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Biomedical subjects

A J Erslev

Publications and source records attributed to A J Erslev.

At least 55 records · Page 3Linked to original sources
PubMed1984

Pure erythrocytosis classified according to erythropoietin titers.

Erythropoietin titers, measured by bioassay of plasma extracts in hypertransfused mice, were determined in 162 patients with absolute erythrocytosis, and the results were correlated with the clinical diagnosis. Fifty-two patients met the diagnostic criteria for polycythemia vera, and all had low or nonmeasurable erythropoietin titers. Of the remaining 110 patients, 62 were suspected clinically as having secondary polycythemia. However, 15 had low erythropoietin titers, casting doubt on the accuracy of the clinical diagnosis. The pathogenesis of the erythrocytosis in the last 48 patients was unknown, and they were designated clinically as having pure erythrocytosis. However, in 20, the erythropoietin titers were increased, and in 28, the titers were low, suggesting that they belonged to at least two different groups. Using erythropoietin titers in the classification of absolute erythrocytosis, the first group should be added to the category of patients with secondary polycythemia as a subgroup with disease due to idiopathic overproduction of erythropoietin (hypererythropoietinemia or essential erythrocytosis). The second group should be added as a subgroup of patients with primary polycythemia under the term erythremia.

Animals↗
PubMed1984

Commitment to erythroid or granulocyte-macrophage differentiation is associated with loss of macromolecular insoluble cold globulin.

In mice a macromolecular insoluble cold globulin (MICG) is present on the surface of resting and stimulated peripheral T lymphocytes, thymocytes, fetal prothymocytes and hemopoietic stem cells forming spleen colonies, colony-forming unit-spleen (CFU-S). Here we demonstrate that removal of MICG positive cells from bone marrow by treatment with antibody and complement does not affect the number of erythroid, burst-forming unit-erythroid (BFU-E) and granulocyte-macrophage, colony-forming unit-granulocyte macrophage (CFU-GM) progenitors developing in vitro. Thus, commitment of stem cells to lineage specific differentiation is associated with the loss of the MICG marker. Furthermore, the removal of MICG positive T lymphocytes from bone marrow does not affect the growth of BFU-E or CFU-GM.

Animals↗
PubMed1984

Biologic and immunologic erythropoietin in extracts from hypoxic whole rat kidneys and in their glomerular and tubular fractions.

The relationship between plasma erythropoietin levels and kidney erythropoietin content was studied in rats subjected to hypoxia for various periods. Plasma and kidney erythropoietin followed a parallel course with detectable levels observed as early as after 1 hour of hypoxia. However, the kidney erythropoietin content reached a maximum at 6 hours, and its plasma erythropoietin content reached its maximum at 24 hours. Despite continuous hypoxia, the erythropoietin in both kidney and plasma decreased after reaching their maximal values, and leveled off after 72 hours. This parallel decrease in plasma and kidney erythropoietin suggests that this decrease in plasma erythropoietin observed after prolonged hypoxia is secondary to a decrease in erythropoietin production rather than to an increase in peripheral consumption. To identify the cell(s) involved in erythropoietin production, kidney cells from anemic-hypoxic animals were separated into their glomerular and tubular components utilizing a successive sieving procedure. Measurement of erythropoietin by bioassay revealed four to five times as much erythropoietin in the tubular fraction as in the glomerular fraction. Radioimmunoassay of these fractions revealed erythropoietin content similar to that by bioassay, ruling out the possible presence of biologically nonactive material. Renin activity, on the other hand, was about equally distributed between both of these fractions. Although our studies do not rule out participation of glomerular or juxtaglomerular cells in erythropoietin production, they suggest that a tubular origin of the bulk of renal erythropoietin is more likely.

Animals↗
PubMed1984

In vitro effect of captopril and three captopril metabolites on neutrophilic progenitor cells from normal mice and mice given busulfan.

