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Biomedical subjects

V R Gordeuk

Publications and source records attributed to V R Gordeuk.

At least 19 recordsLinked to original sources
PubMed2001

Iron status and the outcome of HIV infection: an overview.

BACKGROUND: Theoretical considerations and experiments in the laboratory suggest that excessive iron stores may have an adverse effect on immunity. If so, high iron stores might be especially a problem in patients with human immunodeficiency virus (HIV) infection. OBJECTIVE AND STUDY DESIGN: Review published clinical studies that provide information regarding the effect of iron status on the outcome of HIV infection. RESULTS: Four clinical observations have provided some perspective on the effect of iron status on the outcome of HIV-1 infection. First, in a retrospective study of HIV-positive thalassemia major patients, the rate of progression of HIV disease was significantly faster in patients with lower doses of desferrioxamine and higher serum ferritin concentrations. Second, the inadvertent simultaneous administration of low doses of oral iron with dapsone for the prophylaxis of Pneumocystis carinii pneumonia in HIV-positive patients may have been associated with excess mortality. Third, a study of haptoglobin polymorphisms in HIV-positive subjects indicated that the haptoglobin 2-2 polymorphism is associated with higher iron stores and shortened survival as compared with the haptoglobin 1-1 or 2-1 phenotypes. Fourth, a retrospective study of bone marrow macrophage iron in HIV-positive patients suggested that survival is shorter with high iron stores. CONCLUSION: These four observations raise the possibility that high iron status may adversely influence the outcome of HIV-1 infection.

AIDS-Related Opportunistic Infections↗
PubMed2001

Iron and Mycobacterium tuberculosis infection.

BACKGROUND: iron is known to play a role in the susceptibility to and outcome of several infections. In view of the increasing worldwide problem of tuberculosis, it may be important to ascertain whether this is also the case with this infection. OBJECTIVES: (1) to review studies conducted in vitro, in experimental animals, and in humans that provide evidence that iron status may influence the occurrence and outcome of tuberculosis. (2) To perform an in vivo study in mice, examining the effect of iron loading on experimental infection caused by a virulent strain of Mycobacterium tuberculosis. RESULTS: we studied the effect of iron loading on the growth in spleen and lungs of a virulent strain of M. tuberculosis, injected i.v. in female Balb/C mice. At sacrifice on day 42 after the experimental infection, the iron-loaded mice presented a significantly enhanced multiplication of M. tuberculosis in both the spleen and the lungs, when compared to the mice without iron loading. CONCLUSION: Most of the studies, including our experimental study in mice, tend to suggest that an excess of iron may enhance the growth of M. tuberculosis and worsen the outcome of human tuberculosis.

Animals↗
PubMed2000

Influence of hemoglobin E trait on the antimalarial effect of artemisinin derivatives.

To determine whether hemoglobin E trait influences the antimalarial effect of artemisinin derivatives, we retrospectively compared 32 case patients with hemoglobin E trait to 32 control patients who did not have hemoglobin E, beta-thalassemia, glucose-6-phosphate dehydrogenase deficiency, or alpha-thalassemia trait on the basis of a mean corpuscular volume > or =78 femtoliters. All patients were admitted to the Hospital for Tropical Diseases in Bangkok, Thailand, with acute falciparum malaria. Control patients were matched to case patients with hemoglobin E trait by treatment with artemisinin derivatives versus other antimalarial drugs, by ethnic group, and by parasite count. Among 38 patients treated with artemisinin derivatives, the presence of hemoglobin E trait was associated with significantly faster parasite clearance (2.9-fold; 95% confidence interval [CI], 1.4-6.3; P=.006). Among 26 patients treated only with other antimalarial drugs, hemoglobin E trait did not significantly enhance parasite clearance (hazards ratio, 1.1; 95% CI, 0.5-2.5; P=. 8). Hemoglobin E trait may potentiate the antimalarial effect of artemisinin derivatives.

Adult↗
PubMed2000

Aminothiol multidentate chelators against Chagas disease.

