Measurement of serum transferrin by the γ−γ perturbed angular correlation method

In this work, the average perturbed angular correlation integral attenuation factor G2 of the transferrin in the serums from the normals and the patients with liver cancer were determined using time integral perturbed angular correlation method (PAC). The average values of G2 were 0.1945 +/- 0.0155 for the cancer serum transferrin and 0.2865 +/- 0.0411 for the normal serum transferrin. The difference between these two groups is significant. Mathematical deduction and theoretical analysis suggested that the equivalent radius of the transferrin molecules in the serum of cancer patients becomes smaller than normal, because of a change in the molecular conformation. Similar results were also observed in experiments with rat serum transferrin.     

The association between iron metabolism with the change of blood pressure and risk of hypertension: A large cross-sectional study

BackgroundThe relationship between iron metabolism and variations in blood pressure and hypertension risk is still not clear. This study aimed to determine whether iron metabolism is associated with changes in blood pressure and hypertension prevalence in the general United States population.MethodsThe National Health and Nutrition Examination Survey (NAHNES) database contains data on 116876 Americans from 1999 to 2020 years. Data from the NHANES database were used to examine the relationships between iron metabolism (serum iron [SI], serum ferritin [SF], and soluble transferrin receptor [sTfR]) and changes in blood pressure and hypertension prevalence. Generalized linear models and restricted cubic spline (RCS) plot curves were used to estimate the relationship between iron metabolism and hypertension. Further, generalized additive models with smooth functions were used to identify the relationship between iron metabolism and blood pressure. Finally, a stratified subgroup analysis was performed.ResultsA total of 6710 participants were included in our analysis. The RCS plot showed a linear relationship between SI, as well as sTfR, and hypertension prevalence. SF and hypertension prevalence were associated in a J-shape. In addition, the relationship between SI and systolic blood pressure (SBP) and diastolic blood pressure (DBP) decreased initially and then increased. A correlation between SF, SBP, and DBP first decreased, then increased, and finally decreased. A positive linear correlation existed between sTfR and SBP, but it increased and then decreased with DBP.ConclusionThe correlation between SF and hypertension prevalence displayed a J-curve. In contrast, the correlation between SI, as well as sTfR, and hypertension risk was negative and positive, respectively.     

The Ratio of sTfR/Ferritin is Associated with the Expression Level of TfR in Rat Bone Marrow Cells After Endurance Exercise

Currently, it is unclear which index of haematological parameters could be used to most easily monitor iron deficiency during endurance training. To address this question, 16 male Wistar rats were randomly assigned to two groups: a sedentary group (n = 8) and an exercised group (n = 8). Initially, animals in the exercise group started running on a treadmill at a rate of 30 m/min, on a 0% grade, for 1 min/session. Running time was gradually increased by 2 min/day. The training plan was one session per day during the initial 2 weeks and two sessions per day during the third to ninth week. At the end of the 9-week experiment, we analysed the blood of the experimental animals for haemoglobin levels, erythrocyte numbers, haematocrit, serum iron levels, total iron binding capacity, transferrin saturation, serum ferritin levels and soluble transferrin receptor (sTfR) levels, and we calculated the ratio of sTfR/ferritin. Erythrocyte numbers, haemoglobin levels and haematocrit values were decreased after 9 weeks of exercise, but sTfR and sTfR/ferritin values were increased (P < 0.01 or P < 0.05). The training regime significantly increased TfR mRNA levels in the bone marrow cells of the exercised rats compared with the sedentary group (1.8 ± 0.5 vs. 1.1 ± 0.2, P < 0.01). These results revealed a significant correlation between TfR levels in the bone marrow cells and the ratio of sTfR/ferritin (r = 0.517; P < 0.01) and sTfR levels (r = 0.206; P < 0.05) in sedentary and exercised rats. In conclusion, we show that sTfR indices and the ratio of sTfR/ferritin could be useful indicators for monitoring iron deficiency during endurance training.     