Neutrophilic progenitor cells (CFU-NM) in mice with busulfan-induced latent bone marrow hypoplasia have been shown to be selectively suppressed by captopril in vivo. To study this further, marrow from mice given busulfan was used to test for myelotoxicity in vitro. It was found that myelotoxic agents, such as doxorubicin, cytarabine, 1,3-bis(2-chloroethyl)-1-nitrosourea, and chloramphenicol have the same suppressive effect in vitro on CFU-NM obtained from normal marrow as obtained from marrow of mice given busulfan. Our results suggest that in vitro, the CFU-NMs from mice given busulfan are not excessively sensitive to the action of at least these myelotoxic agents. It was also found that neither captopril nor three known captopril metabolites suppress CFU-NM from mice given busulfan. This result suggests either that the myelotoxicity induced in vivo by captopril is not caused by the parent compound or any of the three metabolites tested, or more likely, that the suppressive action of captopril on CFU-NM in vivo is caused by the suppression of an earlier myeloid progenitor cell.

Animals↗
PubMed1984

Secondary polycythemia: a boon or a burden?

The development of a secondary erythrocytosis is usually considered a compensatory effort to counteract tissue hypoxia. However, the associated increase in viscosity tends to decrease blood flow and in theory should augment rather than relieve tissue hypoxia. Clinical observations have supported this concern and phlebotomies have been used to treat cardiopulmonary patients with high hematocrits and to prepare acclimatized mountain climbers for strenuous exercises. Direct measurements of tissue tension in rats and mice have shown that a moderate increase in hematocrit does increase the tissue tension of oxygen, probably due to a concomital increase in blood volume, and only severe increases in hematocrit are detrimental. In contrast, it was found that erythropoietin production in mice and man is decreased at even the most extreme hematocrits, suggesting that the tissue tension in the kidneys is not affected by high hematocrits and sluggish blood flow. This lack of renal hypoxia at high blood viscosities appears to serve an important purpose by preventing a vicious circle in which hypoxia will cause erythrocytosis leading to more hypoxia and more erythrocytosis and so on. However, well maintained secondary erythrocytosis cannot always be considered optimal for overall oxygen transport and has to be evaluated clinically for its potential benefit or harm.

Animals↗
PubMed1983

Erythropoietin in liver tissue extracts and in liver perfusates from hypoxic rats.

An attempt to evaluate the role of the liver in extrarenal erythropoietin production was made by measuring the content of erythropoietin in homogenates and perfusates from hypoxic rat livers. Extracts from livers from nephric or anephric animals rendered both anemic and hypoxic showed no detectable erythropoietin despite the fact that both plasma and kidney extracts contained large amounts of erythropoietin. This lack of measurable erythropoietin in the liver is not caused by degradation of erythropoietin during the extraction procedure because exogenously added rat erythropoietin was recovered to the same extent from livers or kidney homogenates. More likely, however, it is caused by the fact that extrarenal erythropoietin production accounts for only one-fifth of total erythropoietin production and that the liver mass is about six times that of both kidneys. Consequently, the erythropoietin content of 1 g of liver should be about one-thirtieth of that of 1 g of kidney, an amount that is below the limit of detection of the assay. On the other hand, the 2-h in situ perfusates of livers from similarly stimulated animals contained significant amounts of secreted erythropoietin. It is concluded that the liver participates actively in extrarenal erythropoietin production in the adult rat. However, the small amount expected to be present in tissue homogenates cannot be detected with our current bioassay.

Anemia↗
PubMed1982

The effect of a low-phosphate diet on hematocrit and oxygen transport in uremic rats.

Dietary restriction of phosphate was found to prevent the development of anemia in partially nephrectomized rats. In an attempt to examine the reason for this beneficial effect, hematologic and nephrologic studies were carried out on normal and on partially nephrectomized rats fed either a normal or a low-phosphate diet. It was first found that a low-phosphate diet ameliorates the degree of renal impairment found four weeks after partial nephrectomy. Nevertheless, it did not eliminate it, and the degree of uremia actually observed should have been associated with a significant reduction in hemoglobin and red cell mass. However, it did reduce serum phosphate and red cell 2,3-diphosphoglycerate (2,3 DPG) levels and increase hemoglobin affinity for oxygen to a degree that should impair oxygen transport to the tissues. That the low phosphate actually caused tissue hypoxia with increased stimulation of the bone marrow was furthermore suggested by the observation that normal rats fed a low-phosphorous diet developed a significant increase above normal in hemoglobin concentration and red cell mass. It was concluded that the effect of a low-phosphate diet on the anemia of uremia is caused by a combination of reduced renal failure and increased tissue hypoxia.

Animals↗
PubMed1982

Erythropoietin production in response to anemia or hypoxia in the newborn rat.

