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Biomedical subjects

Victor R Gordeuk

Publications and source records attributed to Victor R Gordeuk.

At least 37 records · Page 2Linked to original sources
PubMed2005

Ferroportin (Q248H) mutations in African families with dietary iron overload.

BACKGROUND: Dietary iron overload found in sub-Saharan Africa might be caused by an interaction between dietary iron and an iron-loading gene. Caucasian people with ferroportin gene mutations have iron overload histologically similar to that found in African patients with iron overload. Ferroportin is also implicated in the hypoferremic response to inflammation. The prevalence of the ferroportin Q248H mutation, unique to African people, and its association with dietary iron overload, mean cell volume (MCV) and C-reactive protein (CRP) were examined in 19 southern African families. METHODS: Polymerase chain reaction (PCR) and restriction enzyme digestion were used to identify the Q248H mutation. Statistical analysis was carried out to correlate the presence of the mutation with markers of iron overload and inflammation. RESULTS: We identified three (1.4%) Q248H homozygotes and 53 (24.1%) heterozygotes in the families examined in the present study. There was no increased prevalence of the mutation in index subjects or their families. Logistic regression showed significantly higher serum ferritin concentrations with the mutation. The mean cell volume (MCV) was significantly lower, and the serum CRP significantly higher in subjects who carried the mutation. CONCLUSIONS: The present study of 19 families with African iron overload failed to show evidence that the ferroportin (Q248H) mutation is responsible for the condition. Logistic regression, correcting for factors influencing iron status, did show increased ferritin levels in individuals with the mutation. The strong association with low MCV suggests the possibility that the ferroportin (Q248H) mutation might interfere with iron supply, whereas the elevated serum CRP might indicate that the ferroportin mutation influences the inflammatory response in African populations.

Biomarkers↗
PubMed2005

Effects of root extracts of Fagara zanthoxyloides on the in vitro growth and stage distribution of Plasmodium falciparum.

The development of resistance by Plasmodium falciparum to conventional drugs poses a threat to malaria control. There is therefore a need to find new, effective, and affordable remedies for malaria, including those derived from plants. This study demonstrates that crude, reverse-phase high-pressure liquid chromatography (RP-HPLC)-semipurified, and RP-HPLC-purified root extracts of Fagara zanthoxyloides inhibit the growth of P. falciparum in vitro, with 50% inhibitory concentrations (IC(50)s) of 4.90, 1.00, and 0.13 microg/ml, respectively. Roots of F. zanthoxyloides, known as chewing sticks, are widely used for tooth cleaning in West Africa. Microscopic examination of Giemsa-stained slides showed a virtual absence of schizonts in ring-stage synchronized cultures treated with crude extracts at concentrations of 30 to 60 microg/ml during 36 to 48 h of incubation. These observations suggest that the active constituent in the extract may be cytotoxic for P. falciparum trophozoites, thereby inhibiting their development to the schizont stage. A pure bioreactive fraction was subsequently obtained from the chromatographic separations. When this fraction was mixed with pure fagaronine, the mixture coeluted as a single peak on the analytical RP-HPLC column, suggesting that fagaronine may be the active antimalarial constituent of Fagara root extracts. Additional experiments showed that fagaronine also inhibited P. falciparum growth, with an IC(50) of 0.018 microg/ml. The results of this study suggest that the antimalarial activity of fagaronine deserves further investigation.

Alkaloids↗
PubMed2005

Congenital polycythemias/erythrocytoses.

Congenital polycythemias may result from inherited defects in hypoxia sensing, from inherited intrinsic defects in red blood cell precursors, or from inherited conditions that cause low tissue oxygen tension and secondary polycythemia. Conditions of defective hypoxia sensing feature inappropriately normal or elevated serum erythropoietin (Epo) concentrations in the setting of normoxia and erythrocytosis. They are often due to homozygous or compound heterozygous germline mutations in the von Hippel Lindau tumor suppressor gene (VHL) but without increased incidence of tumors. Affected persons have a high risk of arterial thrombosis and early mortality. The molecular biology of rare polycythemic patients with a single mutated VHL allele remains obscure. Primary congenital and familial polycythemias are characterized by low Epo levels and increased erythroid precursor responsiveness to Epo. They are often due to heterozygous gain-of function mutations in the gene for erythropoietin receptor (EPOR). Secondary congenital polycythemias have low tissue oxygen tension due to hemoglobins with high affinity for oxygen, low erythrocyte 2,3 biphosphoglycerate levels, methemoglobinemia or cyanotic heart or lung disease. Whether phlebotomy therapy reduces complications and prolongs survival in congenital polycythemia is not known.