Malarial anaemia: mechanisms and implications of insufficient erythropoiesis during blood-stage malaria

It has been proposed that the basis of severe malarial anaemia, a major cause of morbidity and mortality in endemic areas, is multifactorial. Inappropriately low reticulocytosis is observed in malaria patients suggesting that insufficient erythropoiesis is a major factor. Clinical studies provide conflicting data concerning the production of adequate levels of erythropoietin (EPO) during malaria. Plasmodium chabaudi AS causes non-lethal infection in resistant C57BL/6 mice, and lethal infection in susceptible A/J mice. In P. chabaudi AS infected C57BL/6 and A/J mice, which experience varying degrees of severity of anaemia, kidney EPO production is appropriate to the severity of anaemia and is regulated by haematocrit level. Neutralisation of endogenous EPO during infection leads to lethal anaemia while timely administration of exogenous EPO rescues mice although reticulocytosis is suppressed in proportion to the parasitemia level. Characterisation of alterations in splenic erythroid compartments in naive and P. chabaudi AS infected A/J mice revealed that infection, with or without EPO treatment, leads to sub-optimal increases in TER119+ erythroblasts compared to EPO-treated naive mice. A lower percentage of TER119+ erythroblasts in infected mice undergo terminal differentiation to become mature haemoglobin-producing cells. Furthermore, there is a shift in transferrin receptor (CD71) expression from TER119+ cells to a non-erythroid population. Deficiencies in the number and maturation of TER119+ erythroblasts during infection coincide with blunted proliferation to EPO stimulation in vitro by splenocytes, although a high frequency express EPO receptor (EPOR). Together, these data suggest that during malaria, EPO-induced proliferation of early EPOR+ erythroid progenitors is suppressed, leading to sub-optimal generation of TER119+ erythroblasts. Moreover, a shift in CD71 expression may result in impaired terminal maturation of erythroblasts. Thus, suppressed proliferation, differentiation, and maturation of erythroid precursors in association with inadequate reticulocytosis may be the basis of insufficient erythropoiesis during malaria.     

Release of the soluble transferrin receptor is directly regulated by binding of its ligand ferritransferrin

The human transferrin receptor (TfR) is shed by an integral metalloprotease releasing a soluble form (sTfR) into serum. The sTfR reflects the iron demand of the body and is postulated as a regulator of iron homeostasis via binding to the hereditary hemochromatosis protein HFE. To study the role of transferrin in this process, we investigated TfR shedding in HL60 cells and TfR-deficient Chinese hamster ovary cells transfected with human TfR. Independent of TfR expression, sTfR release decreases with increasing ferritransferrin concentrations, whereas apo-transferrin exhibits no inhibitory effect. To investigate the underlying mechanism, we generated several TfR mutants with different binding affinities for transferrin. Shedding of TfR mutants in transfected cells correlates exactly with their binding affinity, implying that the effect of ferritransferrin on TfR shedding is mediated by a direct molecular interaction. Analysis of sTfR release from purified microsomal membranes revealed that the regulation is independent from intracellular trafficking or cellular signaling events. Our results clearly demonstrated that sTfR does not only reflect the iron demand of the cells but also the iron availability in the bloodstream, mirrored by iron saturation of transferrin, corroborating the important potential function of sTfR as a regulator of iron homeostasis.     

Evaluation of OptiMAL Assay test to detect imported malaria in Italy

This study evaluated a newly developed rapid malaria diagnostic test, OptiMAL Assay, to detect "Plasmodium falciparum malaria" and "non Plasmodium falciparum malaria" in blood samples from 139 individuals with a presumptive clinical diagnosis of imported malaria in Italy. OptiMAL Assay utilizes a dipstick coated with monoclonal antibodies against the intracellular metabolic enzyme, plasmodium Lactate Dehydrogenase (pLDH) present in and released from parasite-infected erythrocytes. Blood samples from 56 cases out of 139 were found "Plasmodium falciparum malaria" positive by microscopy; with these samples OptiMAL Assay and the ParaSight-F test, which is a kit detecting the P. falciparum histidin-rich protein 2 (HRP-2), showed an overall sensitivity of 83% and 94%, respectively, in comparison with microscopy. Parasitemia levels tested in the 56 P. falciparum positive blood samples by microscopy ranged from <0.004% to 20%. A correlation between sensitivity and parasitemia was evident and OptiMAL Assay and ParaSight-F test were more sensitive (96-100%; 100%) with samples with 0.1%-20% levels of parasitemia, while proved less sensitive (0-44%; 50-88%) with <0.004-0.01% levels of parasitemia.     

