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Biomedical subjects

J Caro

Publications and source records attributed to J Caro.

At least 109 records · Page 6Linked 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

Increased ferritin synthesis and iron uptake in inflammatory mouse macrophages.

Iron metabolism during inflammation was studied in normal and stimulated peritoneal mouse macrophages. A model was developed for detection of ferritin synthesis in these cells, and inflammatory stimulation was produced by i.p. injection of thioglycollate broth or i.m. injection of turpentine. The cells were adhered to culture discs and incubated at 37 degrees C with 59Fe-transferrin and 3H-leucine, and after washing the cell lysate was chromatographed. In the lysate from stimulated macrophages iron and tritium activity was found in a joint peak, and both were precipitated by a specific anti-mouse ferritin antibody. No significant peaks of radioactivity were found in lysates from normal cells. This showed that inflammatory RES cells have an increased ferritin synthesis. The uptake of 59Fe was investigated in a separate study and the stimulated macrophages were found to have a much higher iron uptake than normal macrophages.

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

A case-control study of risk factors for large bowel carcinoma.

Two hundred and seven large bowel cancer patients (93% of all cases diagnosed in a defined community between 1965 and 1976) were matched at random with non-cancer subjects of same age, sex, and place of residence. Men with cancer, aged 75 years and younger than, had a more frequent history of work in a local factory handling synthetic fiber than controls (22 versus 10; P less than 0.025). In this factory 45% of cancers occurred before age 60, while this was true in only 24% of cancer cases outside the factory (P less than 0.05). There was a greater tendency for cancers in factory workers to occur in the colon than in the rectum. Heredity was not found to be a risk factor for large bowel cancer. The rate of prior appendectomy was higher in men with colon cancer (P less than 0.05) and the rate of prior cholecystectomy was lower in females with colonic cancer (P less than 0.05). A previous hemorroidectomy was also found more often in males with colonic cancer (P less than 0.05). Long-standing severe constipation was present more often in patients with cancer (P less than 0.01). There was some evidence for a compounding influence of different risk factors, as studied by relative risk ratio. This study confirms the existence of a high risk of large bowel cancer in a group of workers in a synthetic fiber factory and suggests other factors antecedent to large bowel cancer.

Age Factors↗
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↗
PubMed1983

Macromolecular insoluble cold globulin (MICG): a marker for pluripotential hemopoietic stem cells.

In embryonic mice pluripotential hemopoietic stem cells (PHSC) originate in the yolk sac and migrate to the fetal liver and from there to the bone marrow. Hemopoietic cells from yolk sac and fetal liver also migrate to the thymic primordium, and within the thymic environment these prothymocytes differentiate into mature T cells. We have recently demonstrated that macromolecular insoluble cold globulin (MICG), a T cell marker, is synthesized and inserted into the plasma membrane of embryonic prothymocytes as soon as these cells appear in the early thymus. In addition, we have shown that MICG+ cells are present within the fetal liver before the thymus has fully formed. In the present study we show that pluripotential hemopoietic stem cells in the fetal liver and bone marrow have MICG on their surface and represent a subpopulation of these MICG+ cells. The implications of these findings in relationship to stem cell differentiation and isolation are discussed.

Animals↗
PubMed1982

[Clinical activity of m-Amsa and the combination of m-Amsa with cytosine arabinoside].

Of 91 acute leukaemia patients treated with m-Amsa, 19 received intermittent doses, 23 received daily doses and 49 underwent courses with combined m-Amsa and cytosine arabinoside (Ara-C). Intermittent doses had minimal therapeutic activity and toxicity. Among the 23 patients given daily doses, complete remission was observed in 5/12 relapses of ALL and in 2/11 relapses of AML. When Ara-C (200 mg/m2 x 5 days) was administered concomitantly with m-Amsa (200 mg/m2 x 5 days or 120 mg/m2 x 7 days), 17 out of 37 patients with advanced relapses of ALL (13/25 children and 4/12 adults) went into complete remission. While high doses of m-Amsa alone were well tolerated, the combined treatment with high doses of both drugs resulted in severe gastro-intestinal toxicity. Cardiac disorders were observed in patients who had previously received high doses of anthracyclins; there were 5 cases of dysrhythmia and 1 case each of sudden death, ECG alterations and heart failure. In view of its indisputable activity, m-Amsa should be used at an earlier stage in the treatment of acute leukaemias.

