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M J Pippard

Publications and source records attributed to M J Pippard.

At least 55 records · Page 3Linked to original sources
PubMed1986

Mechanism of anaemia in resistant visceral leishmaniasis.

We have studied the mechanism of a transfusion-dependent anaemia found in a two-year-old Maltese girl with visceral leishmaniasis that was resistant to multiple courses of antimonial therapy. Major factors contributing to the anaemia were haemolysis occurring in both the massively enlarged spleen and liver and haemodilution resulting from expansion of the plasma volume. There was no evidence of significant ineffective erythropoiesis, but a reduced plasma iron in the presence of greatly increased iron stores suggested that reticuloendothelial hyperplasia was accompanied by abnormal iron retention by macrophages typical of the 'anaemia of chronic disorders'. This may limit the erythropoietic response to anaemia in chronic visceral leishmaniasis.

Anemia↗
PubMed1986

Relationship between erythropoiesis and the enhanced intestinal uptake of ferric iron in hypoxia in the mouse.

An in vitro technique was used to determine the unidirectional Fe3+ uptake rates in mouse duodenal fragments. In animals in which erythropoiesis had been stimulated by hypoxia, Fe3+ uptake by the duodenal fragments was enhanced due to an increase in Vappmax, However, when erythropoiesis was increased by injections of erythropoietin, intestinal Fe3+ uptake rates were unaffected. Mice subjected to sub-total nephrectomy showed an increased Vappmax for Fe3+ after exposure to hypoxia, despite the absence of an erythropoietic response. When the bone marrow was obliterated by treatment with 89Sr, a small increase in Vappmax for Fe3+ was found: permeability studies and morphometric analyses demonstrated no apparent irradiation damage to the duodenal mucosa of these animals. Exposure of 89Sr-treated mice to hypoxia caused a further significant increase in Vappmax. These results indicate that the increase in intestinal mucosal iron uptake which follows hypoxia is not mediated by erythropoietin or other factors associated with increased erythropoiesis.

Animals↗
PubMed1986

Iron chelation using subcutaneous infusions of diethylene triamine penta-acetic acid (DTPA).

The iron chelating ability and potential toxicity of subcutaneous infusions of the calcium and zinc salts of diethylene triamine penta-acetic acid (DTPA) have been assessed in metabolic balance studies in 2 iron-loaded thalassaemic patients. Infusions of calcium DTPA were locally well tolerated and the drug was as effective as desferrioxamine in mobilising iron. However, daily infusions in the 1st patient also produced symptomatic zinc depletion which could not be controlled by simultaneous oral zinc supplements. Zinc DTPA proved ineffective as an iron chelator, but zinc balance could be maintained in the 2nd patient by combining intermittent (every 4 d) use of calcium DTPA with oral zinc supplements. Combined studies with desferrioxamine and calcium DTPA showed the drugs to have additive effects, probably as a result of the chelation of iron from different body sites.

Administration, Oral↗
PubMed1986

Acquired immunodeficiency with disseminated cryptococcosis.

A 9 year old Portuguese boy presented with severe wasting and a disseminated cryptococcal infection that resolved after massive doses of intrathecal and parenteral antifungal agents. Clinical and laboratory findings were consistent with AIDS. Apart from neonatal blood transfusions, there were no identified risk factors for HTLV III infection.

Acquired Immunodeficiency Syndrome↗
PubMed1986

Studies of erythroblast function in congenital dyserythropoietic anaemia, type I: evidence of impaired DNA, RNA, and protein synthesis and unbalanced globin chain synthesis in ultrastructurally abnormal cells.

Two patients with congenital dyserythropoietic anaemia, type I (CDA) were studied. Their blood reticulocytes showed unbalanced globin chain synthesis with increased alpha:beta globin chain synthesis ratios. A high proportion of the erythroblasts displayed the characteristic "Swiss cheese" abnormality of the nuclear chromatin and some also showed cytoplasmic intrusions lined with nuclear membrane within the nucleus. Occasional erythroblast profiles contained intracytoplasmic inclusions that were ultrastructurally indistinguishable from precipitated alpha chains. The technique of combined Feulgen microspectrophotometry and 3H-thymidine autoradiography showed gross abnormalities of proliferation in the early polychromatic erythroblasts. The proliferative abnormalities included an arrest of DNA synthesis after the progress of cells through part of the S phase and the formation of several mononucleate and binucleate cells with hypertetraploid total DNA contents. The bone marrow cells gave a normal deoxyuridine suppressed value, indicating that there was no impairment of the methylation of deoxyuridylate. Electron microscope autoradiographic studies showed that a high proportion of the erythroblasts with the "Swiss cheese" nuclear abnormality suffered from a severe impairment, or arrest of DNA, RNA, and protein synthesis.