Increased serum erythropoietin but not red cell production after 4 wk of intermittent hypobaric hypoxia (4,000-5,500 m).

This study tested the hypothesis that athletes exposed to 4 wk of intermittent hypobaric hypoxia exposure (3 h/day, 5 days/wk at 4,000-5,500 m) or double-blind placebo increase their red blood cell volume (RCV) and hemoglobin mass (Hbmass) secondary to an increase in erythropoietin (EPO). Twenty-three collegiate level athletes were measured before (Pre) and after (Post) the intervention for RCV via Evans blue (EB) dye and in duplicate for Hbmass using CO rebreathing. Hematological indexes including EPO, soluble transferrin receptor, and reticulocyte parameters were measured on 8-10 occasions spanning the intervention. The subjects were randomly divided among hypobaric hypoxia (Hypo, n = 11) and normoxic (Norm, n = 12) groups. Apart from doubling EPO concentration 3 h after hypoxia there was no increase in any of the measures for either Hypo or Norm groups. The mean change in RCV from Pre to Post for the Hypo group was 2.3% (95% confidence limits = -4.8 to 9.5%) and for the Norm group was -0.2% (-5.7 to 5.3%). The corresponding changes in Hbmass were 1.0% (-1.3 to 3.3%) for Hypo and -0.3% (-2.6 to 3.1%) for Norm. There was good agreement between blood volume (BV) from EB and CO: EB BV = 1.03 x CO BV + 142, r2 = 0.85, P < 0.0001. Overall, evidence from four independent techniques (RCV, Hbmass, reticulocyte parameters, and soluble transferrin receptor) suggests that intermittent hypobaric hypoxia exposure did not accelerate erythropoiesis despite the increase in serum EPO.     

Plasmodium gallinaceum: response of malarious chicken embryos to injection of serum from hyperimmunized chickens.

The injection of serum from chickens hyperimmune to the avian malaria parasite, Plasmodium gallinaceum, or of nonimmune serum into the chorioallantoic cavity of chicken embryos infected with the same parasite resulted in changes in the blood picture of such embryos. In those embryos receiving serum from hyperimmunized birds: The level and rate of parasite increase were depressed; the maturation of the erythroid elements was reduced; the hematocrit values increased only by 27% as compared with 69% in untreated embryos. While hematocrit levels and rates of erythrocytic maturation were depressed in those embryos injected with nonimmune serum, there was no suppression of parasitemia. The results suggest a definite role of immunity in the anemia accompanying malaria.     

Interrelations between ceruloplasmin and Fe status during human pregnancy

It is well established that Fe and ceruloplasmin interact in animals and in in vitro models. However, Fe-mediated regulation of ceruloplasmin has never been investigated in humans. In an observational study, 53 pregnant women aged 19–39 yr (29.8±0.7 yr, mean ± SEM) were recruited at the Aberdeen Antenatal Clinic, Aberdeen Maternity Hospital, UK. All requirements for local ethical committees were followed. Venous blood samples were taken from each woman at 34 wk gestation for measurement of Fe status and ceruloplasmin. Various parameters were used to test for Fe status. The most sensitive one appeared to be soluble transferrin receptor, which increased with parity. In the population studied, there was no relationship between hemoglobin or ferritin and serum ceruloplasmin. However, using soluble transferrin receptor (sTfR) levels, we were able to demonstrate an inverse linear relationship (r=0.37, p=0.021, n=41) between Fe status and ceruloplasmin. Fe supplementation, number of previous pregnancies, and smoking habits did not affect this relationship. Our data support in vitro results showing regulation of ceruloplasmin by Fe and also suggest that the interactions between Fe and ceruloplasmin should be considered when Fe supplementation is given.     