Adolescent↗
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

Normalization of hematocrit in patients with end-stage renal disease on continuous ambulatory peritoneal dialysis: the role of erythropoietin.

Observations were made retrospectively and prospectively over one year on all patients on continuous ambulatory peritoneal dialysis (CAPD) to determine the effect of this modality on the hematocrit. Serum erythropoietin and parathyroid hormone levels were measured. Within five months the hematocrit increased 47 to 127 percent up to normal in four of nine patients. Five others remained severely anemic. There was no significant difference in serum creatinine levels among the patients within one month of CAPD. The four patients who responded were anemic while on hemodialysis and other modalities of end-stage renal disease management prior to CAPD. The serum erythropoietin level in the four patients who responded was 9.0 mU/ml or greater with a mean of 28 mU/ml, whereas in those who did not respond it was 5.0 mU/ml or less with a mean of 3 mU/ml. Since uremic toxins in the middle molecule range have been postulated to be responsible for erythropoiesis suppression in end-stage renal disease, and in addition, insufficient erythropoietin production and the clearance of some middle molecular weight substances is six times greater with CAPD than with hemodialysis, it appears that CAPD can normalize the hematocrit in patients with end-stage renal disease who were anemic on other modalities with little or no change in serum creatinine, provided the remnant kidneys are capable of producing sufficient erythropoietin. Parathyroid hormone levels were higher in patients who responded than in patients who did not respond.

Adult↗
PubMed1982

Serum erythropoietin levels by radioimmunoassay in polycythaemia.

A radioimmunoassay (RIA) method for erythropoietin (Epo) was developed and validated against the polycythaemic mouse assay. The correlation was good, with a r = 0.94. Several other criteria of specificity were also filled by the RIA, which had a lower detection limit of 5 microU/ml. The mean serum-Epo level in 6 patients with secondary polycythaemia, 50.2 +/- 26.2 microU/ml, was significantly higher than in a group of 11 normal subjects, 28.7 +/- 7.2 microU/ml (P less than 0.0002). However, the Epo level in 31 polycythaemia vera (PV) patients, M = 21.9 +/- 6.6 microU/ml, was not significantly different from normal (P = 0.006). Since previous studies with bioassay of heat-treated and concentrated plasma samples have shown a decreased serum-Epo level in PV, Epo levels were measured before and after heat treatment and concentration of samples from normals and polycythaemics. It was found that the levels of immunoreactive material increased after heat treatment and 40 times concentration in samples from normals and patients with secondary polycythaemias, but decreased in PV. We conclude that the Epo levels in serum in the low range measured by our and previous RIA:s probably are not true Epo levels but are partly due to an unspecific serum effect, that was removed by heat treatment.

Anemia, Aplastic↗
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

Membrane proteins synthesized by human reticulocytes and their precursors.

Membrane protein synthesis in human immature erythroid cells was studied by incubating the cells with 35S-methionine in vitro. The radioactive precursor amino acid was incorporated into membrane protein in a linear fashion for approximately 60 min, after which there was only a slight increase in incorporation. Intracellular protein synthesis, in contrast, was linear for periods up to 2 h. Analysis of isolated membranes by polyacrylamide gel electrophoresis in sodium dodecyl sulphate showed that peripheral blood reticulocytes synthesized two proteins in the 4.5 region (MW=50-60000 D) and a third protein coinciding with band 6 (glyceraldehyde-3-phosphate dehydrogenase). Separation of reticulocytes into different age groups on stractan II gradients showed more immature reticulocytes synthesize a wider range of membrane proteins, extending from bands 4.1 to 8. When nucleated red cells were present in the incubations, synthesis of band 3 was also observed. Earlier erythroid precursor present in erythropoietic BFU-E cultures synthesized spectrin in addition to the other membrane proteins. The data indicate that human red cell membrane protein synthesis follows a programmed pattern and that as the erythroid elements mature they lose the capacity to synthesize certain membrane proteins.

Cell Differentiation↗