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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
PubMed2006

Initial screening transferrin saturation values, serum ferritin concentrations, and HFE genotypes in Native Americans and whites in the Hemochromatosis and Iron Overload Screening Study.

We compared initial screening transferrin saturation (TfSat) and serum ferritin (SF) phenotypes and HFE C282Y and H63D genotypes of 645 Native American and 43,453 white Hemochromatosis and Iron Overload Screening Study participants who did not report a previous diagnosis of hemochromatosis or iron overload. Elevated measurements were defined as TfSat >50% in men and >45% in women and SF >300 ng/ml in men and >200 ng/ml in women. Mean TfSat was 31% in Native American men and 32% in white men (p = 0.0337) and 25% in Native American women and 27% in white women (p < 0.0001). Mean SF was 153 microg/l in Native American and 151 microg/l in white men (p = 0.8256); mean SF was 55 microg/l in Native American women and 63 microg/l in white women (p = 0.0015). The C282Y allele frequency was 0.0340 in Native Americans and 0.0683 in whites (p < 0.0001). The H63D allele frequency was 0.1150 in Native Americans and 0.1532 in whites (p = 0.0001). We conclude that the screening TfSat and SF phenotypes of Native Americans are similar to those of whites. The allele frequencies of HFE C282Y and H63D are significantly lower in Native Americans than in whites.

Adult↗
PubMed2005

Benefits and risks of iron therapy for chronic anaemias.

Iron is used widely for the treatment of anaemias with iron-restricted erythropoiesis. This intervention can be both beneficial and detrimental depending on the type of the underlying process. While in iron deficiency anaemia (IDA), the most frequent anaemia in the world, iron is the therapy of choice, this intervention can be harmful in the anaemia of chronic disease or anaemia associated with renal failure, the most common anaemias in hospitalized adult patients in Western countries. Iron is able to negatively affect cell-mediated immune effector mechanisms directed against invading microorganisms and tumour cells while at the same time, as an essential nutrient, it can stimulate the proliferation of these unwanted cells. In addition, iron catalyses the formation of toxic radicals leading to tissue damage or the promotion of cardiovascular events. Thus, it is essential to correctly diagnose the precise cause of anaemia and to consider the benefits and hazards of targeted iron therapy.

Administration, Oral↗
PubMed2001

Relationship between transferrin saturation and iron stores in the African American and US Caucasian populations: analysis of data from the third National Health and Nutrition Examination Survey.

In previous analyses of transferrin saturation data in African Americans and Caucasians from the second National Health and Nutrition Examination Survey (NHANES II), subpopulations were found consistent with population genetics for common loci that influence iron metabolism. The goal of this new study was to determine if these transferrin saturation subpopulations have different levels of iron stores. Statistical mixture modeling was applied to transferrin saturation data for African Americans and Caucasians from the third National Health and Nutrition Examination Survey (NHANES III), and then the mean serum ferritin concentrations were determined for the transferrin saturation subpopulations that were identified. After adjustment for diurnal variation, 3 subpopulations of transferrin saturation were identified in each racial group. Satisfying Hardy-Weinberg conditions for major locus effects, in both racial groups the sum of the square roots of the proportion with the lowest mean transferrin saturation and the proportion with the highest mean transferrin saturation was approximately 1. When weighted to reflect the US adult population as a whole, these subpopulations of increasing transferrin saturations had progressively increasing mean age-adjusted serum ferritin concentration values in each ethnic grouping as stratified by sex (trend test, P <.002 for all). These results are consistent with the concept that population transferrin saturation subpopulations reflect different levels of storage iron.

Adult↗
PubMed2001

An IRP-like protein from Plasmodium falciparum binds to a mammalian iron-responsive element.

This study cloned and sequenced the complementary DNA (cDNA) encoding of a putative malarial iron responsive element-binding protein (PfIRPa) and confirmed its identity to the previously identified iron-regulatory protein (IRP)-like cDNA from Plasmodium falciparum. Sequence alignment showed that the plasmodial sequence has 47% identity with human IRP1. Hemoglobin-free lysates obtained from erythrocyte-stage P falciparum contain a protein that binds a consensus mammalian iron-responsive element (IRE), indicating that a protein(s) with iron-regulatory activity was present in the lysates. IRE-binding activity was found to be iron regulated in the electrophoretic mobility shift assays. Western blot analysis showed a 2-fold increase in the level of PfIRPa in the desferrioxamine-treated cultures versus control or iron-supplemented cells. Malarial IRP was detected by anti-PfIRPa antibody in the IRE-protein complex from P falciparum lysates. Immunofluorescence studies confirmed the presence of PfIRPa in the infected red blood cells. These findings demonstrate that erythrocyte P falciparum contains an iron-regulated IRP that binds a mammalian consensus IRE sequence, raising the possibility that the malaria parasite expresses transcripts that contain IREs and are iron-dependently regulated.