Aluminum exchange between citrate and human serum transferrin and interaction with transferrin receptor 1

The kinetics and thermodynamics of Al(III) exchange between aluminum citrate (AlL) and human serum transferrin were investigated in the 7.2-8.9 pH range. The C-site of human serum apotransferrin in interaction with bicarbonate removes Al(III) from Al citrate with an exchange equilibrium constant K1 = (2.0 +/- 0.6) x 10(-2); a direct second-order rate constant k1 = 45 +/- 3 M(-1) x s(-1); and a reverse second-order rate constant k(-1) = (2.3 +/- 0.5) x 10(3) M(-1) x s(-1). The newly formed aluminum-protein complex loses a single proton with proton dissociation constant K1a = (15 +/- 3) nM to yield a first kinetic intermediate. This intermediate then undergoes a modification in its conformation followed by two proton losses; first-order rate constant k2 = (4.20 +/- 0.02) x 10(-2) s(-1) to produce a second kinetic intermediate, which in turn undergoes a last slow modification in the conformation to yield the aluminum-loaded transferrin in its final state. This last process rate-controls Al(III) uptake by the N-site of the protein and is independent of the experimental parameters with a constant reciprocal relaxation time tau3(-1) = (6 +/- 1) x 10(-5) x s(-1). The affinities involved in aluminum uptake by serum transferrins are about 10 orders of magnitude lower than those involved in the uptake of iron. The interactions of iron-loaded transferrins with transferrin receptor 1 occur with average dissociation constants of 3 +/- 1 and 5 +/- 1 nM for the only C-site iron-loaded and of 6.0 +/- 0.6 and 7 +/- 0.5 nM for the iron-saturated ST in the absence or presence of CHAPS, respectively. No interaction is detected between receptor 1 and aluminum-saturated or mixed C-site iron-loaded/N-site aluminum-loaded transferrin under the same conditions. The fact that aluminum can be solubilized by serum transferrin in biological fluids does not necessarily imply that its transfer from the blood stream to cytoplasm follows the receptor-mediated pathway of iron transport by transferrins.     

Elevated Systemic Hepcidin and Iron Depletion in Obese Premenopausal Females

Hepcidin, the body's main regulator of systemic iron homeostasis, is upregulated in response to inflammation and is thought to play a role in the manifestation of iron deficiency (ID) observed in obese populations. We determined systemic hepcidin levels and its association with body mass, inflammation, erythropoiesis, and iron status in premenopausal obese and nonobese women (n = 20/group) matched for hemoglobin (Hb). The obese participants also had liver and abdominal visceral and subcutaneous adipose tissue assessed for tissue iron accumulation and hepcidin mRNA expression. Despite similar Hb levels, the obese women had significantly higher serum hepcidin (88.02 vs. 9.70 ng/ml; P < 0.0001) and serum transferrin receptor (sTfR) (P = 0.001) compared to nonobese. In the obese women hepcidin was not correlated with serum iron (r = ?0.02), transferrin saturation (Tsat) (r = 0.17) or sTfR (r = ?0.12); in the nonobese it was significantly positively correlated with Tsat (r = 0.70) and serum iron (r = 0.58), and inversely with sTfR (r = ?0.63). Detectable iron accumulation in the liver and abdominal adipose tissue of the obese women was minimal. Liver hepcidin mRNA expression was ～700 times greater than adipose tissue production and highly correlated with circulating hepcidin levels (r = 0.61). Serum hepcidin is elevated in obese women despite iron depletion, suggesting that it is responding to inflammation rather than iron status. The source of excess hepcidin appears to be the liver and not adipose tissue. The ID of obesity is predominantly a condition of a true body iron deficit rather than maldistribution of iron due to inflammation. However, these findings suggest inflammation may perpetuate this condition by hepcidin‐mediated inhibition of dietary iron absorption.     

Manifestation of cerebral malaria-like symptoms in the WM/Ms rat infected with Plasmodium berghei strain NK65

Conditions required for the induction of cerebral malaria (CM)-like symptoms were investigated using 12 strains of rats and 5 murine malaria strains. Among various combinations, only inbred WM/Ms rats infected with P. berghei (NK65) developed neuropathological complications that closely resembled human CM cases. When young WM/Ms rats were infected with the parasites, neurologic signs were induced followed by death in 5-10 days with almost 100% incidence, whereas aged hosts revealed strong resistance. Histologically, edematous changes, occlusion of vessels, and petechial hemorrhages were found in the brain. There was an optimum dose of parasites to induce the manifestations, and a low incidence was obtained by increased or decreased inoculum size. No correlation was found between the level of parasitemia and incidence of the disease. The other 11 rat strains inoculated with this parasite showed high levels of parasitemia, but most of their infections were self-limiting or malarial death occurred without CM-like signs. Inoculation into WM/Ms rats with other murine malaria parasites, including P. chabaudi, P. vinckei, P. yoelii (17X), and P. yoelii (nigeriensis) failed to induce CM-like manifestations irrespective of the inoculation size and the degree of parasitemia. These results indicated that P. berghei (NK65)-infected WM/Ms rats represent an experimental model for CM and certain appropriate conditions are needed for its development in both parasite and host sides.     