Erythropoietin production in response to hypoxic-hypoxia is markedly reduced in the newborn when compared to the adult rat. This response improves steadily with age and reaches adult values at about 4 wk. When animals of the same age are stimulated with anemic-hypoxia, considerably higher levels of erythropoietin are found. The erythropoietin level is proportional to the degree of anemia and independent of the age of the animal. Extraction of erythropoietin from tissue homogenates revealed a parallelism between the plasma and kidney erythropoietin content, while no erythropoietin could be extracted from liver tissue at any age. The lack of response to hypoxia in the newborn appears to be related to the high hemoglobin oxygen affinity during the neonatal period, which facilitates oxygen loading. Newborn rats have a very low intraerythrocytic concentration of 2-3 DPG and a marked shift to the left in the oxygen hemoglobin dissociation curve that slowly increases to adult values at 4 wk of age. The response to anemia on the other hand, appears to be normal and not affected by age or by hemoglobin oxygen affinity. These studies suggest that the newborn rat, when properly stimulated, is able to produce normal amounts of erythropoietin, most likely renal in origin.

Anemia↗
PubMed1981

Erythroid adaptation to altitude.

In May 1978, Messner and Habeler were the first to reach the summit of Mt. Everest without the use of supplemental oxygen. This feat illuminated the remarkable capacity of blood to adjust to the environment and support transport of oxygen from the lungs to the tissues despite an ambient oxygen pressure lower than that of normal mixed venous blood. It also met the exacting requirements for a true ascent of Mt. Everest set in 1935 by Frank Smythe in his book "The Spirit of the Hills". Although the conquest may seem more related to the breaking of the four minute mile than to any spirit of the hills, mountaineering has always combined emotional fulfillment with keen competition and scientific curiosity. The early mountain climbers from Petrach to Whymper were reaching for a personal spiritual experience but also were strongly influenced by priorities and first ascents. After the scaling in 1865 of Matterhorn, the last conquered peak in the Alps, a period followed during which physiologists from Bert to Hurtado provided insight into the importance of blood and lungs for oxygen transport and survival at high altitudes. The results of these studies combined with technical skill and competitive grit have permitted the current breed of mountaineers to scale successfully the most vertical mountain faces and the most lofty Himalayan peaks. These field trials of physiologic principles have also been of immense importance for our understanding of the pathophysiology of anemias and polycythemias. For whatever successes we have had in our management of patients with such disorders, we must in no small part give credit to man's eternal fascination with the top of the hills.

Altitude↗
PubMed1981

Erythropoietin production in fasted rats. Effects of thyroid hormones and glucose supplementation.

The effect of T3 replacement and glucose supplementation on erythropoietin production was investigated in fasted hypoxic rats. It was found that 48 hr of fasting significantly reduced the circulating levels of thyroid hormones and the production of renal and extrarenal erythropoietin in response to hypoxia. These effects of fasting were completely abolished when the animals had free access to 25% glucose solution as drinking water, despite their lack of protein intake. Replacement doses of T3 (0.5 micrograms/100 gm per day) restored erythropoietin production in the fasted animals but also increased the response of the fed controls. To avoid the effect of endogenous T3, the experiments were repeated in thyroidectomized rats. Erythropoietin production in athyroid rats was found to be markedly decreased, with values equivalent to those found in normal fasted animals, and were not affected by fasting or glucose supplementation. Replacement doses of T3 increased erythropoietin production in all three groups, but the fasted animals needed five times as much T3 to obtain a response similar to that observed in the fed group. Glucose supplementation enhanced the effect of T3 in the fasted animals but did not completely restore it. These results indicate that caloric deprivation is primarily responsible for the decreased erythropoietin production induced by fasting and that this effect is probably mediated by both a decreased level of T3 and a decreased responsiveness to it.

Acid-Base Equilibrium↗
PubMed1980

Spontaneous increase in erythropoietin and hematocrit value associated with transient liver enzyme abnormalities in an anephric patient undergoing hemodialysis.

