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Biomedical subjects

V R Gordeuk

Publications and source records attributed to V R Gordeuk.

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

Chelation of iron within the erythrocytic Plasmodium falciparum parasite by iron chelators.

To examine the site of action of antimalarial iron chelators, iron ligands were added to control erythrocytes and to erythrocytes parasitized with Plasmodium falciparum, and the concentration of intracellular labile iron was monitored with the fluorescent probe, calcein. The fluorescence of calcein quenches upon binding iron and increases upon releasing iron. The chelators included desferrioxamine B, 2',2'-bipyridyl, and aminophenol II, a compound that is being newly reported as having anti-plasmodial properties. Calcein-loaded parasitized cells displayed fluorescence predominantly within the cytosol of both rings and trophozoites. The addition of chelators to both control and parasitized erythrocytes led to significant increases of fluorescence (P < 0.001). Fluorescence was observed to increase within the parasite itself after addition of iron chelators, indicating that these agents bound labile iron within the plasmodium. The relative increases of fluorescence after addition of chelators were greater in control than parasitized erythrocytes (P < 0.05) as were the estimated labile iron concentrations (P < or = 0.001). These results suggest that (i) the anti-malarial action of iron chelators might result from the ability to reach the infected cell's parasite compartment and bind iron within the parasite cytosol, and (ii) the labile iron pool of the host red cell may be either utilized or stored during plasmodial growth.

2,2'-Dipyridyl↗
PubMed1999

Bone marrow macrophage iron grade and survival of HIV-seropositive patients.

OBJECTIVE: Increased iron stores predispose to certain microbial infections. This association might be especially important in patients whose immune system is impaired by HIV. This study examined the relationship between iron stores and the survival times of patients with HIV infection. DESIGN: Retrospective analysis of iron stores, as determined directly in bone marrow aspirates, and of hospital records. SETTING: The George Washington University Hospital, an urban academic tertiary care institution. PATIENTS: Three hundred and forty-eight HIV-seropositive adults who had diagnostic bone marrow aspirates between January 1985 and June 1996. MEASUREMENTS: Bone marrow macrophage iron stores were graded on a scale of 0 to 5. For analysis of the influence of iron stores on survival, we compared patients with grades 4-5 iron stores (markedly or massively increased; n = 188) to those with grades 0-2 iron stores (normal or decreased; n = 130). RESULTS: Infections caused by Candida spp., Pneumocystis carinii, and Mycobacterium spp. were more common in patients with high macrophage iron grades than in patients with low or normal iron grades (P < or = 0.006). The adjusted estimated rate of death (hazards ratio) was higher in patients with high iron stores compared with patients with low or normal iron stores, both from the time of the bone marrow study (ratio of 2.1; 95% confidence interval 1.3-3.5; P = 0.003) and the determination of HIV-seropositivity (ratio of 2.8; 95% confidence interval 1.4-4.9; P = 0.001). CONCLUSION: High iron stores, as determined by bone marrow macrophage iron grade, may be associated with shorter survival times in patients with HIV infection.

AIDS-Related Opportunistic Infections↗
PubMed1999

Plasmodium falciparum and Plasmodium yoelii: effect of the iron chelation prodrug dexrazoxane on in vitro cultures.

To determine if an iron-chelating prodrug that must undergo intracellular hydrolysis to bind iron has antimalarial activity, we examined the action of dexrazoxane on Plasmodium falciparum cultured in human erythrocytes and P. yoelii cultured in mouse hepatocytes. Dexrazoxane was recently approved to protect humans from doxorubucin-induced cardiotoxicity. Using the fluorescent marker calcein, we confirmed that the iron-chelating properties of dexrazoxane are directly related to its ability to undergo hydrolysis. As a single agent, dexrazoxane inhibited synchronized cultures of P. falciparum in human erythrocytes only at suprapharmacologic concentrations (> 200 microM). In combination with desferrioxamine B, dexrazoxane in pharmacologic concentrations (100-200 microM) moderately potentiated inhibition by approximately 20%. In contrast, pharmacologic concentrations of dexrazoxane (50-200 microM) as a single agent inhibited the progression of P. yoelli from sporozoites to schizonts in cultured mouse hepatocytes by 45 to 69% (P < 0.001). These results are consistent with the presence of a dexrazoxane-hydrolyzing enzyme in hepatocytes but not in erythrocytes or malaria parasites. Furthermore, these findings suggest that dexrazoxane must be hydrolyzed to an iron-chelating intermediate before it can inhibit the malaria parasite, and they raise the possibility that the iron chelator prodrug concept might be exploited to synthesize new antimalarial agents.