Shedding of the transferrin receptor is mediated constitutively by an integral membrane metalloprotease sensitive to tumor necrosis factor alpha protease inhibitor-2

The transferrin receptor (TfR) is a transmembrane protein that mediates cellular uptake of iron. Although the serum concentration of the soluble TfR (sTfR) is altered in several diseases and used for diagnostic purposes, the identity and regulation of the shedding protease is unknown. In this study we quantified sTfR release from microsomal membranes and leukocytic cell lines in the presence of numerous protease inhibitors and cell activating compounds. We show that sTfR release is mediated by an integral membrane metalloprotease and can be inhibited by matrix metalloproteinase inhibitor 2 and tumor necrosis factor alpha protease inhibitor-2 (TAPI-2). Cleavage is also inhibited by a specific furin inhibitor, indicating that the protease is activated by a furin-like proprotein convertase. Whereas stimulation of the cells by the ectodomain shedding activator phorbol 12-N-myristate 13-acetate did not alter sTfR release significantly, the phosphatase inhibitor pervanadate led to an increase of TfR shedding in several leukocytic cell lines. Our results suggest that TfR shedding is constitutively mediated by a member of the metalloprotease family known as ADAM (for a disintegrin and metalloprotease).     

Heritability of serum iron, ferritin and transferrin saturation in a genetically isolated population, the Erasmus Rucphen Family (ERF) Study

Background: Iron has been implicated in the pathogenesis of various disorders. Mutations in the HFE gene are associated with an increase in serum iron parameters. The aim of this study was to estimate the heritability in serum iron parameters explained by HFE. Methods: Ninety families (980 subjects) were included in the present analysis. Heritability estimation was conducted using the variance component method. The likelihood ratio test was used to compare models. Phenotypic and genetic correlations between serum iron parameters were calculated. Results: The heritability (h(2) +/- SE) estimates were 0.23 +/- 0.07 (p < 0.0001) for iron, 0.29 +/- 0.09 (p < 0.0001) for ferritin and 0.28 +/- 0.07 (p < 0.0001) for transferrin saturation while adjusting for age, age(2) and sex. The HFE genotypes explained between 2 to 6% of the sex and age-adjusted variance in serum iron, ferritin and transferrin saturation. There was a high genetic correlation between serum iron parameters, suggesting pleiotropy between these traits. Conclusion: A substantial proportion of the variance of iron, ferritin and transferrin saturation can be explained by additive genetic effects, independent of sex and age. The HFE genotypes explained a considerable proportion of serum iron parameters and may be an important factor in the complex iron network.     

Mechanism of formation of the complex between transferrin and bismuth, and interaction with transferrin receptor 1

The kinetics and thermodynamics of Bi(III) exchange between bismuth mononitrilotriacetate (BiL) and human serum transferrin as well as those of the interaction between bismuth-loaded transferrin and transferrin receptor 1 (TFR) were investigated at pH 7.4-8.9. Bismuth is rapidly exchanged between BiL and the C-site of human serum apotransferrin in interaction with bicarbonate to yield an intermediate complex with an effective equilibrium constant K(1) of 6 +/- 4, a direct second-order rate constant k(1) of (2.45 +/- 0.20) x 10(5) M(-1) s(-1), and a reverse second-order rate constant k(-1) of (1.5 +/- 0.5) x 10(6) M(-1) s(-1). The intermediate complex loses a single proton with a proton dissociation constant K(1a) of 2.4 +/- 1 nM to yield a first kinetic product. This product then undergoes a modification in its conformation followed by two proton losses with a first-order rate constant k(2) = 25 +/- 1.5 s(-1) to produce a second kinetic intermediate, which in turn undergoes a last modification in the conformation to yield the bismuth-saturated transferrin in its final state. This last process rate-controls Bi(III) uptake by the N-site of the protein and is independent of the experimental parameters with a constant reciprocal relaxation time tau(3)(-1) of (3 +/- 1) x 10(-2) s(-1). The mechanism of bismuth uptake differs from that of iron and probably does not involve the same transition in conformation from open to closed upon iron uptake. The interaction of bismuth-loaded transferrin with TFR occurs in a single very fast kinetic step with a dissociation constant K(d) of 4 +/- 0.4 microM, a second-order rate constant k(d) of (2.2 +/- 1.5) x 10(8) M(-1) s(-1), and a first-order rate constant k(-d) of 900 +/- 400 s(-1). This mechanism is different from that observed with the ferric holotransferrin and implies that the interaction between TFR and bismuth-loaded transferrin probably takes place on the helical domain of the receptor which is specific for the C-site of transferrin and HFE. The relevance of bismuth incorporation by the transferrin receptor-mediated iron acquisition pathway is discussed.     

