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Biomedical subjects

W Fried

Publications and source records attributed to W Fried.

At least 55 records · Page 3Linked to original sources
PubMed1978

Effect of protein deprivation on hematopoietic stem cells and on peripheral blood counts.

Experiments were performed to determined the effect of protein deprivation on CFU-S in the spleen and femoral marrow, on the peripheral blood counts, and on the rate at which these parameters regenerate following radiation. Splenic CFU-S decrease in number after only 3 days on diets containing 5% protein or less. Marrow CFU-S, on the other hand, decrease only after mice are fed a protein-free diet for 4 weeks or more. The hematocrits, platelet counts, and WBC counts fall in the latter group. Marrow CFU-S regenerate more slowly in irradiated mice fed diets containing 5% protein or less. Also, the hemocrits, WBC counts, and platelet counts of irradiated mice fed diets containing 5% protein regenerate more slowly than do those of irradiated mice fed normal diets. The effect of protein deprivation on erythropoietin production, erythropoiesis, granulocyte function, and immunocompetence is well known. The studies reported here indicate, in addition, that protein deprivation also causes the numbers of CFU-S and the platelet counts to decline.

Animals↗
PubMed1977

Cooperative erythropoietic assay of several steroid metabolites in polycythemic mice.

A blinded cooperative assay of several androstane and pregnane steroid metabolites has been carried out in order to determine whether 5beta-H derivatives are as active as testosterone in stimulating in vivo erythropoiesis. The steroids tested were: testosterone, 5alpha-dihydrotestosterone, 5beta-dihydrotestosterone, 5beta-pregnane-3,20-dione, 3alpha-dihydroxy-5beta-pregnane-11,20-dione and 3beta-hydroxy-5beta-pregnan-20-one. The incorporation of radioactive iron into newly formed red cells in exhypoxic polycythemic mice was used to compare the effects of the steroids. Testosterone and 5alpha-dihydrotestosterone both produced significant increases in 59Fe incorporation. 5beta-dihydrotestosterone, 5beta-pregnane-3,20-dione, 3alpha-hydroxy-5beta-pregnane-11,20-dione and 3beta-hydroxy-5beta-pregnan-20-one were all devoid of significant erythropoietic activity in polycythemic mice in almost all instances. Thus, under the conditions chosen, this study failed to demonstrate that 5beta-steroids increase radioactive iron incorporation in red cells of exhypoxic polycythemic mice.

Androstanes↗
PubMed1977

Effects of cyclophosphamide and of busulfan on spleen colony-forming units and on hematopoietic stroma.

The effects of cyclophosphamide (CY) and busulfan (BU) on the hematopoietic stromal function (HS-P) of mouse marrow were evaluated. Stromal function of femoral marrow was assessed by implanting the test femur s.c. into an isogeneic host and determining the number of CFU-S in the implant 6 weeks later. Since the CFU-S have been shown previously to be primarily of host origin, this presumably measures the abilit- of donor hematopoietic sites to harbor host CFU-S. After injection of CY, the number of CFU-S in the marrow fell but recovered to normal within 6 weeks. The HS-P function fell to half-normal after 10 mg of CY and did not regenerate detectably in 6 weeks. On the other hand, 2 mg of BU i.p. caused a lesser initial decline in the number of CFU-S, but recovery was still incomplete after 6 weeks. BU given p.o. had a more marked effect on CFU-S and caused a significant decline in the HS-P function. Doses of CY (5 mg/dose) given intermittently appear to cause cumulative damage to HS-P function. HS-P function did not, in any experiment, recover significantly in the 6 weeks following the last dose of CY. This result suggests that large doses of the alkylating agent CY causes prolonged and perhaps permanent HS-P damage. This damage to the HS-P is cumulative when the CY is given at weekly intervals. Despite lack of HS-P recovery, CFU-S regenerate rapidly after CY therapy is stopped. On the other hand, BU also causes damage to the HS-P. However, even when BU is given at a dosage that does not significantly affect the HS-P, CFU-S recovery is delayed, suggesting that BU affects the CFU-S in a manner that differs qualitatively from that of CY.

