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Biomedical subjects

A Jacobs

Publications and source records attributed to A Jacobs.

At least 289 records · Page 16Linked to original sources
PubMed1982

Cellular proliferation and susceptibility to iron toxicity in iron loaded cell cultures.

Chang cells from human liver, grown in a medium supplemented with 161 mumol/l ferric nitrilotriacetate become iron loaded with an increase in their ferritin content and total iron content. Their viability is not impaired and they survive indefinitely in this state when subcultured at regular intervals. When the cells are grown in a confluent culture their mitotic index is reduced from 12% to less than 1%. In this state they survive normally in unsupplemented medium but when iron is added at 161 mumol/l concentration the cells die within 6 weeks. The toxic lesion appears to be induced within three weeks and is irreversible unless the cells are transferred to an iron-poor medium. Cultural conditions, particularly proliferative rate, appear to be important in determining susceptibility of the cells to iron toxicity. Cell age, hypopoxia and lysosomal enzyme have been assessed as factors that may affect susceptibility.

Cell Division↗
PubMed1982

Pyridoxal complexes as potential chelating agents for oral therapy in transfusional iron overload.

Iron chelation therapy for patients maintained on a regular transfusion regime is at present best carried out by means of daily infusions of desferrioxamine (Hussain et al 1977; Pippard et al 1978) but this is onerous for the patient and has social and economic disadvantages. Many recent attempts to provide more effective drugs for iron chelation have been summarized by Jacobs (1979) and increasing attention is now being paid to the possibility of oral iron chelation therapy. Hoy et al (1979) showed that when isonicotinic acid hydrazide (INH) and pyridoxal are mixed in equimolar amounts a hydrazone is formed which chelates iron, and oral administration of this compound to rats results in an eightfold increase in faecal iron excretion. It is effective on repeated administration (Cikrt et al 1980), the main route of iron excretion being through the bile. Long term studies in the rat have not been successful in reducing the iron load of test animals and this appears to be related both to their high dietary iron content and instability of the hydrazone. Its effective shelf life at room temperature is no longer than one month and this is a considerable disadvantage from a therapeutic point of view. Pyridoxal is known to form a Schiff base with many amino acids and its reactivity has led us to examine complexes of pyridoxal with a number of substances in an attempt to find an alternative iron chelator of greater stability than the INH complex and of comparable effectiveness on oral administration. The screening procedures used were the effects on Chang cell iron metabolism (White et al 1976) and on iron excretion in the rat (Hoy et al 1979).

Animals↗
PubMed1982

Effect of somatostatin-induced suppression of postprandial insulin response upon the hypertriglyceridemia associated with a high carbohydrate diet.

In an attempt to define the relationship between plasma insulin and triglyceride concentrations, we have studied the effect of suppression of the postprandial insulin response upon the secretion and plasma concentration of very low density lipoprotein (VLDL)-triglycerides. Eight nondiabetic subjects with a wide range of fasting plasma triglyceride levels (100-358 mg/dl) were studied during three dietary periods: base line, high carbohydrate (80% calories), and high carbohydrate (80% calories) with a daily intravenous infusion of somatostatin (SRIF) (1.3 micrograms/min) between 800 and 2,100 h. The significant increase in postprandial insulin response observed during high carbohydrate vs. base line was completely abolished during high carbohydrate-SRIF. However, plasma triglyceride levels rose in all subjects during each high carbohydrate period (with/without SRIF) vs. base line and the mean values reached during each period were the same (476 +/- 165 vs. 482 +/- 152 mg/dl, respectively). The secretion of VLDL-triglyceride into plasma was higher in four subjects, the same in two subjects, and lower in one subject during high carbohydrate-SRIF vs. high carbohydrate alone. The mean production rate of VLDL-triglyceride (mg/kg per h) was 25.6 +/- 4.9 during the high carbohydrate and 40.9 +/- 28.1 during the high carbohydrate-SRIF periods. These values were not significantly different. Postprandial glucose levels were slightly increased during high carbohydrate-SRIF, but overnight glucose concentrations were not affected. Plasma FFA levels were not different during the two high carbohydrate periods. Plasma glucagon levels did not appear to affect the results either. This study indicates that postprandial hyperinsulinemia during a high carbohydrate diet is not necessary for induction of hypertriglyceridemia.

Adult↗
PubMed1982

The clearance of 131I-human plasma ferritin in man.

Ferritin was purified 33,000-fold from the plasma of patients with idiopathic hemochromatosis. The plasma ferritin was labeled with 131I and injected into 2 normal men. Clearance was found to be relatively slow, with 50% 131I-ferritin remaining in the plasma at 27-30 hr. The fraction of plasma ferritin that bound to concanavalin-A was found to be cleared more slowly than the nonbinding fraction. These findings confirm our previous suggestion that glycosylation is a major factor prolonging the survival of ferritin in the plasma, but differ from the results of earlier studies in experimental animals and preterm infants, which indicated very rapid plasma ferritin turnover.

Animals↗
PubMed1981

Changes in the characteristics and distribution of ferritin in iron-loaded cell cultures.