An anephric patient undergoing hemodialysis experienced an increase in his hematocrit value (19 +/- 1 per cent to 31 +/- 1 per cent) as a result of increased erythropoiesis (reticulocyte count 1.8 per cent to 7.4 per cent). This increase occurred in concert with an elevation of the patient's liver enzyme levels and was maintained for four months. The hematocrit value returned to its base line only after the liver function tests showed improvement. During the period when the hematocrit value was increasing, the circulating level of erythropoietin was elavated to 71.0 mU/ml--a level higher than that seen in either anephric or nephric patients undergoing dialysis. When the hematocrit value and liver enzyme levels had returned to their base line values, the erythropoietin level was 4.3 mU/ml--a level in the range seen in anephric patients undergoing dialysis. The observations in this patient suggest that under certain circumstances, the liver can produce erythropoietin in the anephric patient; and, more importantly, that the bone marrow of at least some uremic patients is capable of responding to the endogenous erythropoietin.

Bone Marrow↗
PubMed1980

Renal and extrarenal erythropoietin production in anaemic rats.

Rats were rendered anaemic by a single bleeding or by a single injection of phenylhydrazine. At various times after the onset of anaemia they were nephrectomized and challenged with a 6 h exposure to hypoxia. The erythropoietin titre observed at the end of this hypoxic period was corrected for renal erythropoietin induced by the anaemia alone, and the resulting extrarenal component was compared to total erythropoietin production of nephric rats in response to anaemia plus 6 h hypoxia. Extrarenal erythropoietin production was found to increase from 10.3% in normal rats to 12.5% in moderately anaemic rats to 15.1% in rats with severe bleeding anaemia. In phenylhydrazine-treated rats this extrarenal component was found to be 18.3% possibly due to stimulation of extrarenal erythropoietin by haemolysed red cells. Chronic phenylhydrazine administration resulted in splenomegaly and Kupffer cell hyperactivity but not in any further stimulation of extrarenal erythropoietin production.

Anemia↗
PubMed1980

The biogenesis of erythropoietin.

Aerobic living demands a constant supply of oxygen at the cellular mitochondrial level. Numerous interlocking feedback mechanisms insure the constancy of this supply by adapting the supply lines to changes in the intra and extracellular milieu. Among these mechanisms is the feedback circuit which, triggered by an intracellular decrease in oxygen supply, initiates the production of a polypeptide hormone, erythropoietin, which in turn augments the production of an oxygen carrier, the hemoglobin-containing red cell. The biogenesis of this hormone is an important biologic process which is being studied intensively and slowly unravelled.

Animals↗
PubMed1979

Plasma erythropoietin in polycythemia.

Erythropoietin titers of plasma cannot be used to differentiate polycythemia vera from secondary polycythemia since the limit of sensitivity of our current bioassay technics is 50 mU, considerably higher than levels found in normal subjects and in patients with polycythemia. However, erythropoietin is relatively heat stable, and since abundant plasma is available from therapeutic phlebotomies it is possible to prepare and assay highly concentrated, erythropoietin-containing extracts. In 35 normal subjects, erythropoietin levels ranged from less than 5 mU/ml (the limit of sensitivity) to 18 mU/ml with a mean of 7.8 mU/ml. In 21 patients with proved polycythemia vera, the levels were less than 5 mU/ml in all. In 41 patients with suspected secondary polycythemia or polycythemia of unknown origin, the levels ranged from less than 5 to 3,000 mU/ml. Three of the 11 patients with levels less than 5mU/ml were subsequently shown to have polycythemia vera. These results suggest that this refinement of the routine bioassay for erythropoietin may be of clinical importance in the differential diagnosis of polycythemia.

Erythropoietin↗
PubMed1979

Are the native kidneys responsible for erythrocytosis in renal allorecipients?

The development of erythrocytosis following renal transplantation has been reported to be caused by a number of factors. These include acute and chronic rejection, hydronephrosis and renal artery stenosis. In this study, seven patients were noted to have erythrocytosis with hematocrits ranging between 53.5 and 66%. Serum erythropoietin levels were elevated and ranged between 11 and 60 mU/ml with a mean of 31.9 mU/ml in six of seven patients. Selective catheterization of veins of native and transplanted kidneys in three patients revealed mean serum levels of 40.9 and 13.0 mU/ml, respectively. This suggests that excess erythropoietin is being produced from the diseased native kidneys. Bilateral nephrectomy in one patient cured erythrocytosis and dropped systemic levels of erythropoietin (EP) to 6.1 mU/ml. In four of the remaining five patients, hematocrits came down spontaneously to within normal over a 1- to 3-year period. Consequently, it appears that in a number of transplant patients the retained diseased kidneys, having lost all excretory and concentrating function, may remain capable of functioning as endocrine erythropoietin-producing organs.

Erythropoietin↗