Adult↗
PubMed1986

Plasma ferritin determination as a diagnostic tool.

Plasma ferritin is a secretory component of intracellular ferritin synthesis. In normal persons its amount reflects the size of iron stores. A decrease to less than 12 mug per liter indicates iron deficiency. Increased iron stores are associated with an increased plasma ferritin level. Various other conditions, however, can increase the plasma ferritin concentration including increased metabolism, inflammation, tissue damage and neoplastic disease. The use of the plasma ferritin determination in diagnosing iron overload depends on excluding these other causes, leaving storage iron as the only explanation for the increased plasma ferritin. It is then necessary to establish the parenchymal nature of the iron overload by showing an elevated transferrin saturation and, if elevated, the more definitive liver biopsy should be done.

Ferritins↗
PubMed1985

Storage iron exchange in the rat as affected by deferoxamine.

The initial tissue localization and redistribution of radioactive iron injected intravenously into the rat as ferritin, chondroitin sulfate, and nonviable red cells was determined. Ferritin iron, initially localized in the hepatocyte, showed minimal redistribution over 24 hours in the normal animal. This may be compared with the active release of iron from the reticuloendothelial cell after the intravenous injection of nonviable red cells and chondroitin sulfate iron. All forms of iron were actively mobilized in iron-deficient animals. The effect of chelation of iron by deferoxamine (DFO) on the redistribution pattern over 4 to 6 hours was determined in iron-deficient, normal, iron-loaded, and phenylhydrazine-treated rats to evaluate the effect of iron stores and erythropoiesis. Use of DFO resulted in extensive chelation of radioactive iron within the hepatocyte and greatly reduced the amount of hepatocyte iron available for erythropoiesis. Very little chelation of reticuloendothelial cell-processed iron occurred, and there was little decrease in its utilization for red cell production. Total urinary chelate iron was independent of erythropoiesis but varied in parallel with the iron load of the animal. These studies suggest that DFO does not act on the reticuloendothelial cell but does have at least two sites of action, both of which relate to total storage iron. One involves hepatocyte stores with excretion into the intestinal tract. The other, possibly located at the hepatocyte membrane, results in urinary iron excretion.

Anemia, Hemolytic↗
PubMed1984

Iron absorption in non-transfused iron loading anaemias: prediction of risk for iron loading, and response to iron chelation treatment, in beta thalassaemia intermedia and congenital sideroblastic anaemias.

A variable rate of iron loading, reaching toxic levels in some patients, was seen in a series of non-transfused patients with beta thalassaemia intermedia or sideroblastic anaemia. The degree of anaemia was a poor guide to the risk of iron overload. However the extent of erythroid hyperplasia, judged by ferrokinetic studies or more simply by bone marrow aspiration, was useful in predicting both the rate of iron loading and the need for iron chelation therapy.

Absorption↗
PubMed1983

Iron overload in mild sideroblastic anaemias.

Life-threatening iron overload may occur without severe anaemia in patients with sideroblastic disorders. Assessment of erythroid expansion in bone-marrow aspirates may be as useful as ferrokinetic studies in predicting both the risk of iron loading and the need for prophylactic phlebotomy or iron-chelation therapy.

Adult↗
PubMed1983

The anaemia of Plasmodium falciparum malaria.

Anemia is an important complication of P. falciparum malaria infection. This paper describes recent studies that have attempted to define some of the pathophysiological mechanisms involved in different forms of infection and at different stages of the illness. After an acute infection there is a steady fall in the haemoglobin level with an inappropriate reticulocyte response. Current evidence indicates that this form of anaemia may result from a combination of acute sequestration of iron in the reticuloendothelial system associated with a shortened red cell survival. Recent studies indicate that there may be a dyserythropietic component as well. The mechanism for the shortened red cell survival is uncertain; although it may be due in part to sequestration of parasitized cells, the haemoglobin level continues to fall for several weeks after the acute episode and other factors must be involved. The role of immune haemolysis appears to be relatively small. It is becoming apparent that severe dyserythropoiesis with minimal haemolysis plays a major role in the anaemias of Plasmodium falciparum infection, particularly in immune individuals. This phenomenon has been studied by both light and electron microscopy and by assessing the in vitro kinetics of erythroid precursor proliferation. The results indicate a major defect in erythroid maturation with a significant degree of erythrophagocytosis. Although these studies have provided a clearer picture of the pathophysiology of anaemia at different phases of P. falciparum infection, there is still little indication of how the basic changes in red cell production and survival are mediated.