Three compounds of an aminothiol family of iron chelators were examined for activity against trypomastigote (human) and epimastigote (vector) forms of Trypanosoma cruzi: tetraethyl and tetramethyl derivatives of ethane-1,2-bis (N-1-amino-3-ethyl butyl-3-thiol) (BAT-TE and BAT-TM) and N',N',N'-tris-(2-methyl-2-mercaptopriopyl)- 1,4,7-triazacyclonane (TAT). BAT-TE at 270 microM completely arrested the growth of trypomastigote forms in mouse blood stored at 4 degrees C for 24 h (IC(50) 67.7+/-7 microM), while BAT-TM arrested growth at 630 microM (IC(50) 158+/-17 microM) and TAT at concentrations >800 microM (IC(50) 415+/-55 microM). In T. cruzi-infected mice, BAT-TE and BAT-TM had no anti-trypanosomal activity in doses up to 200 mg/kg, whether the route of administration was intraperitoneal or oral, and TAT was not tested due to insufficient quantity. TAT had an IC(50) of 52+/-7 microM against the epimastigote forms while BAT-TM and BAT-TE were inhibitory only at concentrations >250 microM. The trypanocidal activity of BAT derivatives in blood stored at 4 degrees C makes these compounds potential candidates for the purpose of clearing donated blood of trypomastigotes.

Animals↗
PubMed2000

Reference range of serum haptoglobin is haptoglobin phenotype-dependent in blacks.

Reference values for serum haptoglobin (Hp), were established in a Black Zimbabwean population. The upper limit (2.15 g/l) is comparable to the one in Caucasians, but the lower limit (0.12 g/l) is much lower than the proposed interim international reference limit (0.3 g/l). Subjects that typed as Hp 0-0 by starch gel electrophoresis technique were retyped using high performance gel permeation chromatography. This resulted in a 32% decrease in the frequency of Hp 0-0, but an increase in Hp 2-2 and Hp 2-1M phenotype frequencies. In the Zimbabwean Blacks, the Hp 0-0 frequency was estimated to be 2.9%. Haptoglobin reference values were found to be Hp phenotype-dependent; highest values were found in Hp 1-1 (median 0.88 g/l; range 0.31-1.69 g/l) and in Hp 2-1 (median 0.90 g/l; range 0.31-2.22 g/l) and lower values (median 0.66 g/l; range 0.13-1.79 g/l) in Hp 2-2 subjects. The Hp 2-1M phenotype was characterized by low reference values (0.18-1.25 g/l) (P<0.05). In three cases of the rare variant Hp Johnson, high Hp concentrations were found (median 1. 57 g/l; range 0.98-1.57 g/l).

Adult↗
PubMed2000

Severe anaemia in Zambian children with Plasmodium falciparum malaria.

BACKGROUND: Severe anaemia and cerebral malaria are highly prevalent complications of Plasmodium falciparum malaria among African children. The mechanisms of severe malarial anaemia, and the relative importance of this condition in comparison to cerebral malaria, are not known for many regions of Africa. METHODS We reviewed the records of 6200 children up to 6 years of age admitted to one rural Zambian hospital between 1994 and 1996. Severe malarial anaemia was defined as an haemoglobin concentration < 5.0 g/dl in a patient with asexual forms of P. falciparum in the peripheral blood. Cerebral malaria was defined as impaired consciousness (Blantyre coma score < 5) not attributable to any other cause in a patient with a positive malaria smear. RESULTS Severe malarial anaemia was found in 590 children (9.5% of paediatric admissions) and strictly defined cerebral malaria occurred in 286 children (4.6% of paediatric admissions); 98 of these patients had the combination of both complications. Severe malarial anaemia correlated strongly with the degree of parasitaemia, with malnutrition as indicated by low weight for age, with absence of fever and with presentation late in the malaria season. In comparison, patients with cerebral malaria were more often febrile and presented earlier in the malaria season. The case fatality rate of severe malarial anaemia (0.088) was about half that of cerebral malaria (0.189), but because severe malarial anaemia was more common, these two forms of complicated malaria were implicated in similar numbers of in-hospital paediatric deaths. CONCLUSION Severe anaemia is a more common complication of P. falciparum malaria in hospitalized Zambian children than cerebral malaria and is associated with a similar number of deaths. Malnutrition and changes in immune response patterns due to prolonged exposure to P. falciparum may contribute to the development of this complication.

Anemia↗
PubMed2000

A randomized controlled trial of artemotil (beta-arteether) in Zambian children with cerebral malaria.

The efficacy and safety of intramuscular artemotil (ARTECEF) was compared to intravenous quinine in African children with cerebral malaria. This prospective block randomized open-label study was conducted at two centers in Zambia. Subjects were children aged 0 to 10 years of age with cerebral malaria and a Blantyre Coma Score of 2 or less. Ninety two children were studied; 48 received artemotil and 44 quinine. No significant differences in survival, coma resolution time, neurologic sequelae, parasite clearance time, and fever resolution time were seen between the two regimens. Rates for negative malaria smears one month after therapy were similar in both groups. Artemotil was a well-tolerated drug in the 48 patients in this study. It appears to be at least therapeutically equivalent to quinine for the treatment of pediatric cerebral malaria. It has the advantage of being able to be given intramuscularly once daily for only five days.