Characterization of the human transferrin receptor produced in a baculovirus expression system

Recombinant human transferrin receptor has been produced in a baculovirus expression system. Magnetic particles coated with an anti-transferrin receptor monoclonal antibody were used to immunoselect virus-infected Sf9 insect cells expressing the human transferrin receptor on their cell surface. Recombinant virus containing the human transferrin receptor cDNA was then plaque-purified from these cells. Biosynthetic labeling studies of infected cells showed that the human transferrin receptor is one of the major proteins made 2-3 days postinfection. The recombinant receptor made in insect cells is glycosylated and is also posttranslationally modified by the addition of a fatty acid moiety. However, studies with tunicamycin and endoglycosidases H and F showed that the oligosaccharides displayed on the recombinant receptor differ from those found on the naturally occurring receptor in human cells. As a consequence, the human receptor produced in the baculovirus system has an Mr of 82,000 and is smaller in size than the authentic receptor. About 30% of human transferrin receptors made in insect cells do not form intermolecular disulfide bonds, but are recognized by the anti-transferrin receptor antibody, B3/25, and bind specifically to a human transferrin-Sepharose column. Binding studies using 125I-labeled human transferrin showed that insect cells infected with the recombinant virus expressed an average of 5.8 +/- 0.9 X 10(5) transferrin receptors (Kd = 63 +/- 9 nM) on their cell surface. Thus, the human transferrin receptor produced in insect cells is biologically active and appears suitable for structural and functional studies.     

Cerebral malaria is frequently associated with latent parasitemia among the semi-immune population of eastern Sudan

The accurate diagnosis of malaria starts with clinical suspicion, confirmed by reliable laboratory results. A hospital-based study, described here, was carried out in a malaria mesoendemic area in eastern Sudan, where the inhabitants are semi-immune to malaria, and the fever threshold of parasitemia is not above the detection level of microscopy. Thus, we hypothesized that patients with symptoms highly suggestive of cerebral malaria (CM), but aparasitemic by microscopy, may have submicroscopic parasitemia. Patients in our malaria clinic were screened by microscopy, and 120 individuals were selected for the study, including febrile patients with and without microscopically detectable parasitemia, and apparently healthy individuals. In the two former groups there were patients with severe anemia and deep coma. Polymerase chain reaction (PCR) for parasite detection and ELISA tests for measuring serum antibody levels were carried out on all blood samples. A majority of the febrile patients who were parasite negative by microscopy showed the presence of a Plasmodium falciparum infection by PCR. The occurrence of P. falciparum infection with parasitemia below the detection level of microscopy was recognized more often in patients with CM symptoms than in those with severe malarial anemia (SMA), and in older rather than younger patients. Patients clinically suspected (CS) of having CM ((CS)CM) mostly were infected with a single clone, and a large proportion of them acquired antibodies (Abs) against merozoite surface protein (MSP) antigens (Ags). The therapeutic response to quinine treatment was comparable between patients with (CS)CM and CM. In conclusion, uniquely in this setting, CM can be associated with sub-patent parasitemia; thus, a diagnostic tool more sensitive than microscopy is needed.     