Acute Disease↗
PubMed1982

Simple assay for urinary iron after desferrioxamine therapy.

A simple method for measuring urinary iron following the administration of desferrioxamine (DF) is described. Ferrioxamine iron is reduced by a reagent containing thioglycolic, hydrochloric, and trichloroacetic acids; the latter ensuring precipitation of any protein present in occasional urines. The iron is measured spectrophotometrically using bathophenanthroline sulfonate. Results are indistinguishable from those obtained using a much more time-consuming preliminary acid digestion, except that in baseline samples the very small amount of spontaneous iron excretion is underestimated. The method is suitable for routine use in monitoring DF therapy.

Anemia, Hypochromic↗
PubMed1982

Hepatocyte iron kinetics in the rat explored with an iron chelator.

The hepatocyte metabolism of 59Fe-labelled ferritin, haemoglobin-haptoglobin and transferrin has been examined in rats. All three forms of 59Fe became transiently available to desferrioxamine (DF) at the time they would otherwise have entered storage or alternative pathways of iron metabolism. However, differences in both the patterns of spontaneous 59Fe reutilization by normal and iron deficient rats and the partition of chelate iron excretion between bile and urine, suggested that iron in transit within hepatocytes did not behave as a single common pool. Ferritin 59Fe, entering a pool of non-radioactive iron the size of which is determined by liver iron stores, was chelated predominantly into the bile. Transferrin 59Fe was distinguished by a greater reflux to the erythron in iron deficient rats, and by excretion of a larger proportion of 59Fe chelated by DF in the urine. Haemoglobin-haptoglobin 59Fe followed a metabolic pathway which was relatively independent of both the iron stores and DF. If the heterogeneous behaviour of rat hepatocyte transit iron has a parallel in man, alterations in the size of similar chelatable iron pools could explain the dependence of DF-induced urine and faecal iron excretion on both liver iron stores and the level of erythropoiesis.

Animals↗
PubMed1982

An in vivo evaluation of iron-chelating drugs derived from pyridoxal and its analogs.

Chelating agents related to the newly described iron binding drug, pyridoxal isonicotinoyl hydrazone, were screened for their effects on iron excretion in the rat, employing a new and highly sensitive radioisotopic procedure. Pyridoxal itself induced significant iron excretion when given either parenterally or orally, the excreted iron being derived from the same pool as that tapped by the drug currently used in treating iron overload in man, desferrioxamine B. Schiff base derivatives of pyridoxal produced varying amounts of iron excretion, the hydrazone derivatives being much more effective than pyridoxal alone. These data suggested a number of possible mechanisms for the chelation of endogenous iron by such agents. Pyridoxal benzoyl hydrazone induced approximately 50% more iron excretion than did an equivalent dose of the parent isonicotinoyl analog and bile cannulation studies showed this difference to be associated with a prolonged duration of action of the benzoyl derivative. When give i.v., the benzoyl and isonicotinoyl hydrazones of pyridoxal and the benzoyl hydrazone of salicylaldehyde all produced levels of iron excretion which exceeded that seen with an equivalent dose of desferrioxamine B. It is concluded that the range of active Schiff base derivatives is likely to be large and that some of these, although not necessarily any of the particular compounds described here, may prove to be of clinical use.

Animals↗
PubMed1981

A rapid assay for evaluation of iron-chelating agents in rats.

The animal assay of potential new iron-chelating agents is at present dependent on cumbersome and imprecise iron balance studies in hypertransfused rodents. We report the development of a radioisotope assay in intact rats based on the transient labeling by ferritin 59Fe of the main source of chelatable iron within hepatocytes. The isotope was maximally available to chelators during the first 6 hr after its injection, nearly all the excretion being in the bile. The bile 59Fe/total iron ratio was independent of both the chelator and its dose. However, in iron-loaded rats, the ratio was reduced, and the isotope excretion was a less sensitive measure of intrahepatic chelation. In the proposed assay, test chelators were given to normal rats 2 hr after an intravenous injection of 59Fe-ferritin. Four hours later, the radioiron in the liver and in the gut gave a sensitive measure of the mobilization of hepatic iron to the bile. In addition, chemical iron determinations identified a small alternative source of urinary chelate with agents known to promote urine excretion in man. The assay gave a rapid and precise screen for chelators given by parenteral and oral routes.

Animals↗