Antimalarials↗
PubMed2000

Markers of inflammation in children with severe malarial anaemia.

OBJECTIVE: To investigate if severe malarial anaemia is associated with a specific immune response pattern, we determined serum levels of neopterin (a marker of activation of macrophages by interferon-gamma) and of the anti-inflammatory cytokines, interleukins 4 and 10. METHODS: Zambian children < 6 years of age presenting to a rural hospital with cerebral malaria were studied. Twenty-one children with admission haemoglobin concentrations </= 5 g/dl were classified as having severe anaemia and 40 with haemoglobin concentrations >/= 7 g/dl served as a control group. RESULTS: Logistic regression modelling indicated that a 10-fold rise in serum neopterin concentrations was associated with a 50-fold increase in the estimated odds of having severe anaemia (P = 0.015), while a 10-fold rise in serum interleukin 4 concentrations was associated with a 10-fold decrease in the estimated odds of having severe anaemia (P = 0.023). Increasing serum interleukin 10 concentrations, measured in less than half of the subjects, were associated with a nonsignificant reduction in the odds of having severe anaemia (P = 0.095). CONCLUSION: Development of severe malarial anaemia may be directly associated with serum neopterin concentrations and inversely correlated with serum interleukin 4 levels.

Anemia↗
PubMed2000

Haptoglobin polymorphism and mortality in patients with tuberculosis.

SETTING: A rural Zimbabwean hospital and the surrounding community. OBJECTIVES: To determine whether a particular haptoglobin phenotype is associated with increased susceptibility to clinical pulmonary tuberculosis, and to determine the outcome of treatment for pulmonary tuberculosis according to haptoglobin phenotype. DESIGN: A case-control study, and a prospective cohort study. RESULTS: We studied 98 consecutive patients with sputum-positive pulmonary tuberculosis and 98 sex- and age-matched controls. The haptoglobin (Hp) phenotype distributions did not differ significantly between the tuberculosis patients and controls (P = 0.5). During the 18-month follow-up period after the start of tuberculosis treatment, 6/18 (33%) cases with Hp 2-2 phenotype died compared to 9/47 (19%) with Hp 2-1 and 3/31 (10%) with Hp 1-1. In a logistic regression model, the odds of dying were 6.1-fold greater with Hp 2-2 than with Hp 1-1 (95%CI 1.04-35.1, P = 0.04). CONCLUSION: Our results suggest that there is equal susceptibility to clinical pulmonary tuberculosis disease amongst different haptoglobin phenotypes. Nonetheless, tuberculosis patients with Hp 2-2 phenotype had a higher risk of mortality.

Adult↗
PubMed2000

Transferrin polymorphism influences iron status in blacks.

BACKGROUND: Genetic variants of human transferrin (TF) have been described, but little is known about their functional differences. We studied iron status according to TF phenotype in a healthy Zimbabwean population and in subjects at risk of African iron overload. METHODS: The study population consisted of 483 nondrinkers, 31 drinking spouse pairs, and 5 family pedigrees (n = 88) with index cases of iron overload. TF phenotypes were determined using starch gel electrophoresis. To evaluate iron status, serum iron, total iron-binding capacity (TIBC), ferritin, and soluble TF receptors were measured, and the percentage of saturation and the serum iron:TF ratio were calculated. The binding of the TF variants was studied by equilibrium dialysis. RESULTS: The reference population was characterized by a high TF D allele frequency (0.050) and a complete absence of homozygous TF DD individuals. Similar allele frequencies were observed in subjects at risk of African iron overload. In the reference population, male TF CD heterozygotes had significantly lower (P <0.01) values for serum iron, TIBC, TF saturation, and serum iron:TF ratio than the TF CC homozygotes; in females, only TIBC was significantly different. Overall red blood cell indices did not differ according to TF phenotype. In the population at risk of African iron overload, only serum iron:TF ratio was consistently significantly lower in TF CD phenotypes (P <0.05). After equilibrium dialysis, the amount of iron bound by TF was significantly lower (P <0.01) in TF CD individuals. CONCLUSIONS: The present data demonstrate a functional difference between TF phenotypes in blacks.

Adult↗
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↗