High Transferrin Research Articles

Iron catalyzed oxidative damage, in spite of normal ferritin and transferrin saturation levels and its possible role in Werner’s syndrome, Parkinson’s disease, cancer, gout, rheumatoid arthritis, etc.

Iron loading in hemochromatosis attains extremely high levels and is accompanied by many signs (ferritin >300 μg/l, hematocrit >50%, transferrin saturation >70%, etc.). Nevertheless, the disease is often overlooked by physicians, until several organs have been damaged permanently (heart, liver, brain, pancreas, kidneys, spleen, etc.). Therefore, severe oxidative damage catalyzed by Fe could occur, without the extremely high ferritin, hematocrit and transferrin saturation levels of hemochromatosis, and it is unlikely that it would ever be detected or even suspected. I postulate a mechanism, by which a cell can continue to express transferrin receptors, without producing ferritin, even when it is saturated with iron. Furthermore, I suggest that this silent iron loading, induced by cadmium and other metals, plays an important role in many degenerative diseases involving free radicals, DNA damage and peroxynitrite, all of which are intimately linked to iron.Moreover, since ferritin, transferrin saturation and hematocrit levels are not directly related to cellular iron levels, and since excess iron can wreak havoc in the cell, we can conclude that there is a need for a better way to evaluate intracellular iron levels and especially the intracellular free iron levels by a non-invasive technique.Finally, phlebotomy is suggested as the best way to reduce Fe and Mo stores, and chelation with succimer is recommended in order to eliminate Cd.

Speciation of insulin-mimetic VO(IV)-containing drugs in blood serum

The biospeciations of three potential insulin-mimetic VO(IV) compounds, VO(maltolate) 2, VO(picolinate) 2 and VO(6-Me-picolinate) 2, in blood serum were assessed via modelling calculations, using the stability constants reported in the literature for the binary insulin-mimetic complexes and their ternary complexes formed with the most important low molecular mass binders in the serum: oxalic acid, lactic acid, citric acid and phosphate. The binding capabilities of two high molecular mass serum proteins, albumin and transferrin, were also taken into account.

HFE S65C Variant Is Not Associated with Increased Transferrin Saturation in Voluntary Blood Donors

ABSTRACT: Two amino acid variants in the HFE gene, C282Y and H63D, have been reported in most cases of hereditary hemochromatosis. A recently discovered novel amino acid variant of HFE, namely S65C, has been implicated to be responsible for a mild form of iron overload.We determined genotypes of the HFE S65C variant in 230 voluntary blood donors with a transferrin saturation >45%, who did not carry the HFE C282Y variant. The control group consisted of 248 first time blood donors who had a transferrin saturation < 45%. We also determined genotypes of the HFE H63D variant in the two groups.For the HFE S65C variant, the frequency of the HFE C65 allele was 1.7% and 2.2% in the high and low transferrin saturation groups, respectively (p = 0.65). In contrast, for the HFE H63D variant, the frequency of the HFE D63 allele was 24.8% and 14.7% in the high and low transferrin saturation groups, respectively (p = 0.0009).This study demonstrates no association of the HFE C65 allele with the phenotype of high transferrin saturation. The results do not support the use of DNA genotyping for the HFE S65C mutation in population screening studies for hemochromatosis.

Importance of Anemia and Transferrin Levels in the Regulation of Intestinal Iron Absorption in Hypotransferrinemic Mice

The hypotransferrinemic mouse (trf hpx) is a mutant strain exhibiting transferrin deficiency, marked anemia, hyperabsorption of iron, and elevated hepatic iron stores. We set out to investigate the relative roles of anemia and of transferrin in the malregulation of intestinal iron absorption in these animals. Transfusion of erythrocytes obtained from littermate controls increased hemoglobin levels and reduced reticulocyte counts in recipient animals. Although mucosal to carcass 59Fe transfer was reduced, total duodenal iron uptake was not significantly affected. Iron absorption in homozygotes, in contrast to littermate controls, was not reduced by hyperoxia. Mouse transferrin injections, in the short term, increased delivery of iron to the marrow and raised hemoglobin levels. Although mucosal transfer and total iron uptake were reduced at the higher transferrin doses, total uptake was still higher than in controls. Daily injections of mouse/human transferrin for 3 weeks from weaning, normalized hemoglobin values, and markedly reduced liver iron and intestinal iron absorption values in trf hpxanimals. When such daily-injected mice were left for a week to allow transferrin clearance, iron absorption values were significantly enhanced; hemoglobin or hepatic iron levels were, however, not significantly altered. These data indicate that hyperabsorption of iron in trf hpx mice is not solely because of the anemia; transferrin levels per se do affect iron absorption, possibly via a direct effect on the intestinal mucosa.