Aconitate Hydratase↗
PubMed2001

Association of pulmonary tuberculosis with increased dietary iron.

To determine whether increased dietary iron could be a risk factor for active tuberculosis, dietary iron history and human immunodeficiency virus (HIV) status were studied in 98 patients with pulmonary tuberculosis and in 98 control subjects from rural Zimbabwe. Exposure to high levels of dietary iron in the form of traditional beer is associated with increased iron stores in rural Africans. HIV seropositivity was associated with a 17.3-fold increase in the estimated odds of developing active tuberculosis (95% confidence interval [95% CI], 7.4-40.6; P<.001), and increased dietary iron was associated with a 3.5-fold increase (95% CI, 1.4-8.9; P=.009). Among patients treated for tuberculosis, HIV seropositivity was associated with a 3.8-fold increase in the estimated hazard ratio of death (95% CI, 1.0-13.8; P=.046), and increased dietary iron was associated with a 1.3-fold increase (95% CI, 0.4-6.4; P=.2). These findings are consistent with the hypothesis that elevated dietary iron may increase the risk of active pulmonary tuberculosis.

Adult↗
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↗
PubMed2001

Assessment of antimalarial effect of ICL670A on in vitro cultures of Plasmodium falciparum.

We tested in vitro the antimalarial properties of ICL670A, a newly developed iron chelator for the long-term oral treatment of iron overload. Ring-stage synchronized cultures of Plasmodium falciparum cultured in human erythrocytes were exposed to different concentrations of ICL670A and the conventional iron chelator, desferrioxamine B (DFO), for 48 h. Malarial growth was measured by incorporation of [3H]-hypoxanthine. ICL670A at 30 micromol/l had marked antimalarial activity that was observable by 6 h after beginning the exposure of ring-stage parasites to the agent. Over 48 h of culture, malarial growth was significantly lower with ICL670A than with DFO at concentrations of both 30 micromol/l (P = 0.008) and 60 micromol/l (P = 0.001). At 48 h, growth relative to control was 53% with ICL670A and 83% with DFO at concentrations of 30 micromol/l, and 20% with ICL670A and 26% with DFO at concentrations of 60 micromol/l. Standard 50% inhibitory concentrations (IC50s) were similar for ICL670A and DFO. Precomplexation with iron completely abolished the inhibitory effect of ICL670A, indicating that this new agent, like DFO, probably inhibits parasite growth via deprivation of iron from critical targets within the parasite. Further studies to address the question of the antimalarial potential of ICL670A in combination with classic antimalarials would be of interest.

Analysis of Variance↗
PubMed2001

Carbohydrate-deficient transferrin and chronic alcohol ingestion in subjects with transferrin CD-variants.

Carbohydrate-deficient transferrin (CDT) is widely accepted as screening test for excessive alcohol consumption. However, results from subjects with transferrin variants must be interpreted with caution since chromatography-based methods may give false-positive results. Furthermore, due to the co-elution in HPLC or the co-migration in capillary zone electrophoresis (CZE) of the di- and trisialylated C transferrins with the tetrasialylated D peak, exact measurement of CDT is impossible in CD-variants. Therefore, in this study, we tried to offer a different solution, including only the asialo-D, asialo-C, monosialo-D, monosialo-C, disialo-D and trisialo-D transferrins in the CDT calculation and referring to a different cut-off value for CDT in transferrin CD-variants. Comparison of alcohol consumers with teetotalers demonstrated area under the receiver operating characteristic curve of 0.79 and 0.76 for carbohydrate-deficient transferrin, 0.71 and 0.71 for mean corpuscular volume and 0.51 and 0.68 for gamma-glutamyltransferase in 43 subjects with transferrin CD-variants and 225 subjects with CC-phenotypes, respectively. Since false-positive carbohydrate-deficient transferrin results due to a transferrin CD-variant have major social implications, capillary electrophoresis-based or similar methods (HPLC, FPLC) should be preferred in populations carrying a high D-allele frequency.

Adult↗
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↗