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Biomedical subjects

G M Brittenham

Publications and source records attributed to G M Brittenham.

At least 37 records · Page 2Linked to original sources
PubMed1999

Treatment of malarial acute renal failure by hemodialysis.

We studied 112 patients with malarial acute renal failure (ARF) during the period 1991-1997 at Bangkok Hospital for Tropical Diseases (Mahidol University, Bangkok, Thailand). Hemodialysis was performed in 101 (90.2%) of these patients. The mean number of times the patients were hemodialyzed was 6.5 (range = 1-27). Ninety-three (83.0%) patients were oliguric and the remainder were nonoliguric. Patients who had oliguric renal failure required more hemodialyses and had more complications than the nonoliguric patients. The oliguric patients had an eight-fold higher risk of requiring six or more hemodialyses (95% confidence interval = 1.2-53.9, P = 0.0008). The overall mortality rate was 10.7% (12 of 112). Eleven of the patients who died were jaundiced and eight of them had cerebral malaria with a Glasgow Coma Score < or = 8. We conclude that hemodialysis is a useful treatment for oliguric and nonoliguric ARF from severe malaria, particularly when initiated early in the course of the illness.

Acute Kidney Injury↗
PubMed1998

Research priorities in hereditary hemochromatosis.

The Working Group on Research Priorities used a formal nominal group technique to identify and prioritize the specific aims of applied research needed to provide the scientific basis for population screening for iron overload disorders. The most important applied research goal was characterization of the natural history of the relation between genotype and phenotype in hereditary hemochromatosis and other iron overload disorders. Three other important research objectives were development of an optimal approach to screening for iron overload; analyses of the cost-effectiveness of screening; and assessment of the ethical, legal, and social implications of screening. To achieve these specific aims, two research studies were recommended as being of the highest priority: a multicenter, cross-sectional, population-based study of the natural history of iron overload and a multicenter, case-control study of patients with disease manifestations potentially attributable to hereditary hemochromatosis in primary care and subspecialty clinics.

Cost-Benefit Analysis↗
PubMed1998

Long-term safety and effectiveness of iron-chelation therapy with deferiprone for thalassemia major.

BACKGROUND: Deferiprone is an orally active iron-chelating agent that is being evaluated as a treatment for iron overload in thalassemia major. Studies in an animal model showed that prolonged treatment is associated with a decline in the effectiveness of deferiprone and exacerbation of hepatic fibrosis. METHODS: Hepatic iron stores were determined yearly by chemical analysis of liver-biopsy specimens, magnetic susceptometry, or both. Three hepatopathologists who were unaware of the patients' clinical status, the time at which the specimens were obtained, and the iron content of the specimens examined 72 biopsy specimens from 19 patients treated with deferiprone for more than one year. For comparison, 48 liver-biopsy specimens obtained from 20 patients treated with parenteral deferoxamine for more than one year were similarly reviewed. RESULTS: Of the 19 patients treated with deferiprone, 18 had received the drug continuously for a mean (+/-SE) of 4.6+/-0.3 years. At the final analysis, 7 of the 18 had hepatic iron concentrations of at least 80 micromol per gram of liver, wet weight (the value above which there is an increased risk of cardiac disease and early death in patients with thalassemia major). Of 19 patients in whom multiple biopsies were performed over a period of more than one year, 14 could be evaluated for progression of hepatic fibrosis; of the 20 deferoxamine-treated patients, 12 could be evaluated for progression. Five deferiprone-treated patients had progression of fibrosis, as compared with none of those given deferoxamine (P=0.04). By the life-table method, we estimated that the median time to progression of fibrosis was 3.2 years in deferiprone-treated patients. After adjustment for the initial hepatic iron concentration, the estimated odds of progression of fibrosis increased by a factor of 5.8 (95 percent confidence interval, 1.1 to 29.6) with each additional year of deferiprone treatment. CONCLUSIONS: Deferiprone does not adequately control body iron burden in patients with thalassemia and may worsen hepatic fibrosis.

Adolescent↗
PubMed1998

Elimination of transfusions through induction of fetal hemoglobin synthesis in Cooley's anemia.

Pharmacological stimulation of fetal hemoglobin production is of considerable interest as an alternative approach to therapy for Cooley's anemia. While intravenous compounds have been effective in inducing short-term increases in fetal hemoglobin in a few patients, long-term elimination of transfusion requirement has not been reported. In patients with Cooley's anemia, treatment with oral sodium phenylbutyrate alone, sodium phenylbytyrate combined with hydroxyurea, and hydroxyurea alone, has augmented fetal hemoglobin production and increased total hemoglobin concentration as much as 5 g/dl over baseline eliminating transfusion requirement in two patients. Parallel declines in circulating nucleated red cell count, and concentrations of serum transform receptor and erythropoietin, are consistent with more effective erythropoiesis. Over extended periods of treatment, no induction of other fetal proteins and no adverse effects were observed. Particular disease mutations and other genetic factors may be of prime importance in determining the response to agents that induce production of fetal hemoglobin.