Animals↗
PubMed1999

Iron chelation therapy for malaria: a review.

Malaria is one of the major global health problems, and an urgent need for the development of new antimalarial agents faces the scientific community. A considerable number of iron(III) chelators, designed for purposes other than treating malaria, have antimalarial activity in vitro, apparently through the mechanism of withholding iron from vital metabolic pathways of the intra-erythrocytic parasite. Certain iron(II) chelators also have antimalarial activity, but the mechanism of action appears to be the formation of toxic complexes with iron rather than the withholding of iron. Several of the iron(III)-chelating compounds also have antimalarial activity in animal models of plasmodial infection. Iron chelation therapy with desferrioxamine, the only compound of this nature that is widely available for use in humans, has clinical activity in both uncomplicated and severe malaria in humans.

Animals↗
PubMed1999

Dexrazoxane (ICRF-187).

1. Dexrazoxane (ICRF-187) is the only clinically approved drug for use in cancer patients to prevent anthracycline mediated cardiotoxicity. 2. The mode of action appears to be mainly due to the potential of the drug to remove iron from iron/anthracycline complexes and thus reduce free radical formation by these complexes. 3. Dexrazoxane also influences cell biology by its ability to inhibit topoisomerase II and its effects on the regulation of cellular iron homeostasis. 4. Although the cardioprotective effect of dexrazoxane in cancer patients undergoing chemotherapy with anthracyclines is well documented, the potential of this drug to modulate topoisomerase II activity and cellular iron metabolism may hold the key for future applications of dexrazoxane in cancer therapy, immunology, or infectious diseases.

Animals↗
PubMed1999

A traditional beverage prevents iron deficiency in African women of child bearing age.

OBJECTIVE: To determine if a traditional item in the diet might be useful in preventing iron deficiency in African women of child-bearing age. DESIGN: In a prospective study, the iron status of women who did and did not drink traditional beer high in iron and folic acid, was compared. Iron status was determined by a combination of haemoglobin, serum ferritin and transferrin saturation. SETTING: The study was conducted amongst rural villagers in the Murehwa and Zaka districts of Zimbabwe and in Mpumalanga Province, South Africa. SUBJECTS: 112 women aged between 12 and 50 y from a population of 425 rural people participating in on-going family genetic studies. RESULTS: Women who consumed traditional beer had significantly higher serum ferritin concentrations and transferrin saturations compared to non-drinkers (P = 0.0001 and 0.03 respectively). Iron deficiency anaemia was not present in drinkers but the prevalence in non-drinkers was 13%. Forty seven percent of the non-drinkers and only 14% of the drinkers had evidence of iron deficiency (P = 0.002). Six (21%) of the drinkers and none of the non-drinkers had evidence of iron overload (transferrin saturation > 55% and serum ferritin > 400 ug/l). CONCLUSION: We conclude that the consumption of traditional beer, rich in iron, protects women against iron deficiency. While the use of an alcoholic beverage is not ideal, our findings suggest that indigenous cultural practices might be successfully employed or adapted for promoting iron nutrition.

Adolescent↗
PubMed1999

The eosinophilic response and haematological recovery after treatment for Plasmodium falciparum malaria.