The transferrin receptor: role in health and disease

The transferrin receptor is a membrane glycoprotein whose only clearly defined function is to mediate cellular uptake of iron from a plasma glycoprotein, transferrin. Iron uptake from transferrin involves the binding of transferrin to the transferrin receptor, internalization of transferrin within an endocytic vesicle by receptor-mediated endocytosis and the release of iron from the protein by a decrease in endosomal pH. With the exception of highly differentiated cells, transferrin receptors are probably expressed on all cells but their levels vary greatly. Transferrin receptors are highly expressed on immature erythroid cells, placental tissue, and rapidly dividing cells, both normal and malignant. In proliferating nonerythroid cells the expression of transferrin receptors is negatively regulated post-transcriptionally by intracellular iron through iron responsive elements (IREs) in the 3′ untranslated region of transferrin receptor mRNA. IREs are recognized by specific cytoplasmic proteins (IRPs; iron regulatory proteins) that, in the absence of iron in the labile pool, bind to the IREs of transferrin receptor mRNA, preventing its degradation. On the other hand, the expansion of the labile iron pool leads to a rapid degradation of transferrin receptor mRNA that is not protected since IRPs are not bound to it. However, some cells and tissues with specific requirements for iron probably evolved mechanisms that can override the IRE/IRP-dependent control of transferrin receptor expression. Erythroid cells, which are the most avid consumers of iron in the organism, use a transcriptional mechanism to maintain very high transferrin receptor levels. Transcriptional regulation is also involved in the receptor expression during T and B lymphocyte activation. Macrophages are another example of a cell type that shows ‘unorthodox’ responses in terms of IRE/IRP paradigm since in these cells elevated iron levels increase (rather than decrease) transferrin receptor mRNA and protein levels. Erythroid cells contain the highest mass of the total organismal transferrin receptors which are released from reticulocytes during their maturation to erythrocytes. Hence, plasma contains small amounts of transferrin receptors which represent a soluble fragment of the extracellular receptor domain. Measurements of serum transferrin receptor concentrations are clinically useful since their levels correlate with the total mass of immature erythroid cells.

HFE gene mutation and transferrin saturation in very low birthweight infants

AIMTo determine if there is an association between high transferrin saturation and the C282Y HFE gene mutation in very low birthweight (VLBW) infants.METHODSOne hundred and forty three VLBW infants receiving...

Iron Release From Human Monocytes After Erythrophagocytosis In Vitro: An Investigation in Normal Subjects and Hereditary Hemochromatosis Patients

This study investigated the release of erythrocyte-derived iron from purified human monocytes obtained from healthy volunteers and hereditary hemochromatosis (HH) patients. After erythrophagocytosis of59Fe-labeled erythrocytes, a complete transfer of iron from hemoglobin (Hb) to ferritin was observed within 24 hours in both control and HH monocytes. The iron was released from the monocytes in the form of ferritin, Hb, and as nonprotein bound low molecular weight iron (LMW-Fe). During the initial rapid phase (&lt;1.5 hours), iron release mostly consisted of Hb and LMW-Fe, while in the later phase (&gt;1.5 hours), it was composed of ferritin and LMW-Fe. The kinetics of iron release were identical for HH monocytes. A high percentage of the total amount of iron was released as Hb both by viable normal and HH monocytes, suggesting that iron release as Hb is a physiologic process, which may occur whenever the erythrocyte-processing capacity of macrophages is exceeded. Most remarkably, HH monocytes released twice as much iron in a LMW form as control cells. Iron released in the form of LMW-Fe readily binds to plasma transferrin and may contribute to the high transferrin saturation and the occurrence of circulating nontransferrin-bound iron observed in HH patients.

Iron Release From Human Monocytes After Erythrophagocytosis In Vitro: An Investigation in Normal Subjects and Hereditary Hemochromatosis Patients

This study investigated the release of erythrocyte-derived iron from purified human monocytes obtained from healthy volunteers and hereditary hemochromatosis (HH) patients. After erythrophagocytosis of59Fe-labeled erythrocytes, a complete transfer of iron from hemoglobin (Hb) to ferritin was observed within 24 hours in both control and HH monocytes. The iron was released from the monocytes in the form of ferritin, Hb, and as nonprotein bound low molecular weight iron (LMW-Fe). During the initial rapid phase (<1.5 hours), iron release mostly consisted of Hb and LMW-Fe, while in the later phase (>1.5 hours), it was composed of ferritin and LMW-Fe. The kinetics of iron release were identical for HH monocytes. A high percentage of the total amount of iron was released as Hb both by viable normal and HH monocytes, suggesting that iron release as Hb is a physiologic process, which may occur whenever the erythrocyte-processing capacity of macrophages is exceeded. Most remarkably, HH monocytes released twice as much iron in a LMW form as control cells. Iron released in the form of LMW-Fe readily binds to plasma transferrin and may contribute to the high transferrin saturation and the occurrence of circulating nontransferrin-bound iron observed in HH patients.