Animals↗
PubMed1977

Effect of erythropoietin therapy on the red cell volume of uraemic and non-uraemic rats.

Studies were performed to determine the effect of injecting repeated doses of erythropoietin (Ep) on the red cell volume of chronically uraemic rats and on that of non-uraemic sham operated ones. After 13 doses of Ep (5 u/dose), started either 5 or 21 d after removal of five-sixths of the renal mass, the increase in the red cell volume of uraemic rats was as great as that of non-uraemic ones. The significance of these results is discussed.

Anemia↗
PubMed1977

Effects of partial hepatectomy on extrarenal erythropoietin production in rats.

Studies were performed to determine the effects of partial hepatectomy on extra-renal erythropoietin production. Rats were either partially hepatectomized or sham operated. At intervals of from 5 min to 7 days afterward, both kidneys were removed from cohorts of the above two groups of rats and the animals were then exposed to hypoxia for 7.5 hr. Immediately afterward, their plasma was collected and its erythropoietin titer was assayed. Rats which were partially hepatectomized 2-4 days prior to nephrectomy and hypoxia had significantly higher plasma erythropoietin levels than did sham-operated controls, whereas rats hepatectomized 5 min, 1 day, or 7 days prior to nephrectomy and hypoxia did not. These data are consistent with the conclusion that extrarenal erythropoietin production is enhanced in association with rapid regeneration of hepatic cells.

Animals↗
PubMed1977

Effect of protein deprivation on erythropoiesis.

The effects of protein deprivation on erythropoietin (Ep) production were studied. The posthypoxia plasma Ep levels of rats fed a protein-free diet for only 1 day prior to being exposed to 0.5 atmosphere for 7 hr were significantly lower than those of comparably hypoxic rats maintained on a normal diet. The postthypoxia plasma Ep levels were even lower in rats kept on protein-depleted diets for longer periods of time. Rats fed diets with 0.5%, 5% or 12% protein content for 6 days had lower posthypoxia plasma Ep levels than those fed a normal diet (20% protein content). When a single protein meal was force-fed to protein-deprived rats 0-4 hr after initiating the exposure to hypoxia, the posthypoxia plasma Ep levels were significantly higher than in protein-deprived rats that were fed water or dextrose. The posthypoxia plasma Ep titers of protein-deprived rats fed protein 4-8 hr prior to exposure to hypoxia did not differ significantly from those of protein-deprived rats. Although the posthypoxia plasma Ep levels of protein-deprived rats fed a hemolysate containing 0.8 g of hemoglobin 4 hr after beginning hypoxia were greater than those of protein-deprived rats fed only water, the rate of oxygen consumption in these two groups did not differ. We conclude that, in addition to its response to the availability of oxygen, Ep production is infl,enced by the availability of amino acids.

Animals↗
PubMed1976

Regeneration of CFUs in the marrow of mice exposed to 300 rads after having recovered from 950 rads.

Exposure to 950 rads 60Co radiation has been reported to cause long-lasting damage to the hematopoietic stroma (HS), although the size of the CFUs population recovers to pre-irradiation levels. In these studies HS damage was detected only after subcutaneously implanting the femurs of the irradiated mice into syngeneic hosts. To exclude the possibility that what was considered to be HS damage was merely caused by artifacts due to the process of implantation in a new host, we compared the rate of regeneration of CFUs in mice which had recovered from 950 rads prior to receiving 300 rads 60Co radiation (950 + 300 rads group) with that of mice which received only 300 rads (0 + 300 rads group). The CFUs population in the 950 + 300 rads group grew exponentially for 2 weeks at a rate which did not differ significantly from that of CFUs in the 0 + 300 rads group. However, the rate of CFUs growth reached a plateau before full recovery was achieved in contrast to that in the 0 + 300 rads mice. We therefore conclude that the incomplete regeneration of CFUs in the marrows of 950 + 300 rads mice was most likely caused by X-irradiation-induced damage to the HS rather than damage to the inherent repopulating potential of the CFUs per se.