To examine a possible relationship between the immune response and haematological recovery after acute falciparum malaria, we followed peripheral blood eosinophil counts and haemoglobin concentrations for 4 weeks after starting effective treatment in 70 adult Thai patients. Eosinophils are induced by Th-2 cytokines as well as other stimuli. Eosinophil counts were elevated in only 8 (11%) of the subjects at presentation, but were increased in 65 (93%) by day 7. Eosinophil counts then decreased markedly by day 14, followed by a second increase until day 28. A significant positive correlation was found between peak eosinophil counts on day 7 and the haemoglobin concentration on day 28, both in 16 subjects without stool parasites (r = 0.65, P = 0.006) and in 54 patients with stool parasites (r = 0.32; P = 0.0019). These results suggest that a robust eosinophilic response shortly after completing antimalarial therapy predicts a good recovery from malaria-associated anaemia.

Adult↗
PubMed1999

Non-transferrin-bound iron and hepatic dysfunction in African dietary iron overload.

BACKGROUND: Circulating iron is normally bound to transferrin. Non-transferrin-bound iron (NTBI) has been described in most forms of iron overload, but has not been studied in African dietary iron overload. This abnormal iron fraction is probably toxic, but this has not been demonstrated. METHODS: High-pressure liquid chromatography was used to assay serum NTBI in 25 black African subjects with iron overload documented by liver biopsy and in 170 relatives and neighbours. Levels of NTBI were correlated with indirect measures of iron status and conventional liver function tests. RESULTS: Non-transferrin-bound iron (> 2 micromol/L) was present in 43 people, 22 of patients of whom underwent liver biopsy and 21 relatives and neighbours. All but four of these had evidence of iron overload on the basis of either liver biopsy or elevated transferrin and serum ferritin concentrations. Among all 195 subjects, the presence of NTBI in serum was independently related to elevations in alanine and aspartate aminotransferase activity and bilirubin concentration. This relationship between serum NTBI and hepatic dysfunction was confirmed in the subgroup of 25 subjects with iron overload documented by liver biopsy. Non-transferrin-bound iron correlated significantly with elevations in alanine and aspartate aminotransferase activities after adjustment for hepatic iron grades, inflammation and diet. CONCLUSIONS: Non-transferrin-bound iron was found to be commonly present in African patients with dietary iron overload and to correlate with transferrin saturation and serum ferritin concentration. The independent relationship between NTBI and elevated liver function tests suggests that it may be part of a pathway leading to hepatic injury.

Aspartate Aminotransferases↗
PubMed1999

Influence of hemoglobin E trait on the severity of Falciparum malaria.

To determine if hemoglobin E trait influences the course of acute malaria, adults hospitalized for the treatment of symptomatic infection with Plasmodium falciparum were studied retrospectively. Forty-two patients with hemoglobin E trait were compared with 175 reference subjects who did not have hemoglobin E, beta-thalassemia, glucose-6-phosphate dehydrogenase deficiency, or alpha-thalassemia. One patient (2.4%) with hemoglobin E trait had a severe complication of malaria by World Health Organization criteria (cerebral malaria), while 32 subjects in the reference group (18.3%) had one or more severe complications: cerebral malaria (n=18), hyperparasitemia (n=16), renal failure (n=10), and severe anemia (n=1) (P=.044 after adjustment for ethnic categories). The estimated odds of severe complications in the reference subjects were 6.9 times the odds in patients with hemoglobin E trait (95% confidence interval, 1.2-146. 4). These results suggest that hemoglobin E trait may ameliorate the course of acute falciparum malaria.

Acute Disease↗
PubMed1999

Associations between cellular immune effector function, iron metabolism, and disease activity in patients with chronic hepatitis C virus infection.

We studied the associations of macrophage activity, T-helper cell types 1 and 2 (Th-1/Th-2) responses, and iron status in 55 patients with hepatitis C virus (HCV)-related liver disease and 28 control patients with noninfectious liver disease. Serum concentrations of soluble tumor necrosis factor receptor type II (sTNFrec 75), a macrophage activation marker, were higher in cirrhotic than in noncirrhotic patients (P<.001) regardless of their HCV status, whereas levels of neopterin, interleukin (IL)-4 and IL-10 did not differ significantly. In HCV-positive patients, sTNFrec 75 levels and transferrin saturation (TfS) correlated positively with levels of aspartate transaminase (P<.001 for sTNFrec 75 and P=.028 for TfS) and alanine transaminase (P=.003 for sTNFrec 75 and P=.039 for TfS). Increased TfS correlated significantly with both advanced liver disease and a predominant Th-2 pattern in HCV patients. Our data suggest that an association exists between macrophage activation and hepatic dysfunction, and that iron status may affect the clinical course of HCV infection by modulating Th-1/Th-2 responses in vivo.