Anorexigen (TNF-alpha, cholecystokinin) and orexigen (neuropeptide Y) plasma levels in peritoneal dialysis (PD) patients: their relationship with nutritional parameters.

Malnutrition has definitely been related to mortality among dialysis patients. Persistent loss of appetite is one of the major symptoms found in these patients. It is also well recognized that several substances produce anorexia or disorders of the hunger-satiety cycle in several diseases. The aim of this study was to identify the role of anorexigen substances (TNF-alpha and cholecystokinin or CCK) and an orexigen substance (neuropeptide Y or NPY) in anorexia and malnutrition among 55 clinically stable peritoneal dialysis (PD) patients. High TNF-alpha plasma levels were found in 41 of 42 patients (97.6%) with a mean of 70.5+/-32.3 pg/ml. Patients with anorexia (n=11) or anorexia with nausea or vomiting (n=5) had higher TNF-alpha values than patients without these symptoms (75.9+/-34 vs 52.1 +/-24.5 pg/ml, P<0.05). Eight patients with a prior diagnosis of acid pylori disease showed higher TNF-alpha values (87.2+/-24.3) than 30 unaffected patients (63.6+/-30.5, P<0.05). TNF-alpha showed a significant negative linear correlation with retinol binding protein (RBP) (r=-0.37, n=34, P<0.05), and venous pH (r=-0.4, n=42, P<0.01); also, TNF-alpha values higher than 65 pg/ml were inversely associated with transferrin, cholesterol, blood urea nitrogen (BUN) and CCK. Patients with prealbumin levels lower than 30 mg/dl, a BMI lower than 30 kg/m2, nPCR lower than 1.1 g/kg/day and urea KT/V lower than 2.2 showed higher serum TNF-alpha levels. Patients who had been on CAPD treatment for longer periods showed higher TNF-alpha values. High plasma CCK levels were found in 38 of 45 patients (84%), mean 45.9+/-32.3 pg/ml. Patients with anorexia had no difference in CCK values compared with those without. A direct association was found between CCK levels and some nutritional markers (albumin, fibronectin, triglycerides, folic acid and nPCR in non diabetic patients). Although CCK has a recognized anorectic effect, this direct association might be because of an abnormal stimulation of CCK glucose feedback (trypsin) due to continuous peritoneal glucose absorption. This suggests that CCK could be an immediate food intake marker in PD patients. The NPY plasma levels were normal in 33 patients, high in 6 and low in 11. Patients with anorexia showed lower NPY levels than those without. NPY values greater than 50 pg/ml were directly associated with higher transferrin, prealbumin, RBP, nPCR and urea KT/V values. Importantly, a negative linear correlation between NPY and TNF-alpha was found (r=-0.42, n= 41, P<0.01). There was no significant relationship between residual renal clearance and the serum levels of the three peptides. In conclusion, our data suggest that high TNF-alpha and low NPY serum levels are associated with anorexia. High TNF-alpha, low CCK and low NPY serum levels are also related to a poor nutritional status. Further research on these circulating substances is required.

Comparison of the Axis %CDT TIA and the CDTect method as laboratory tests of alcohol abuse

Carbohydrate-deficient transferrin (CDT) has been suggested as a specific marker of alcohol abuse. We designed this study to compare the conventional CDTect method (Pharmacia & Upjohn) and the new semiautomated Axis %CDT turbidimetric immunoassay (%CDT TIA) for their diagnostic performance to identify problem drinking. The sensitivities of the %CDT TIA and CDTect for correctly classifying heavy drinkers (n = 90) were 29% and 59% with the thresholds currently recommended by the manufacturers, respectively. In the control group (n = 114), which included hospitalized patients with abnormal serum transferrin concentrations, the CDTect assay gave 21 false-positive values (18%), whereas the %CDT TIA showed 100% specificity. With the cutoff limits based on the present healthy control group (mean + 2 SD), the sensitivities of the %CDT TIA and CDTect were 61% and 86%, respectively. For men, the ROC plot area of the CDTect results in comparisons of alcohol abusers and healthy controls was significantly (P < 0.05) higher than that of the %CDT TIA results, whereas for women, there was no significant difference in this respect. The slope and intercept (with 95% confidence intervals) for linear regression between CDTect and %CDT TIA were 0.13 (0.12-0.15) and 1.16 (0.73-1.59), respectively (S(y/x) = 1.51, r = 0.744). CDTect results correlated positively with serum transferrin (r = 0.224, P < 0.001), whereas the %CDT TIA results showed a slight inverse correlation with serum transferrin (r = -0.132, P = 0.07). The data suggest that CDTect is more sensitive than %CDT TIA in detecting drinking problems. However, the %CDT TIA method yields more specificity when analyzing samples from patients with high serum transferrin concentrations.