Serum vascular endothelial growth factor and its receptor level in patients with chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a disorder which encompasses not only morphological changes in parenchyma, central and peripheral airways but also in structural and functional changes of pulmonary vessels. The role of angiogenic factors leading to abnormal pulmonary vessel remodeling remains unclear. We have investigated a cytokine vascular endothelial growth factor (VEGF) known to be involved in angiogenesis, and its soluble receptors (sVEGF R1, sVEGF R2) in the serum of 20 patients with mild COPD and 10 patients with very severe COPD, using sensitive enzyme-linked immunoassays. The control group consisted of 10 healthy volunteers. We found that the concentration of VEGF in the serum of patients with mild COPD was significantly higher (665.31 +/- 102.20 pg/mL) in comparison to the control group (318.94 +/- 51.40 pg/mL; p < 0.05), and there was a strong negative correlation with FEV1 (r = -0.859; p < 0.001). Additionally, the level of sVEGF R1 in the serum of patients with very severe COPD was also significantly higher (96.60 +/- 26.85 pg/mL) than in the control (36.01 +/- 3.29 pg/mL; p < 0.05) and a positive correlation between the serum level of sVEGF R1 and FEV1 was found (r = 0.748; p < 0.01). Moreover, we observed an insignificant increase of sVEGF R2 in the serum of patients with mild COPD and those with very severe COPD. These results suggest that VEGF and sVEGF R1 receptor are involved in the development of abnormal pulmonary vascular remodelling in patients with COPD.     

Association between Serum Ferritin and Osteocalcin as a Potential Mechanism Explaining the Iron-Induced Insulin Resistance

Background

Increased iron stores are associated with increased risk of type 2 diabetes, however, the mechanisms underlying these associations are poorly understood. Because a reduction of circulating osteocalcin levels after iron overload have been demonstrated in cell cultures, and osteocalcin is related to glucose and insulin metabolism, the iron-induced osteocalcin reductions could contribute to explain the role of iron metabolism in the development of type 2 diabetes mellitus.

Objective

To analyzed the associations between serum total and uncarboxylated osteocalcin and adiponectin concentrations with serum ferritin and soluble transferrin receptor (sTfR) in elderly subjects.

Design

We evaluated a total of 423 subjects from the PREDIMED cohort in a population-based cross-sectional analysis. Extensive clinical, nutritional and laboratory measurements, including total and uncarboxylated osteocalcin, adiponectin, ferritin and sTfR were recorded.

Results

Serum ferritin was positively correlated with increased glucose and insulin circulating levels but also with HOMA-IR, and was inversely associated with total osteocalcin and adiponectin. A regression analysis revealed that serum ferritin and transferrin receptor levels were significantly associated with a decrease in total and uncarboxylated osteocalcin. Serum sTfR levels were associated with lower uncarboxylated osteocalcin levels in the whole-study subjects and remained significant only in the IFG (impaired fasting glucose) individuals.

Conclusions

We described, for the first time, an inverse association between serum ferritin and sTfR with osteocalcin and extend previous results on adiponectin, thus supporting that factors related to iron metabolism could contribute to the insulin resistance and the development of type 2 diabetes mellitus.

Trial Registration

Controlled-Trials.com ISRCTN35739639 <ISRCTN35739639>.     

Iron deficiency in obese postmenopausal women

Objective: This study evaluates whether the iron deficiency suggested in children and adolescents with overweight is also present with increasing age. Research Methods and Procedures: We examined 50 consecutive postmenopausal nondiabetic white women with a BMI ≥30 kg/m² and 50 non‐obese seemingly healthy women as a control group. In addition to the traditional indices of iron status, we measured the soluble transferrin receptor (sTfR) levels, a sensitive and highly quantitative indicator of early iron deficiency not influenced by the acute phase response. Results: Obese women have higher serum sTfR levels than control subjects [1.38 (range, 0.89 to 2.39) vs. 1.16 mg/dL (range, 0.69 to 2.03 mg/dL); p < 0.001]. However, no difference in ferritin concentration was observed between the groups [70.50 (range, 18 to 219) vs. 69.50 ng/mL (range, 24 to 270 ng/mL); p = not significant]. A positive correlation between BMI and sTfR concentration was detected. On multiple regression analyses, BMI (positively) and ferritin (inversely) were independent predictors accounting for sTfR. Discussion: These results suggest that a moderate degree of iron deficiency is also present among adult women with obesity. The determination of sTfR is useful in the evaluation of iron status in this condition. Further studies with a greater number of patients are required to investigate the relationship between tissue iron concentrations and obesity.