Adult↗
PubMed1998

Long-term trials of deferiprone in Cooley's anemia.

Deferoxamine is the currently available agent for the iron-chelation therapy required by Cooley's anemia patients. The difficulties associated with parenteral administration have mandated a search for alternative therapies, especially orally active iron chelators, to remove excess iron that results in damage to the liver, endocrine organs, and heart. Four orally active agents have reached clinical trials in the last decade. The agent under consideration in this paper, deferiprone (1,2-dimethyl-3-hydroxypyridin-4-one), has shown some promise, but, according to the studies discussed here, may not provide adequate sustained control of body iron in a substantial proportion of Cooley's anemia patients.

Clinical Trials as Topic↗
PubMed1998

Distribution of transferrin saturations in the African-American population.

To determine if transferrin saturations in African Americans may reflect the presence of a gene that influences iron metabolism, we analyzed the distribution of these values in 808 African Americans from the second National Health and Nutrition Survey. We tested for a mixture of three normal distributions consistent with population genetics for a major locus effect in which the proportion of normal homozygotes is p2; of heterozygotes, 2pq; of affected homozygotes, q2; and in which p+q = 1. Three subpopulations based on transferrin saturation were present (P < .0001) and the fit to a mixture of three normal distributions was good (P = .2). A proportion of .009 was included in a subpopulation with a mean +/- standard deviation transferrin saturation of 63.4% +/- 5.7% (postulated homozygotes for a gene that influences iron metabolism), while a proportion of .136 had an intermediate saturation of 38.0% +/- 5.7% (postulated heterozygotes) and .856 a saturation of 24.6% +/- 5.7% (postulated normal homozygotes). These proportions were consistent with population genetics because the sum of the square roots of the proportions with the lowest mean transferrin saturation (P = .925) and the highest (q = 0.093) was approximately 1 (1.018). The results are consistent with the presence in African Americans of a common locus that influences iron metabolism.

Adult↗
PubMed1998

HBED: A potential alternative to deferoxamine for iron-chelating therapy.

To examine the potential clinical usefulness of the hexadentate phenolic aminocarboxylate iron chelator N, N-bis(2-hydroxybenzyl)ethylenediamine-N,N-diacetic acid (HBED) for the chronic treatment of transfusional iron overload, we compared the iron excretion induced by subcutaneous (SC) injection of HBED and deferoxamine (DFO), the reference chelator, in rodents and primates. In the non-iron-overloaded, bile-duct-cannulated rat, a single SC injection of HBED, 150 micromol/kg, resulted in a net iron excretion that was more than threefold greater than that after the same dose of DFO. In the iron-loaded Cebus apella monkey, a single SC injection of HBED, 150 micromol/kg, produced a net iron excretion that was more than twice that observed after the same dose of SC DFO. In patients with transfusional iron overload, SC injections of HBED may provide a much needed alternative to the use of prolonged parenteral infusions of DFO.

Animals↗
PubMed1998

Hemoglobin concentration of high-altitude Tibetans and Bolivian Aymara.

Elevated hemoglobin concentrations have been reported for high-altitude sojourners and Andean high-altitude natives since early in the 20th century. Thus, reports that have appeared since the 1970s describing relatively low hemoglobin concentration among Tibetan high-altitude natives were unexpected. These suggested a hypothesis of population differences in hematological response to high-altitude hypoxia. A case of quantitatively different responses to one environmental stress would offer an opportunity to study the broad evolutionary question of the origin of adaptations. However, many factors may confound population comparisons. The present study was designed to test the null hypothesis of no difference in mean hemoglobin concentration of Tibetan and Aymara native residents at 3,800-4,065 meters by using healthy samples that were screened for iron deficiency, abnormal hemoglobins, and thalassemias, recruited and assessed using the same techniques. The hypothesis was rejected, because Tibetan males had a significantly lower mean hemoglobin concentration of 15.6 gm/dl compared with 19.2 gm/dl for Aymara males, and Tibetan females had a mean hemoglobin concentration of 14.2 gm/dl compared with 17.8 gm/dl for Aymara females. The Tibetan hemoglobin distribution closely resembled that from a comparable, sea-level sample from the United States, whereas the Aymara distribution was shifted toward 3-4 gm/dl higher values. Genetic factors accounted for a very high proportion of the phenotypic variance in hemoglobin concentration in both samples (0.86 in the Tibetan sample and 0.87 in the Aymara sample). The presence of significant genetic variance means that there is the potential for natural selection and genetic adaptation of hemoglobin concentration in Tibetan and Aymara high-altitude populations.