Homeostasis↗
PubMed2004

Congenital disorder of oxygen sensing: association of the homozygous Chuvash polycythemia VHL mutation with thrombosis and vascular abnormalities but not tumors.

Adaptation to hypoxia is critical for survival and regulates multiple processes, including erythropoiesis and vasculogenesis. Chuvash polycythemia is a hypoxia-sensing disorder characterized by homozygous mutation (598C>T) of von Hippel-Lindau gene (VHL), a negative regulator of hypoxia sensing. Although endemic to the Chuvash population of Russia, this mutation occurs worldwide and originates from a single ancient event. That VHL 598C>T homozygosity causes elevated normoxic levels of the transcription factor hypoxia inducible factor-1alpha (HIF-1alpha), serum erythropoietin and hemoglobin is known, but the disease phenotype has not been documented in a controlled manner. In this matched cohort study, VHL 598C>T homozygosity was associated with vertebral hemangiomas, varicose veins, lower blood pressures, and elevated serum vascular endothelial growth factor (VEGF) concentrations (P <.0005), as well as premature mortality related to cerebral vascular events and peripheral thrombosis. Spinocerebellar hemangioblastomas, renal carcinomas, and pheochromocytomas typical of classical VHL syndrome were not found, suggesting that overexpression of HIF-1alpha and VEGF is not sufficient for tumorigenesis. Although hemoglobin-adjusted serum erythropoietin concentrations were approximately 10-fold higher in VHL 598C>T homozygotes than in controls, erythropoietin response to hypoxia was identical. Thus, Chuvash polycythemia is a distinct VHL syndrome manifested by thrombosis, vascular abnormalities, and intact hypoxic regulation despite increased basal expression of hypoxia-regulated genes.

Adaptation, Physiological↗
PubMed2004

Novel aroylhydrazone and thiosemicarbazone iron chelators with anti-malarial activity against chloroquine-resistant and -sensitive parasites.

Iron (Fe) is crucial for cellular proliferation, and Fe chelators have shown activity at preventing the growth of the malarial parasite in cell culture and in animal and human studies. We investigated the anti-malarial activity of novel aroylhydrazone and thiosemicarbazone Fe chelators that show high activity at inhibiting the growth of tumour cells in cell culture [Blood 100 (2002) 666]. Experiments with the chelators were performed using the chloroquine-sensitive, 3D7, and chloroquine-resistant, 7G8, strains of Plasmodium falciparum in vitro. The new ligands were significantly more active in both strains than the Fe chelator in widespread clinical use, desferrioxamine (DFO). The most effective chelators examined were 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone and 2-hydroxy-1-naphthylaldehyde-4-phenyl-3-thiosemicarbazone. The anti-malarial activity correlates with anti-proliferative activity against neoplastic cells demonstrated in a previous study. Our studies suggest that this class of lipophilic chelators may have potential as useful agents for the treatment of malaria.

Animals↗
PubMed2004

Obese African Americans: the prevalence of dyslipidemia, hypertension, and diabetes mellitus.

CONTEXT: The prevalence of the cardiovascular disease risk factors, dyslipidemia, hypertension, and diabetes mellitus, is increased in the setting of obesity. OBJECTIVE: To determine whether the prevalence of these risk factors increases with increasing body mass index in an obese cohort, or whether there is a threshold for their appearance. DESIGN AND SETTING: Individuals with body mass index > or = 30 kg/m2 joined a weight reduction program in the Howard University General Clinical Research Center. PARTICIPANTS: Five hundred fifteen African Americans (aged 12-74 years, mean body mass index of 42.8 +/- 8.5 kg/m2). OUTCOME MEASURES: The cohort was divided by incremental increases in body mass index of 4.99 kg/m2, and the prevalence rates of hypertension (blood pressure > or = 140/90 mm Hg), dyslipidemia (total cholesterol > 200 mg/dL, or low-density lipoprotein > 130 mg/dL, or elevated ratio of total or low-density to high-density lipoprotein cholesterol) and diabetes mellitus (fasting blood glucose > or = 126 mg/dL or random blood glucose > 200 mg/dL) were determined for each group. RESULTS: The cohort prevalence rates were: dyslipidemia, 27.0%; hypertension, 56.9%; and diabetes mellitus, 24.1%. These rates are higher than those found in the African-American population by the third National Health and Nutrition Examination Survey. After adjusting for age and sex, there were no significant differences in the prevalence rates of these risk factors according to increasing body mass index, suggesting a threshold of between 30 kg/m2-34.99 kg/m2 for maximal appearance of these risk factors. CONCLUSION: The incidence rates of dyslipidemia, hypertension, and diabetes mellitus do not increase with a greater degree of obesity above a body mass index of 34.99 kg/m2.