Animals↗
PubMed1976

Suppressive effect of endotoxin on erythropietin-responsive cells in mice.

Infection may be associated with failure of erythropoiesis, and endotoxin has been shown to cause a decrease in the number of erythroid cells in the marrow of mice. We have investigated the effect of endotoxin on erythropoiesis in BDF1 mice by studying its effect on the incorporation of intravenously administered 59Fe into peripheral red cells. In normal mice the injection of endotoxin 2 and 3 days prior to the administration of 59Fe results in suppression of its incorporation into red cells. In exhypoxic polycythemic mice, endotoxin suppresses the response to erythropoietin injection when the endotoxin is given prior to or at the same time as the erythropoietin. This effect is much less marked when endotoxin is given after erythropoietin. We conclude that endotoxin either 1) impairs the function of erythropoietin-responsive cells, 2) competively decreases erythroid progenitors by stimulating granulocytes, or 3) inactivates erythropoietin.

Animals↗
PubMed1976

The utilization of senescent red cell and hemolysate iron for erythropoiesis.

We report experiments to determine the availability for new hemoglobin production of radioiron from nonviable red cells at various times after deposition in the reticulo-endothelial system and to determine the relative availability of radioiron derived from hemolysates versus that derived from nonviable red cells. When heated nonviable red cells labeled with 59Fe are injected into polycythemic mice the iron is deposited in the reticulo-endothelial system, and less than 1% of it is reutilized for hemoglobin synthesis. If the polycythemic mice are given nonviable red cells 48 hours after exposure to hypoxia, when hemoglobin synthesis is maximal, 25% of the iron is reutilized. When the cells are given 36 hr after exposure to hypoxia, iron reutilization declines to 16%, and when exposure to hypoxia is further delayed, reutilization of the iron falls to a plateau level of 11%. Radioiron from hemolysates, primarily deposited in parenchymal cells of the liver, is less available for new hemoglobin synthesis than is radioiron from nonviable red cells, which is primarily deposited in Kupffer cells of the liver. When transferrin-bound iron is given to polycythemic mice, this iron is also deposited in parenchymal cells of the liver and is also less available for new hemoglobin synthesis. Thus, in relation to an erythropoietic stimulus, the site and time of deposition of iron influence its accessibility for erythropoiesis.

Animals↗
PubMed1976

Normal colony stimulating factor (CSF) production by bone marrow stromal cells and abnormal granulopoiesis with decreased CFUc in S1/S1d mice.

The concentration of CFUC and the production of stromal-derived CSF in the femora of S1/S1d mice were determined. There was a lower concentration CFUC and a smaller total number of nucleated cells in the femoral marrow of WCB6. S1/S1d (S1/S1d) mice than in WCB6. +/+/(+/+) mice or in C57B1/6. +/+ (C57Bl) mice. On the other hand stromal-derived CSF production by femora from S1/S1d mice did not differ significantly from that of +/+'s. These observations indicate that the microenvironmental defect of S1/S1d mice results in decreased growth of granulocytic precursors as well as those of erythroid and megakaryocytic cells. This is consistent with the reported decrease in multipotential stem cell proliferation. Stromal cell derived CSF production was normal and could not be implicated in the decreased production of granulocytic precursors.

Animals↗
PubMed1976

Dynamics of leukemic and normal stem cells in leukemic RFM mice.