Adaptation, Physiological↗
PubMed1998

Preclinical cardiac dysfunction in transfusion-dependent children and young adults detected with low-dose dobutamine stress echocardiography.

Transfusion-dependent (TD) patients develop cardiac iron overload that will eventually lead to cardiac pump failure. Low-dose dobutamine stress echocardiography may complement resting echocardiography and identify preclinical myocardial dysfunction caused by early cardiac hemosiderosis. Twenty-six iron-overloaded TD patients had stress echocardiography with 5 microg/kg per minute of dobutamine. Indexed left ventricular (LV) mass, LV dimensions, meridional wall stress, and cardiac index were significantly increased. TD patients had similar LV shortening fraction by M-mode (40.5% +/- 5.6% vs 39.4% +/- 4.5%) but had a lower mean LV ejection fraction (53.3% +/- 3.9% vs 46.8% +/- 6.9%, P < .002) and a subnormal increase in cardiac index during dobutamine stress (35% +/- 20% vs 11% +/- 16%, P < .0001). Impairment in LV relaxation was demonstrated by a prolonged isovolumetric relaxation time (0.060 +/- 0.005 vs 0.088 +/- 0.019 seconds, P < .0001), increased peak mitral E wave, and abnormal E/A ratio. Asymptomatic TD patients demonstrate decreased systolic functional reserve and abnormal left ventricular relaxation that may be caused by cardiac hemosiderosis. Low-dose dobutamine stress echocardiography may be useful for detecting and following cardiac dysfunction in patients at risk for cardiac hemosiderosis.

Adolescent↗
PubMed1998

The course of anaemia after the treatment of acute, falciparum malaria.

To determine the course of anaemia following treatment for acute falciparum malaria, 72 adult Thai patients were followed for 4 weeks after starting effective therapy. Using the criteria of haemoglobin concentrations of < 13 g/dl in males and < 12 g/dl in females to define anaemia, all but two (97%) of the patients were anaemic at some point during the study period. At weekly observations, the erythropoietic response of each patient with anaemia was categorized clinically, on the basis of absolute reticulocyte counts (ARC) and indirect bilirubin concentrations (IBC). At 4 weeks, 40 (56%) of the patients were still anaemic. The results of tests on samples of peripheral blood from these 40 patients were consistent with hypoproliferative erythropoiesis (low-normal ARC and IBC; 33 patients), ineffective erythropoiesis (low-normal ARC but elevated IBC; five patients) or an appropriate response (elevated ARC and normal IBC; two patients). Of the variables measured at the time of enrolment into the study, only low serum albumin (P = 0.002) and elevated direct bilirubin (P = 0.009) were independently associated with persisting anaemia at 4 weeks. Anaemia may therefore persist in about one in every two Thai patients for up to 28 days after beginning effective treatment for acute Plasmodium falciparum malaria, hypoproliferative erythropoiesis appearing to be the most common mechanism of this anaemia. While it is likely that the malarial episode itself is somehow responsible for these persistent haematological changes, other, underlying, chronic processes might have a contributory role. Whatever the cause, the continuing anaemia appears to be related to the degree of hepatic dysfunction on admission.

Adult↗
PubMed1998

Assessment of the effect of the oral iron chelator deferiprone on asymptomatic Plasmodium falciparum parasitemia in humans.

While the parenteral iron-chelating agent desferrioxamine B has anti-malarial activity in humans, the usefulness of an orally active chelator for this indication has not been investigated previously in vivo. We conducted a prospective, double-blind, placebo-controlled, cross-over trial of deferiprone (L1; CP20; 1,2-dimethyl-3-hydroxypyridin-4-one) in 25 adult Zambians with asymptomatic Plasmodium falciparum parasitemia. Deferiprone was administered daily for three or four days in divided doses of 75 or 100 mg/kg of body weight, dosages that are effective for treating iron overload. No reduction in asexual intra-erythrocytic parasites was observed during or after deferiprone treatment. The mean peak plasma concentration of deferiprone (108.9 +/- 24.9 micromol/L) achieved was within the range demonstrated to inhibit the growth of P. falciparum in vitro, but the systemic exposure as determined by the 24-hr plasma concentration-time curve would not be predicted inhibit growth in vivo. No evidence of deferiprone-associated hematological toxicity was noted in this short-term study of these subjects, all of whom had clinical evidence of normal body iron stores. Because of the risk of neutropenia and other adverse effects with higher doses or prolonged use of the chelator, additional trials of deferiprone as a sole anti-malarial agent would not seem to be justified. In contrast, further efforts are needed to develop other orally active iron-chelating agents specifically for their anti-malarial action.

