Non-invasive in vivo measurement of human iron overload by magnetic susceptibility studies.
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Hemochromatosis↗
Biomedical subjects
G M Brittenham
Publications and source records attributed to G M Brittenham.
[The mother-newborn relationship: limit of adaptability].
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Female↗
Field methods for the assessment of health and disease in pre-agricultural societies.
The few surviving pre-agricultural societies preserve the best available indication of human adaptation during more than 99% of the species' history. The field methods described allow collection of data that may explain why hunters and gatherers are physically small in the face of apparent plenty, what causes their death and how they control population growth. Observations of daily life, especially family, food and work, provide the context within which biological data can be interpreted. Computer-compatible event-recording systems make possible the collection and encoding of quantitative behavioural observations. A careful census permits characterization of fertility and mortality. Physical assessment, by medical history, physical examination and anthropometry, establishes the patterns of growth and development in the population and the prevalence of clinically recognizable diseases and nutritional disorders. If blood, urine or faeces can be collected, lightweight portable field-proven equipment and techniques are available for the collection, analysis and preservation of specimens for biochemical, nutritional, haematological and genetic determinations.
Adaptation, Biological↗
The mother-newborn relationship: limits of adaptability.
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Adaptation, Psychological↗
Hepatic mitochondrial oxidative metabolism in rats with chronic dietary iron overload.
We examined the effects of chronic dietary iron overload on hepatic mitochondrial oxidative metabolism. Experimental iron overload was produced by feeding rats a chow diet supplemented with carbonyl iron over a 7-week period. Biochemical and histologic evaluations of liver tissue confirmed moderate degrees of hepatic parenchymal iron overload. Electron microscopy showed no abnormalities in hepatic mitochondrial ultrastructure in blocks of tissue or in mitochondrial fractions from iron-loaded liver. Studies of mitochondrial oxidative metabolism revealed a consistent and progressive decrease in state 3 (ADP-stimulated) respiration and in respiratory control ratios at hepatic iron concentrations above 1,000 micrograms per gm for all three substrates studied, glutamate, beta-hydroxybutyrate and succinate. Changes in state 4 (ADP-limited) respiration and ADP/O ratios were not progressive with increasing hepatic iron concentrations. At hepatic iron concentrations at which there were decreases in state 3 respiration and respiratory control ratios, there was also evidence of lipid-conjugated diene formation, indicative of mitochondrial lipid peroxidation. There were no changes in mitochondrial function when iron as either ferritin or hemosiderin or as a combination of ferritin, hemosiderin and ferric nitrilotriacetate was added in vitro to normal liver homogenates. Use of density gradient centrifugation to reduce iron and lysosomal contamination of mitochondrial fractions failed to prevent the reduction in mitochondrial function. We conclude that moderate degrees of chronic hepatic iron overload in vivo result in an inhibitory defect in the mitochondrial electron transport chain as evidenced by a decrease in state 3 respiration and respiratory control ratios.
Acetylglucosaminidase↗
The antimalarial effect of iron chelators: studies in animal models and in humans with mild falciparum malaria.
In this study we explore the antimalarial effects of 3-hydroxypyridin-4-ones (CP compounds), a family of bidentate orally effective iron chelators in experimental animal systems in vivo and in vitro, and examine whether the iron chelator deferoxamine (DF) is active against human infection with P. falciparum. There was direct relation between lipid solubility of the CP compounds, which would facilitate membrane transit, and their in vivo antimalarial action, suggesting direct intracellular iron chelation as the most likely explantation for the antimalarial effect of iron chelators. Results of the double-blind, placebo controlled trial of DF in humans with asymptomatic parasitemia provided unequivocal evidence that this iron-chelating agent has antimalarial activity. Depriving the parasite of a metabolically important source of iron may represent a novel approach to antimalarial drug development. DF is a relatively ineffective intraerythrocytic chelator, and our data indicate that other orally effective iron chelators may have superior antimalarial activity in vivo. A systematic screening of available iron chelating drugs may result in the identification of potentially useful antimalarial compounds.
Animals↗
Effect of iron chelation therapy on mortality in Zambian children with cerebral malaria.
