripheral blood and marrow from one patient revealed a substantial number of G-6-PD type B erythroid burst-forming units (BFU-E) and granulocyte/macrophage colony-forming units. Detailed analysis demonstrated: (a) where detectable, normal BFU-E and granulocyte/macrophage colony-forming units were found with similar frequencies; (b) the same frequencies for normal progenitors characterized cultures of peripheral blood and marrow; (c) inhibition of normal erythroid differentiation between BFU-E and the more mature erythroid colony-forming unit; (d) a decline in the prevalence of normal colony-forming units with time, suggesting that disease progression is associated with further suppression of normal hematopoiesis by products of the abnormal clone.

Bone Marrow Cells↗
PubMed1980

Restoration of nonclonal hematopoiesis in chronic myelogenous leukemia (CML) following a chemotherapy-induced loss of the Ph1 chromosome.

After intensive chemotherapy, marrow cells of some patients with Philadelphia chromosome (Ph1) positive chronic myelogenous leukemia (CML) become partially or completely Ph1-negative. However, without a second marker for the neoplastic clone, it could not be determined if these Ph1-negative cells arose from normal progenitors or were still members of an abnormal clone. In the present study, a patient with Ph1-positive CML, also heterozygous for glucose-6-phosphate dehydrogenase (G6PD), was studied before and after intensive chemotherapy. Prior to treatment only G6PD type B was detected in the patient's red cells, platelets, and granulocytes, and all unstimulated marrow metaphases had Ph1. After four cycles of chemotherapy, 76% of marrow cells were Ph1-negative, and approximately 80% of the granulocytes were nonclonal by G6PD analysis. Thus, the frequency of nonclonal cells by G6PD analysis correlated closely with that of the Ph1-negative cells. The data indicate that intensive chemotherapy can restore nonclonal and presumably non-neoplastic hematopoiesis in CML.

Adult↗
PubMed1979

Acute nonlymphocytic leukemia: expression in cells restricted to granulocytic and monocytic differentiation.

Two patients with acute nonlymphocytic leukemia who were heterozygous for the X-chromosome-linked enzyme glucose-6-phosphate dehydrogenase were studied to determine the number and type of cells in which the disease arises. Both type A and B isoenzymes were found in normal tissues, but the myeloblasts showed only one enzyme type, indicating that at the time of study, the disease had a clonal origin. The observation in one patient that erythroid cells did not arise from this clone contrasts with conclusions reached in patients previously studied with chromosomal markers. The results suggest that in this patient, the leukemic clone suppressed expression of normal granulopoiesis but did not inhibit erythroid differentiation from normal progenitors. They suggest also that the disease is heterogeneous. In some patients, the disease is expressed in cells with differentiation restricted to the granulocyte-macrophage pathway; in others, it involves stem cells that also differentiate into erythrocytes. This heterogeneity may reflect differences in causation and could have prognostic importance.

Acute Disease↗
PubMed1979

Cellular origins of the fetal-haemoglobin-containing cells of normal adults.

The origin of the small population of adult red cells which contain Hb F (F-cells) has been studied in a clonal disorder of haemopoiesis, polycythaemia rubra vera (P.R.V.). In eleven patients who had not received cytotoxic therapy F-cells comprised less than 0.1% to 11.9% of the circulating red cells, compared with 0.34% to 4.6% in 21 haematologically normal controls. Two additional patients were glucose-6-phosphate-dehydrogenase heterozygotes in whom the clonal nature of the P.R.V. could be demonstrated directly; they had F-cell values of 2.1% and 8.3%. These observations indicate that F-cells arise from the same population of stem cells as other adult cells and not from a separate stem-cell pool.

Aged↗