RFM mice spontaneously develop a myelogenous leukemia that is transplantable into nonleukemic RFM mice. On transplantation, hemopoietic stem cells from leukemic mice (L-CFU-S) will seed in the spleen and grow as discrete colonies, as will hemopoietic stem cells from normal mice (N-CFU-S). As the leukemic cells used in these experiments have 39 chromosomes and normal murine cells have 40, it has been possible to estimate the numbers of N-CFU-S and L-CFU-S in RFM mice at weekly intervals after these mice had been given i.v. injections of 10(6) leukemic spleen cells (spleen cells from preterminal leukemic mice). At each study time, splenic weights, peripheral blood counts, and nucleated cell counts and colony forming units (CFU-S) of marrow, spleen, and blood were assayed. The karyotypes of dividing cells from and the histology of the resultant spleen colonies were also studied. Two weeks after the injection of leukemic spleen cells, the number of CFU-S in the marrow had increased to 3 to 10 times normal, that in the spleen to 100 times normal, and that in the blood was markedly increased. Three weeks after injection, the number of CFU-S in the marrow fell from the peak level at 2 weeks, the number in the spleen rose modestly, and the number in the blood continued to be markedly increased. A normal distribution of erythroid, myeloid, and megakaryocytic colonies was obtained from CFU-S assayed 1 week after injection of leukemic spleen cells, but from CFU-S assayed 2 or 3 weeks after injection of leukemic spleen cells, the colonies formed were comprised almost exclusively of myeloid cells. From spleen colonies formed from marrow or spleen cells obtained 1 week after the injection of leukemic spleen cells, all karyotypes contained 40 chromosomes, whereas from spleen colonies formed from marrow or spleen cells obtained 2 or 3 weeks after injection of spleen cells, almost all karyotypes contained 39 chromosomes. In contrast, most of the karyotypes found in spleen colonies formed from the injection of blood cells even 3 weeks after injection of leukemic spleen cells contained 40 chromosomes. All colonies containing cells with 39 chromosomes, leukemic colonies, contained only myeloid cells. We conclude that L-CFU-S differentiate only into the myeloid series. Early in the course of the disease there is an increase in both N-CFU-S and L-CFU-S in the spleen and marrow. As the disease progresses, the numbers of N-CFU-S in both spleen and marrow decline and, during the final week of the illness, the number of L-CFU-S in the marrow declines. The CFU-S in the peripheral blood are predominantly of normal type, even late in the disease when N-CFU-S are rare in the spleen and marrow.

Animals↗
PubMed1976

Factors which affect erythropoiesis in partially nephrectomized and sham-operated rats.

Current concepts of the pathogenesis of anemia in uremic animals are derived mainly from the results of studies performed either in vitro or in bilaterally nephrectomized animals. These data may not be applicable to the situation which exists in more chronically uremic animals. In 1932, Chanutin and Ferris showed that removal of five-sixths of the renal mass caused rats to become uremic and to remain so for a prolonged period of time. Rats made uremic in this manner were utilized as models for studying the pathogenesis of the anemia of uremia. Removeal of five-sixths of the renal mass of rats caused their BUNs to rise to over 100 mg/100 ml and to remain at this level for over 3 wk. The hematocrits of these uremic rats fell from 42% to approximately 30% in 3 wk. Erythropoietin (Ep) production immediately fell to a barely detectable level postoperatively and did not increase significantly in 3 wk, although the renal remnant hypertrophied. Extrarenal Ep production also remained at a low level and did not increase during the 3-wk observation period. The response of plethoric uremic rats to 2 units of Ep was as great (in some experiments greater) as that of sham-operated ones. A surprising finding was that plethoric uremic rats, injected with saline rather than with Ep, incorporated more 59Fe into their red blood cells than did sham-operated ones. This finding suggested that in uremic rats erythropoiesis was less markedly suppressed by plethora than it was in non-uremic rats.

Anemia↗
PubMed1976

Vitreochorioretinal degeneration associated with trichomegaly.

A 15-year-old white boy had bilateral vitreochorioretinal degeneration associated with trichomegaly. Findings on electroretinography and fluorescein angiography provided additional information on the retinal changes not noted in 3 previously reported cases having these associated features. Although similar on ophthalmoscopy, fluourescein angiography, and by electroretinography, the retinal disease in our patient differed from cases of gyrate atrophy of the choroid and retina in having normal plasma ornithine levels.

Abnormalities, Multiple↗
PubMed1976

Effects of radiation on hematopoietic stroma.