To examine the effect of iron chelation on mortality in cerebral malaria, we enrolled 352 children in a trial of deferoxamine in addition to standard quinine therapy at 2 centres in Zambia, one rural and one urban. Entrance criteria included age < 6 years, Plasmodium falciparum parasitaemia, normal cerebral spinal fluid, and unrousable coma. Deferoxamine (100 mg/kg/d infused for a total of 72 h) or placebo was added to a 7 d regimen of quinine that included a loading dose. Mortality overall was 18.3% (32/175) in the deferoxamine group and 10.7% (19/177) in the placebo group (adjusted odds ratio 1.8; 95% confidence interval 0.9-3.6; P = 0.074). At the rural study site, mortality was 15.4% (18/117) with deferoxamine compared to 12.7% (15/118) with placebo (P = 0.78, adjusted for covariates). At the urban site, mortality was 24.1% (14/58) with deferoxamine and 6.8% (4/59) with placebo (P = 0.061, adjusted for covariates). Among survivors, there was a non-significant trend to faster recovery from coma in the deferoxamine group (adjusted odds ratio 1.2; 95% confidence interval 0.97-1.6; P = 0.089). Hepatomegaly was significantly associated with higher mortality, while splenomegaly was associated with lower mortality. This study did not provide evidence for a beneficial effect on mortality in children with cerebral malaria when deferoxamine was added to quinine, given in a regimen that included a loading dose.
Antidotes↗
Loading dose of quinine in African children with cerebral malaria.
The majority of deaths from cerebral malaria occur within 48 h after admission to hospital. Because of the possibility of inadequate treatment within this period, the use of a loading dose of quinine has been proposed. We reviewed clinical and laboratory data for 113 children with cerebral malaria, who were treated with intravenous quinine, 10 mg/kg every 8 h, at Macha Mission Hospital in rural Zambia. In 1990-1991, 39 children were not given a loading dose of quinine while, in 1992-1993, 74 children received a loading dose of 20 mg/kg. Elevated serum iron levels, as reflected in transferrin saturation, were strongly associated with higher mortality. A loading dose of quinine was associated with faster recovery from coma and enhanced clearance of parasitaemia and fever. The loading dose was also associated with trends to lower mortality and higher haemoglobin levels, but these differences were not statistically significant.
Anemia, Iron-Deficiency↗
Carbonyl iron for short-term supplementation in female blood donors.
A randomized, double-blind trial of iron replacement after repeated blood donation was conducted in 75 menstruating women; 51 completed the study. Volunteers were assigned randomly to one of three treatment groups: 1) carbonyl iron (nontoxic elemental iron powder), 600 mg; 2) ferrous sulfate, 300 mg (60 mg Fe++); or 3) placebo, each given three times daily for 1 week immediately after blood donation. Blood samples obtained initially and 56 days later were tested for hemoglobin, mean corpuscular volume (MCV), free erythrocyte protoporphyrin, serum ferritin, serum iron, total iron binding capacity (TIBC), and percent saturation of TIBC. The prevalence of gastrointestinal side effects was similar in both groups taking iron. At the end of the study there was no laboratory evidence of change in iron status in women who received carbonyl iron (n = 15). In those treated with ferrous sulfate (n = 17) the mean TIBC increased (p less than 0.001), and in the placebo group (n = 19) there were decreases in mean MCV (p less than 0.01), serum ferritin (p less than 0.001), and percent saturation (p = 0.027) with an increase in mean TIBC (p = 0.004). Carbonyl iron seems to be effective for short-term iron replacement in repeat blood donors and may have the advantage of decreased or absent risk of poisoning if accidentally ingested by children.
Blood Donors↗
Red blood cell mass in autologous and homologous blood units. Implications for risk/benefit assessment of autologous blood crossover and directed blood transfusion.
A prospective analysis of 300 consecutively collected homologous blood (HB) units from a regional blood center and an analysis of 188 consecutively collected autologous blood (AB) units from a community hospital was conducted. Analysis of the red blood cell (RBC) mass content of these blood units revealed that HB contained 13 percent more RBC than AB: 200 +/- 1.1 vs 177.1 +/- 1.1 mL, (m +/- SE), respectively (p less than 0.05). Of 174 AB units eligible for crossover by AABB criteria for RBC mass (greater than or equal to 154 mL), 35 (20%) were below the 95 percent confidence interval range for RBC mass of HB units collected; mean RBC mass of 300 HB units was 12 percent greater than that of 174 AB units (200.1 +/- 1.1 vs 178.9 +/- 0.9 mL, p less than 0.001) and 20 percent greater than that of the 35 AB units outside the 95 percent confidence interval (200.1 +/- 1.1 vs 161.2 +/- 0.5 mL, p less than 0.001). These findings indicate that an evaluation of the issues of AB crossover for HB transfusion should include a risk/benefit analysis of AB units with lower RBC mass. These findings also indicate that the proposed changes in AABB standards regarding directed donation (DD) should consider the reduced benefits of DD units with lower RBC mass in a risk/benefit analysis of this practice, and support retention of homologous donor standards for directed donors.
Blood Banks↗
Prevention of iron deficiency with carbonyl iron in female blood donors.