Administration, Oral↗
PubMed1998

The synergistic effects of vitamin E and selenium in iron-overloaded mouse hearts.

OBJECTIVES: To determine whether supplementation with vitamin E and selenium can improve myocardial antioxidant defenses in iron-overloaded mouse hearts. INTERVENTIONS: Iron-overload state was created in B6D2F1 mice (n = 20) by daily injection of iron dextran (5 mg intraperitoneally/mouse) for four weeks. The mice were also simultaneously randomly assigned to receive vitamin E (alpha-tocopherol acetate, 40 mg intraperitoneally, n = 5), selenium (sodium selenite, 1 part/million orally, n = 5), both (vitamin E + selenium, n = 5) or iron-only treatment (n = 5). The hearts were harvested for determination of selenium concentration and glutathione peroxidase activity. In a subsequent study, 15 B6D2F1 mice were randomly assigned to receive daily injections of iron (n = 5) or iron and combined antioxidant treatment (vitamin E + selenium, n = 5), or to serve as controls (n = 5) for four weeks. The hearts were harvested for determination of total iron concentrations. MAIN RESULTS: Significantly greater concentrations of heart selenium and glutathione peroxidase activity were observed in groups supplemented with both agents, as opposed to iron-only treated or single supplemented mice. Significantly lower concentrations of iron were found in controls and in those receiving combined iron and antioxidant treatment (vitamin E + selenium) than in iron-only treated mice. CONCLUSIONS: Vitamin E and selenium function synergistically in the myocardium to provide important antioxidant defenses in iron-overload states, including increased concentrations of selenium, increased glutathione peroxidase activity and decreased concentrations of iron.

Animals↗
PubMed1997

Limitations of magnetic resonance imaging in measurement of hepatic iron.

To evaluate the usefulness of magnetic resonance imaging for the quantitative determination of hepatic iron, we examined 43 patients with thalassemia major and assessed the influence of pathologic changes in the liver on the precision of estimates of the hepatic iron concentration. Tissue signal intensities were measured from magnetic resonance T1-weighted images derived from gradient-echo (GE) pulse sequences and the ratio of the signal intensity of liver to muscle calculated. By excluding patients (n = 9) having a signal intensity ratio (SIR) less than or equal to 0.2, a linear relationship with hepatic iron was found and subsequent analyses were limited to these 34 patients. In 27 patients with hepatic fibrosis, an overall correlation of -0.848 was found between hepatic iron and SIR. By contrast, in the seven patients with no fibrosis, the correlation coefficient (-0.993) was significantly greater (P < .0001). Despite the differences in correlation, the regression line between hepatic iron and SIR for the patients with no fibrosis did not differ significantly with respect to either slope or intercept from that of the patients with fibrosis. Thus, the presence of fibrosis did not seem to affect the pattern of the relationship between hepatic iron and the SIR, but rather to increase the variability of the relationship. Clinically, the presence of fibrosis makes estimates of hepatic iron derived from magnetic resonance imaging so variable as to be of little practical use in the management of transfusional iron overload.

Adolescent↗
PubMed1997

Iron-chelating therapy and the treatment of thalassemia.

Iron-chelating therapy with deferoxamine in patients with thalassemia major has dramatically altered the prognosis of this previously fatal disease. The successes achieved with deferoxamine, as well as the limitations of this treatment, have stimulated the design of alternative strategies of iron-chelating therapy, including orally active iron chelators. The development of the most promising of these, deferiprone, has progressed rapidly over the last 5 years; data from several trials have provided direct and supportive evidence for its short-term efficacy. At the same time, the toxicity of this agent mandates a careful evaluation of the balance between risk and benefit of deferiprone in patients with thalassemia, in most of whom long-term deferoxamine is safe and efficacious therapy.

Animals↗
PubMed1997

Iron overload in the rat pancreas following portacaval shunting and dietary iron supplementation.