Adolescent↗
PubMed2003

Mixture distribution analysis of phenotypic markers reflecting HFE gene mutations.

The goal of this study was to determine whether statistical modeling of population data for a phenotypic marker could reflect a major locus gene defect. Identifying mutations in the HFE gene makes it possible to assess the association between transferrin saturation (TS) subpopulations and HFE mutations. Data were analyzed from 27 895 white patients who attended a health appraisal clinic and who had TS and common mutations of HFE determined. Mixture distribution modeling of TS was performed, and the proportion of HFE mutations in TS subpopulations was assessed on a probability basis. Three subpopulations of TS were identified, consistent with Hardy-Weinberg conditions for major locus effects. For men, 72% of the subpopulation with the highest mean TS had HFE gene mutations; they were primarily homozygotes or compound heterozygotes. Seventy-three percent of the subpopulation with moderate mean TS also had HFE gene mutations; they were predominantly simple heterozygotes. Sixty-seven percent of the subpopulation with the lowest mean TS were wild-type homozygotes. Similar results were observed for women. These results suggest that statistical modeling of population clinical laboratory test data can reveal the influence of a major locus gene defect and perhaps can be applied to other aspects of body metabolism than iron.

Adult↗
PubMed2003

Expression of a recombinant IRP-like Plasmodium falciparum protein that specifically binds putative plasmodial IREs.

Plasmodium falciparum iron regulatory-like protein (PfIRPa, accession AJ012289) has homology to a family of iron-responsive element (IRE)-binding proteins (IRPs) found in different species. We have previously demonstrated that erythrocyte P. falciparum PfIRPa binds a mammalian consensus IRE and that the binding activity is regulated by iron status. In the work we now report, we have cloned a C-terminus histidine-tagged PfIRPa and overexpressed it in a bacterial expression system in soluble form capable of binding IREs. To overexpress PfIRPa, we used the T7 promoter-driven vector, pET28a(+), in conjunction with the Rosetta(DE3)pLysS strain of E. coli, which carries extra copies of tRNA genes usually found in organisms such as P. falciparum whose genome is (A+T)-rich. The histidine-tagged recombinant protein (rPfIRPa) in soluble form was partially purified using His-bind resin. We searched the plasmodial database, plasmoDB, to identify sequences capable of forming IRE loops using a specially developed algorithm, and found three plasmodial sequences matching the search criteria. In gel retardation assays, rPfIRPa bound three 32P-labeled putative plasmodial IREs with affinity exceeding the affinity for the mammalian consensus IRE. The binding was concentration-dependent and was not inhibited by heparin, an inhibitor of non-specific binding. Immunodepletion of rPfIRPa resulted in substantial inhibition of the signal intensity in the gel retardation assays and in Western blot-determinations of rPfIRPa protein levels. Endogenous PfIRPa retained all three putative 32P-IREs at the same position on the gel as the recombinant PfIRPa.

Animals↗
PubMed2003

Hemochromatosis and Iron Overload Screening (HEIRS) study design for an evaluation of 100,000 primary care-based adults.

BACKGROUND: The HEIRS Study will evaluate the prevalence, genetic and environmental determinants, and potential clinical, personal, and societal impact of hemochromatosis and iron overload in a multiethnic, primary care-based sample of 100,000 adults over a 5-year period. Participants are recruited from 5 Field Centers. Laboratory testing and data management and analysis are performed in a Central Laboratory and Coordinating Center, respectively. METHODS: Participants undergo testing for serum iron measures and common mutations of the hemochromatosis gene ( ) on chromosome 6p and answer questions on demographics, health, and genetic testing attitudes. Participants with elevated values of transferrin saturation and serum ferritin and/or C282Y homozygosity are invited to undergo a comprehensive clinical examination (CCE), as are frequency-matched control subjects. These examinations provide data on personal and family medical history, lifestyle characteristics, physical examination, genetic counseling, and assessment of ethical, legal, and social implications. Primary and secondary causes of iron overload will be distinguished by clinical criteria. Iron overload will be confirmed by quantification of iron stores. Recruiting family members of cases will permit DNA analysis for additional genetic factors that affect iron overload. RESULTS: Of the first 50,520 screened, 51% are white, 24% are African American, 11% are Asian, 11% are Hispanic, and 3% are of other, mixed, or unidentified race; 63% are female and 37% are male. CONCLUSIONS: Information from the HEIRS Study will inform policy regarding the feasibility, optimal approach, and potential individual and public health benefits and risks of primary care-based screening for iron overload and hemochromatosis.