The effectiveness of elemental, nontoxic carbonyl iron in replacing iron lost at blood donation was examined. In a randomized double-blind design, 99 women, aged 18 to 40, were given placebo or low-dose carbonyl iron (100 mg orally) at bedtime for 56 days after phlebotomy. Compliance was equivalent for the two regimens. Mild side effects were slightly greater with carbonyl iron. At Day 56, estimated net iron absorption from therapy or diet, or both, was sufficient to replace iron in 85 percent of those receiving carbonyl iron but in only 29 percent of those taking placebo (p less than 0.001). The rates of deferral from repeat donation were 8 percent in the carbonyl iron group and 36 percent in the placebo group (p less than 0.01), and the positive predictive value of routine screening in identifying participants without iron deficiency was 83 versus 13 percent (p less than 0.01). It can be concluded that short-term carbonyl iron supplementation in female blood donors can replace the iron lost at phlebotomy, protect the women against iron deficiency, and enhance their ability to give blood.
Anemia, Hypochromic↗
Salivary testosterone concentration of Aymara men native to 3600 m.
This paper explores the possibility that variation in the normal physiological range of testosterone concentration modulates men's adaptation to hypobaric high-altitude hypoxia through stimulating haemoglobin production and/or causing respiratory disturbances and exacerbated hypoxaemia during sleep. These effects of testosterone are observed clinically at sea level and have potentially opposing consequences at high altitude, the former perhaps enhancing and the latter diminishing the effectiveness of adaptations to hypoxia. Seventeen young (average age 27 years) and 22 older (average age 57 years) healthy adult high altitude native Aymara men tested at 3600 m have average morning salivary testosterone concentrations of 282 and 241 pmol/l, respectively. The 31 urban men of both age groups have higher testosterone concentrations than the eight rural men and have mean haemoglobin concentrations significantly 0.7-1.0 g/dl higher within the normal high-altitude range, consistent with known effects of testosterone at sea level. Older urban men have slightly more frequent respiratory disturbances during sleep, associated with significantly greater hypoxaemia. There appear to be modest benefits to testosterone concentrations in the upper end of the observed range; however, the direction of these responses towards more haemoglobin production and more hypoxaemia during sleep of older men suggests the hypothesis that very high testosterone concentrations such as those in the upper ranges of sea level values could compromise adaptation to high altitude, particularly among older men.
Adult↗
Blood pressure variation among Ethiopians on the Simien Plateau.
This report presents information on determinants of blood pressure variation in a rural sample of 263 Ethiopian highlanders 14-86 years of age, resident at 3530 m on the Simien Plateau. Mean systolic and diastolic blood pressures for males and females were 109/ 75 and 106/73, respectively, and there were no age differences. These findings confirmed that men and women can have low normal blood pressure throughout adulthood. Blood pressures increased with increasing body mass index (BMI) among adult males, although the mean BMI of 19.1 kg/m2 was low compared with US values. This illustrates that BMI variation may be associated with blood pressure variation in men even at low mean values of both. Blood pressure did not vary with adult haemoglobin concentration.
Adolescent↗
Iron overload and iron-chelating therapy in hemoglobin E-beta thalassemia.
Whereas hemoglobin (Hb) E-beta thalassemia is recognized as probably the most common serious hemoglobinopathy worldwide, its natural history remains poorly defined. The interaction of hemoglobin E and beta-thalassemia result in a wide spectrum of clinical disorders, some indistinguishable from thalassemia major and some milder and not transfusion-dependent. Partially as a result of this wide range of phenotypes, clear guidelines for approaches to transfusion and to iron-chelating therapy for patients with Hb E-beta thalassemia have not been developed. By contrast, data that have accumulated during the past 10 years in patients with beta-thalassemia permit a quantitative approach to the management of iron overload and provide guidelines for the control of body iron burden in individual patients treated with iron-chelating therapy. These guidelines may be applicable to patients with Hb E-beta thalassemia. Preliminary evidence from our studies of iron loading in affected patients with Hb E-beta thalassemia in Sri Lanka suggest that this disorder may be associated with variable, but accelerated, gastrointestinal iron absorption, and that the iron loading associated with chronic transfusions in patients with Hb E-beta thalassemia is similar to that observed in patients with beta-thalassemia. These data, in the only cohort of patients with Hb E-beta thalassemia to have undergone quantitative assessment of body iron burden, suggest that the principles that guide assessment of iron loading and initiation of chelating therapy in patients with beta-thalassemia may be generally applicable to those with Hb E-beta thalassemia. Further quantitative studies in both nontransfused and transfused patients will be necessary to permit firm conclusions.
Adult↗