Reproduction of pancreatic iron overload in an animal model has been difficult to achieve primarily because of the first-pass extraction of iron by the liver. We hypothesized that portacaval shunting would avoid this hepatic phenomenon and increase pancreatic iron deposition. An end-to-side portacaval shunt was surgically created in male Sprague-Dawley rats, and they were subsequently fed a carbonyl iron-supplemented diet for 17 weeks. This resulted in marked iron accumulation in the pancreas (1621 +/- 188 micrograms/g) compared to minimal deposition in sham-operated rats fed the same diet (138 +/- 53 micrograms/g). Iron deposition in the acinar and centroacinar cells was confirmed histologically by Gomori staining, as well as by ultrastructural examination. Iron overloading was associated with enhanced oxidative stress evidenced by a twofold increase in the levels of glutathione disulfide and thiobarbituric acid-reactive substances. Also, adducts of proteins with malondialdehyde and 4-hydroxynonenal were demonstrated in acinar and ductal cells. Other apparent consequences of iron overload were a 50% reduction in pancreatic amylase content and a decrease in pancreatic protein concentration. These hypotrophic changes were associated with a reduced mass of zymogen granules in the acinar cells noted histologically. Our results show that a combination of portacaval shunting and carbonyl iron feeding achieve pancreatic iron overload and support the role of oxidative stress in the pathogenesis of iron-induced damage in the pancreas.

Aldehydes↗
PubMed1997

Quantitative genetic analysis of arterial oxygen saturation in Tibetan highlanders.

This study was designed to test the hypothesis that genetic differences inferred from biological kinship relationships among individuals contribute to individual variation in percentage of oxygen saturation of arterial hemoglobin (SaO2) in a high-altitude native population. SaO2 data were obtained by pulse oximetry from 354 nonpregnant, healthy Tibetan residents of Pen-Dri, two rural agropastoral villages at 3800-4065 m altitude in Lhasa Municipal District, Tibet Autonomous Region, China. Statistical analyses of these data from 46 pedigrees tested the hypothesis of a significant genetic contribution to SaO2 variation. The average SaO2 was 89.4 +/- 0.2%, with a range of 76-97%. Additive genetic effects account for 44% of the interindividual phenotypic variation in SaO2 in the sample. Complex segregation analysis and variance decomposition analysis determined that 21% of the total phenotypic variation could be explained by a major gene influencing SaO2. Homozygotes for the low-SaO2 allele have a mean SaO2 of 83.6%, whereas heterozygotes and homozygotes for the high-SaO2 allele have means of 87.6% and 88.3%, respectively. This confirms findings in another Tibetan sample and extends the known geographic distribution of the major gene. These results suggest the hypothesis that individuals with the dominant allele for higher SaO2 have a selective advantage in their high-altitude hypoxic environment.

Adaptation, Physiological↗
PubMed1996

Giant mitochondria induced in rat pancreatic exocrine cells by ethanol and iron.

BACKGROUND: Mitochondria are sensitive indicators of cellular pathology. Under certain circumstances, these organelles respond to cellular insult by a marked increase in size, resulting in the formation of giant mitochondria (megamitochondria). Ethanol has been implicated in the induction of giant mitochondria in rat hepatocytes. Since ethanol is reported to affect pancreatic mitochondria, we examined this organ for evidence of mitochondrial giantism in rats administered ethanol and a relatively small amount of supplementary iron. METHODS: Diets were administered via a chronically implanted gastrostomy catheter. Rats were segregated in four groups: 1) basic high-fat diet, 2) ethanol and a high fat diet, 3) carbonyl iron and a high-fat diet, and 4) ethanol and carbonyl iron combined with a high-fat diet. After the animals were on their respective diets for 16 weeks, specimens of pancreas were extirpated and processed for and examined by transmission electron microscopy. RESULTS: Mitochondria in rats on the basic high fat diet resemble those in untreated controls. With ethanol and a high-fat diet, some mitochondria in virtually every exocrine cell are profoundly altered. Such organelles, which are of normal size, have undergone rearrangement of their internal membranes, with three of four parallel cristae residing at one or both poles of spherical to ovate mitochondria. In rats receiving both ethanol and carbonyl iron, giant mitochondria are present in pancreatic exocrine cells. Except for their size, megamitochondria in many cases are virtual likenesses of the altered mitochondria in the alcohol-high-fat rats, having several stacked cristae at either pole and an enhanced matrix compartment. Many of the giant mitochondria have at least one expanded crista, which contains packets of helically coiled filaments. When control rats are fed carbonyl iron without ethanol, the pancreatic mitochondria display a marked propensity for forming clusters of tightly interlocked organelles, formations that may be a prelude to mitochondrial fusion. CONCLUSIONS: It appears that iron supplementation sets the stage for organelle fusion, hence enlargement, with the ethanol providing the stimulus for fusion to actually take place, and controlling the final morphology of the resultant megamitochondria.

Animals↗