Antigens, CD↗
PubMed1999

Iron chelators as anti-infectives; malaria as a paradigm.

Malaria is the major life threatening parasitic disease and the cause of a global public health problem. The failure of vector eradication programs and the appearance and spread of drug resistant parasites have posed the urgent challenge of developing effective, safe and affordable anti-malarial drugs. The design of such drugs is largely based on the targeting of agents to the parasite-based machinery for host digestion and to the products of hemoglobin catabolism. Iron chelators, by depriving intracellular parasites from essential iron, lead to selective suppression of parasite growth. However, by acting on parasite-impaired macrophages, chelators can also expedite resumption of phagocytosis and elimination of parasites. In order to be clinically effective, chelators need to be maintained in the blood for extensive time periods. Therapeutic doses can be attained with appropriate drug combinations and formulations or delivery devices and these must be presented in a form well tolerated by the host. The early documentation that chelation therapy has activity against human malaria has paved the road for the design of novel and more efficient remedies based on short-term iron deprivation.

Animals↗
PubMed1999

Iron overload in urban Africans in the 1990s.

BACKGROUND: In a previously described model, heterozygotes for an African iron loading locus develop iron overload only when dietary iron is high, but homozygotes may do so with normal dietary iron. If an iron loading gene is common, then homozygotes with iron overload will be found even in an urban population where traditional beer, the source of iron, is uncommon. AIMS: To determine whether iron overload and the C282Y mutation characteristic of hereditary haemochromatosis are readily identifiable in an urban African population. METHODS: Histological assessment, hepatocellular iron grading, and dry weight non-haem iron concentration were determined in post mortem tissue from liver, spleen, heart, lungs, and skin. DNA of subjects with elevated hepatic iron indexes was analysed for the C282Y mutation. Iron concentrations in other tissues were compared. RESULTS: A moderate increase (>30 micromol/g) in hepatic iron concentrations was found in 31 subjects (23%; 95% confidence interval 15.9 to 30.1%), and they were considerably elevated (>180 micromol/g) in seven subjects (5.2%; 95% confidence interval 1.5 to 8.9%). Appreciably elevated hepatic iron concentrations were associated with heavy iron deposition in both hepatocytes and macrophages, and either portal fibrosis or cirrhosis. All were negative for the C282Y mutation. Very high concentrations were uncommon in subjects dying in hospital. Concentrations of iron in spleen, heart, lung, and skin were significantly higher in subjects with elevated hepatic iron. CONCLUSIONS: Iron overload is readily identified among urban Africans and is associated with hepatic damage and iron loading of several tissues. The condition is unrelated to the genetic mutation found in hereditary haemochromatosis.

Adult↗
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↗
PubMed1999

Iron and alcohol content of traditional beers in rural Zimbabwe.

OBJECTIVES: To determine the concentrations of iron and alcohol in traditional beer, as well as how these may be related to the brewing process. DESIGN: Cross sectional study. SETTING/SUBJECTS: Rural communities living in four of Zimbabwe's nine provinces. MAIN OUTCOME MEASURES: Ionic iron concentration and alcohol concentration in 94 different types of alcoholic beverages prepared in rural areas, and 18 commercially produced beers. RESULTS: The commonest types of traditional beer were a seven day beverage called 'doro rematanda', a by-product of this seven day beer called 'muchaiwa,' and a one-day beverage called 'chikokiyana'. Methods of preparation were similar in the four provinces. Median (Q1, Q3) ionic iron concentrations were 52 (31 to 75) mg/L for the seven-day beer (n = 51), 24 (18 to 36) mg/L for muchaiwa (n = 30) and 21 (17 to 63) mg/L for chikokiyana (n = 13). In contrast, ionic iron concentrations in 12 samples of commercially prepared clear beers were 0.1 mg/L and in commercial opaque beer were 3.6 mg/L. Mean (SD) alcohol concentration in traditional beer was 4.1 g/100 ml (+/- 0.873) compared to 2.8 g/100 ml +/- 1.394) in the muchaiwa and 3.6 g/100 ml (+/- 1.445) in the one day brew, chikokiyana. Mean alcohol concentrations in the three commercial beers are reportedly 3.5 g/100 ml in the opaque beer (Scud), and 4.7 to 5.0 g/ml in clear beer (Zambezi and Castle lagers). CONCLUSIONS: Several preparation methods lead to traditional fermented beverages with very high iron concentrations. Measures to prevent dietary iron overload should include all of these beverages in their scope.