When Chang liver cells are grown in an iron-rich medium for up to 20 weeks, iron loading up to 50 times the normal cellular iron content may be obtained, although ferritin increases only to about 10 times normal. Ferritin has been isolated from such cells, and the isoferritin pattern found on elution from DEAE-Sephadex A-50 by increasing chloride concentrations has been used as a basis for studying changes in the properties of ferritin under conditions of cellular loading. A consistent shift of peak ferritin-elution position to higher chloride concentrations (lower pI) occurs when cells are loaded with ferric nitrilotriacetate for increasing lengths of time. A change in immunoreactivity also takes place on loading, the ratio of ferritin reacting with heart and spleen ferritin antibodies increasing at any particular value of pI. Cells were pulse-labelled with [59Fe]ferric nitrilotriacetate and [3H]leucine followed by non-radioactive iron in the same form. During the 72 h after the synthesis of new protein and its incorporation of iron, there is a slight acid shift in its isoelectric point. This effect is seen in both normal and loaded cells, with the whole spectrum being shifted towards lower pI in the loaded state. These findings suggest that the shift to more acidic ferritins on iron loading and the associated changes in antigenicity may be unrelated to subunit composition.

Cells, Cultured↗
PubMed1981

Myoglobin depletion in childhood iron deficiency.

Serum concentrations of myoglobin are significantly lower in iron-deficient than in non-iron-deficient children. In the iron-deficient subjects there is a correlation between haemoglobin concentration and serum myoglobin suggesting that the synthesis of both haem compounds is affected in parallel. No abnormality of serum myoglobin concentration was found in adults with iron deficiency anaemia.

Adolescent↗
PubMed1981

Contact activation of factor XI.

Factor XI is a circulating trace plasma protein composed of two similar or identical chains of about 80 000 daltons which upon activation undergo proteolytic cleavage. Recently, we have shown that trypsin activation leads to an active factor XI (factor XIa) which, on reduction, yields three chains of 46 000, 37 000 and 26 000 daltons. Herein, we re-evaluate the effect of contact activation of factor XI at an activating surface both in normal human plasma and in a mixture of purified factors XI, XII, and high molecular weight kininogen (HMWK). Mixtures were analysed by coagulant activity and by reduced sodium dodecyl sulphate polyacrylamide gel electrophoresis using [125I]factor XI. In the purified system, fully activated factor XI on reduction yielded chains of 46 000, 37 000 and 23 000 daltons. In contrast, factor XI activated by surface contact in plasma yielded on reduction only chains of 46 000 and 37 000 daltons in addition to some uncleaved 80 000 chain. We propose that factor XIa containing only 46 000 and 37 000 chains be designated factor XIa alpha, and that factor XIa containing the third chain of 23 000 daltons be designated factor XI a beta. Sequential elution of contact activated plasma factor XI revealed that factor XIa was attached to the glass surface through the 46 000 dalton chain.

Autoradiography↗
PubMed1981

Ferritin concentration in normal and abnormal erythrocytes measured by immunoradiometric assay with antibodies to heart and spleen ferritin and Mössbauer spectroscopy.

Immunoradiometric assays using antibodies to spleen and heart ferritin were combined with Mössbauer studies on normal and pathological erythrocytes. All erythrocytes examined were found to contain greater amounts of heart type than spleen type ferritin. The ferritin concentration in erythrocytes from patients with beta thalassaemia, sickle cell disease and sideroblastic anaemia is much higher than in normal cells. When the concentration of ferritin-like iron in the pathological erythrocytes measured by Mössbauer spectroscopy is compared to the total amount of ferritin assayed by the two antibodies in the same haemolysates the iron/protein ratio ranges between 0.3 and 3.4. The iron/protein ratio in iron-filled ferritin molecules is about 0.56 and values in excess of this suggest that the iron detected in these cells is a mixture of ferritin molecules, partly denatured ferritin polymers and 'haemosiderin'. There is a possibility that erythrocytes contain an immunologically distinct type of ferritin that is not detected by existing assays, but we have no direct evidence for this.

Anemia, Sickle Cell↗
PubMed1981

Ferritin polymers and the formation of haemosiderin.

When ferritin is isolated from Chang liver cells in culture iron loading is found to be associated with changes in the surface of the protein shell characterized by a change in immunoreactivity to anti "heart' and anti"spleen' antibodies at each specific pI and an overall shift in isoferritins to a lower pI range (Hoy & Jacobs, 1981). Ferritin polymers have been isolated from human tissues and their biochemical properties assessed in terms of these surface changes and the iron/protein ratio of the molecules. The results suggest that changes in the surface of ferritin molecules are associated with the formation of stable polymers. These are precursors of clumps of ferritin and eventually haemosiderin. Changes in the surface of the molecule may provide a signal for polymerization and incorporation of the protein within the lysosomes.

Biopolymers↗
PubMed1981

Iron uptake and ferritin synthesis by peripheral blood leucocytes in patients with primary idiopathic haemochromatosis.

Iron uptake and storage in peripheral blood leucocytes has been studies to test the hypothesis that the basic lesion in idiopathic haemochromatosis resides in a failure of mononuclear phagocytic cells to store iron. In seven fully treated cases of this disease there was no evidence of any abnormality in iron uptake, synthesis of the storage protein ferritin or its ability to incorporate iron. The ferritin content of leucocytes was found to be increased.

Ferritins↗
PubMed1981

Ferritin.

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Animals↗