The effects of x-irradiation on the CFU-S and on the hematopoietic stroma (HS-P) were studied and compared. Exposure to 300 rad reduced the CFU-S population to less than 1% of normal; by contrast more than 500 rad was required to detectably damage the HS-P. Although exposture to 500 rad did not detectably affect HS-P function, a second exposure to 500 rad as much as 4 weeks later did appreciably affect the HS-P. In addition, whereas the CFU-S returned to the pre-irradiation level within 6 weeks, the HS-P did not significantly recover. From these data we conclude that, with respect to the initial impact and exposure dose, HS-P is more radioresistant than CFU-S, but recovery from radiation induced damage of HS-P occurs slowly or does not take place.

Animals↗
PubMed1976

Mechanism of the increased splenic erythropoiesis in mice treated with estradiol benzoate.

Pharmacological doses of estrogens induce osteosclerosis of the bone marrow, and depress colony-forming units (CFU's) and platelet and leukocyte counts in mice. A compensatoryincreasts in mice. A compensatory increase in splenic erythropoiesis prevents a fall in the hematocrit. The mechanism of this compensation was investigated as follows, BDF1 female mice were injected subcutaneously thrice weekly for 6 weeks wiht 50 mugg of estradiol benzoate (EB) or sesame oil (SO). Subsequently the hematocrit, red cell mass (RCM), and 4 hour per cent of 59Fe uptake into the femurs and spleens were determined in groups of five mice for 4 consecutive days. The RCM and hematocrit were not significantly different in the two groups. The per cent of 59Fe uptake into the femurs of EB-treated mice was less than 30 per cent of that in SO-treated mice and the per cent of 59Fe uptake into the spleens of EB mice was more than two times that in SO mice. To ascertain whether the increase in plenic erythropoiesis resulted from an increase in the number of splenic erythropoietin-responsive cells (ERC), the 4 hours per cent 59Fe uptake into the spleen was determined in continuously hypertransfused EB and SO mice injected with erythropoietin (Ep). Whereas hypertransfuction depressed the splenic per cent of 59Fe uptake in EB and SO mice equally, injection of Ep increased the per cent of 59Fe uptake into the spleens of of EB mice to greater than two times that of SO mice. Next, the plasma Ep level of mice injected with EB or SO for 2, 4, or 6 weeks was determined after exposure of the animals to hypoxia. Ep titers were greater than three times higher in EB mice than in SO mice, We conclude that at least two mechanisms act to cause the compensatory increase in splenic erythropoiesis after marrow suppression by EB: (1) the Ep levels rise and (2) the splenic ERC population increases. The latter is probably not due to the increased plasma Ep level because it also occurs in mice whose Ep production is suppressed by plethora.

Animals↗
PubMed1976

Effect of renin on extrarenal erythropoietin production.

Extracts containing renal erythropoietic factor (REF) and others which contain renin reportedly enhance erythropoietin (Ep) titers in the plasma of hypoxic nephrectomized rats. Studies reported here were designed to elucidate the mechanism by which renin increases Ep production in the anephric rat. Injection of a renal extract containing renin significantly raised the blood pressure of anephric rats, and when it was injected just prior to exposure to hypoxia and 15 hour postnephrectomy, the resultant plasma Ep level exceeded that observed in rats exposed to the same hypoxic conditions immediately postnephrectomy. In contrast rats made hypoxic 15 hours after nephrectomy, but not given renin, had plasma Ep levels which were lower than those of anephric rats made hypoxic immediately postoperatively. When renin was injected immediately after nephrectomy or into normal rats, it failed to stimulate Ep production. When diazoxide was injected with the renin extract into hypoxic nephrectomized rats, the vasopressor effect of renin was abolished for 4 hours, and the plasma Ep levels were significantly lower than those of hypoxic nephrectomized animals injected only with renin, Injection of angiotensin II into anephric, hypoxic rats had an effect comparable to that of renin on extrarenal Ep roduction. REF was not detectable in the renin preparation. These results are best explained by the concept that renin and angiotensin increase extrarenal Ep production by causing vasoconstriction and consequently hypoxia in extrarenal sites of Ep production. Also of interest is the finding that plasma EP levels of rats, injected with renin and made hypoxic 15 hours postnephrectomy, are higher than those previously reported to occur in anephric rats.

Angiotensin II↗