Beer↗
PubMed1999

Measurements of iron status and survival in African iron overload.

INTRODUCTION: Dietary iron overload is common in southern Africa and there is a misconception that the condition is benign. Early descriptions of the condition relied on autopsy studies, and the use of indirect measurements of iron status to diagnose this form of iron overload has not been clarified. METHODS: The study involved 22 black subjects found to have iron overload on liver biopsy. Fourteen subjects presented to hospital with liver disease and were found to have iron overload on percutaneous liver biopsy. Eight subjects, drawn from a family study, underwent liver biopsy because of elevated serum ferritin concentrations suggestive of iron overload. Indirect measurements of iron status (transferrin saturation, serum ferritin) were performed on all subjects. Histological iron grade and hepatic iron concentration were used as direct measures of iron status. RESULTS: There were no significant differences in either direct or indirect measurements of iron status between the two groups. In 75% of these subjects the hepatic iron concentration was greater than 350 micrograms/g dry weight, an extreme elevation associated with a high risk of fibrosis and cirrhosis. Serum ferritin was elevated in all subjects and the transferrin saturation was greater than 60% in 93% of the subjects. Hepatomegaly was present in 20 of the 22 cases and there was only a moderate derangement in liver enzymes except for a tenfold increase in the median gamma-glutamyl transpeptidase concentration. There was a strong correlation between serum ferritin and hepatic iron concentrations (r = 0.71, P = 0.006). After a median follow-up of 19 months, 6 (26%) of the subjects had died. The risk of mortality correlated significantly with both the hepatic iron concentration and the serum ferritin concentration. CONCLUSIONS: Indirect measurements of iron status (serum ferritin concentration and transferrin saturation) are useful in the diagnosis of African dietary iron overload. When dietary iron overload becomes symptomatic it has a high mortality. Measures to prevent and treat this condition are needed.

Adult↗
PubMed1999

Increased serum transferrin saturation is associated with lower serum transferrin receptor concentration.

BACKGROUND: Serum transferrin receptor (sTfR) concentrations are increased in iron deficiency. We wished to examine whether they are decreased in the presence of potential iron-loading conditions, as reflected by increased transferrin saturation (TS) on a single occasion. METHODS: We compared sTfR concentrations between 570 controls with normal iron status and 189 cases with increased serum TS on a single occasion; these latter individuals may be potential cases of iron overload. Cases and controls were selected from adults who had been examined in the third National Health and Nutrition Examination Survey (1988-1994) and for whom excess sera were available to perform sTfR measurements after the survey's completion. Increased TS was defined as >60% for men and >55% for women; normal iron status was defined as having no evidence of iron deficiency, iron overload, or inflammation indicated by serum ferritin, TS, erythrocyte protoporphyrin, and C-reactive protein. RESULTS: Mean sTfR and mean log sTfR:ferritin were approximately 10% and 24% lower, respectively, in cases than in controls (P <0.002). Cases were significantly more likely to have an sTfR value <2.9 mg/L, the lower limit of the reference interval, than were controls (odds ratio = 1.8; 95% confidence interval, 1.04-2.37). CONCLUSION: Our results support previous studies that suggested that sTfR may be useful for assessing high iron status in populations.

Adult↗
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↗