Adult↗
PubMed2003

Basal endocrine status in African dietary iron overload.

Endocrine disturbances, notably diabetes, have been well described as a complication of iron overload due to hereditary hemochromatosis and beta-thalassemia. Dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis has also been well documented. The pattern of iron loading in African iron overload with saturated transferrin is similar to that seen in hereditary hemochromatosis. In addition, many symptoms ascribed to pituitary dysfunction are common to both conditions. The present study was undertaken to assess whether a similar pattern of endocrine dysfunction occurs in African iron overload. Thirty subjects with African iron overload and transferrin saturation >50%, plus 30 age and sex matched normal controls were studied. An iron profile, fasting plasma glucose, cortisol, DHEA-S, LH, FSH, growth hormone, prolactin, TSH, and FT4 levels were measured in all 60 subjects as well as testosterone in the males and estradiol in the females. Iron loading in the subjects with increased transferrin saturation ranged from moderate to severe. No significant differences were found in the mean testosterone, estradiol, LH, DHEA-S, growth hormone, prolactin, or TSH levels between the subjects and normal controls. In female subjects, although within the normal range, the mean FSH level was significantly higher, probably due to their being somewhat older and in a more advanced stage of menopause than the control females. Mean cortisol concentrations were increased in both genders in the patient group, significantly so in the females; however, values were within the reference range. We conclude therefore that there appears to be no major impairment of endocrine function in the basal state in African iron overload subjects with moderate to severe degrees of iron loading.

Africa↗
PubMed2002

Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia.

Chuvash polycythemia is an autosomal recessive disorder that is endemic to the mid-Volga River region. We previously mapped the locus associated with Chuvash polycythemia to chromosome 3p25. The gene associated with von Hippel-Lindau syndrome, VHL, maps to this region, and homozygosity with respect to a C-->T missense mutation in VHL, causing an arginine-to-tryptophan change at amino-acid residue 200 (Arg200Trp), was identified in all individuals affected with Chuvash polycythemia. The protein VHL modulates the ubiquitination and subsequent destruction of hypoxia-inducible factor 1, subunit alpha (HIF1alpha). Our data indicate that the Arg200Trp substitution impairs the interaction of VHL with HIF1alpha, reducing the rate of degradation of HIF1alpha and resulting in increased expression of downstream target genes including EPO (encoding erythropoietin), SLC2A1 (also known as GLUT1, encoding solute carrier family 2 (facilitated glucose transporter), member 1), TF (encoding transferrin), TFRC (encoding transferrin receptor (p90, CD71)) and VEGF (encoding vascular endothelial growth factor).

Adolescent↗
PubMed2002

African iron overload.

Iron overload is common in rural sub-Saharan African populations that have the custom of drinking a traditional fermented beverage with high iron content. As with both excessive alcohol exposure and HFE hemochromatosis, hepatic portal fibrosis and micronodular cirrhosis are prominent sequelae of African iron overload. Two observations are therefore important in characterizing iron overload in Africa. First, the hepatic iron concentrations associated with African iron overload often far exceed those seen in alcoholic liver disease and histologic changes of alcohol effect are almost always absent. Second, the pattern of iron accumulation in African dietary iron is prominent in both macrophages and hepatic parenchymal cells; this pattern is in contrast to HFE homochromatosis, which is marked by predominantly parenchymal iron-loading. For a long time, it was thought that African iron overload was purely dietary in nature, that increased iron and alcohol in the diet could fully explain markedly elevated tissue iron levels sometimes seen with this condition. Recent studies of pedigrees suggest that, in addition to high dietary iron content, a genetic defect may also be implicated in iron overload in Africans. These studies indicate that the possible defect is different from mutations in the HFE gene frequently found in Caucasians with iron overload, but the putative gene has not been identified. Recent studies also indicate that non-HFE iron overload occurs in African-Americans, but the prevalence and possible genetic basis is yet to be determined.

Africa↗