Hereditary haemochromatosis as an immunological disease.

Hereditary haemochromatosis as an immunological disease.

Transferrin Variants as Markers of Migrations and Admixture between Populations in the Baltic Sea Region

Transferrin (TF) types were examined by isoelectric focusing in an attempt to elucidate migrations and admixture between populations in the Baltic Sea region. A highly significant heterogeneity between populations was found with respect to TF*C subtypes as well as the rare TF variants B2, B0-1 and DCHI. With the exception for Estonia, increased frequencies of the TF*C3 allele were observed east of the Baltic Sea. The island of Gotland in the middle of the Baltic Sea also showed a high TF*C3 frequency indicating an eastern influence. The TF*DCHI allele, a marker of eastern (Finno-Ugric) influence, was found in Finland and Estonia and on the island of Gotland, but not in mainland Sweden and in the Baltic peoples (Latvians and Lithuanians). These results indicate the presence of a Finno-Ugric, most likely Estonian or Livonian, genetic influence in the Gotland population.

Evaluation of Erythropoietic Activity on the Basis of the Red Cell and Reticulocyte Distribution Widths during Epoetin Beta Therapy in Patients Undergoing Cardiac Surgery

The changes in the red cell and reticulocyte distribution widths during preoperative treatment with recombinant human erythropoietin (rhEPO) were evaluated in a double-blind, placebo-controlled trial in cardiac surgery patients. The increases in the reticulocyte count, in the hemoglobin and in all distribution widths are the expression of the marked preoperative stimulation of erythropoiesis in the patients treated with rhEPO. Only placebo patients with a hemoglobin ≤7.5 mmol/l or a transferrin >4.0 g/l at baseline showed an increase in the red cell distribution width or in the reticulocyte hemoglobin distribution width on oral iron therapy alone. While the reticulocyte count and the distribution widths of red cells in the rhEPO patients decreased postoperatively, only the increases in the distribution widths of reticulocytes after the second postoperative day indicate that stimulation of erythropoiesis had taken place. In patients with a low hemoglobin or a high transferrin the rhEPO therapy should be preceded by iron therapy in order to raise the hemoglobin level and reduce the cost of treatment.

Influence of malaria on markers of iron status in children: implications for interpreting iron status in malaria-endemic communities

To investigate Fe nutritional indices in malaria infection in children, haematology (blood haemoglobin, plasma ferritin, transferrin, Fe, and transferrin saturation), acute phase markers (albumin and caeruloplasmin) and liver function tests were studied in fifty consecutive cases of severe and mild falciparum malaria, fifty matched controls and twenty-three cases of asymptomatic malaria. Blood haemoglobin and transferrin were lower, while ferritin and transferrin saturation were higher, in groups with symptomatic malaria in comparison with the control group. The differences were greatest with the severest form of the disease. There were no differences between any of the groups in plasma Fe. Plasma transferrin correlated directly with albumin in asymptomatic, mild and severe malaria groups (r 0.48, 0.65 and 0.83; P < 0.05, P < 0.05, P < 0.01 and P < 0.001 respectively), and inversely with caeruloplasmin (r -0.65, -0.34 and -0.43; P < 0.01, P < 0.05 and P < 0.01 respectively). For ferritin, the correlation was inverse with albumin (r -0.65, -0.57 and -0.64; P < 0.01, P < 0.001 and P < 0.001 respectively and direct with caeruloplasmin (r 0.83, 0.21 and 0.49, P < 0.001, NS and P < 0.001 respectively). Multiple regression analysis on data from all patients combined indicated that albumin, and to a lesser extent alanine aminotransferase (EC 2.6.1.2) activity, explained 62 % of the variance in transferrin. Caeruloplasmin, parasite count and albumin explained 59 % of the variance in ferritin, and transferrin and unconjugated bilirubin explained 62 % of the variance in Fe values. In conclusion, these data suggest that low transferrin and high ferritin values are primarily due to the acute phase response. High transferrin saturation and lack of differences in plasma Fe between the groups are probably due to Fe released from lysed erythrocytes. Finally, in both symptomatic and asymptomatic malaria, indices of Fe status can be misleading and may be especially problematic in community studies in malaria-endemic areas where asymptomatic malaria may be common.

Sequence analysis of the structuraltbpAgene: protein topology and variable regions within neisserial receptors for transferrin iron acquisition

The gene coding for the 98-kDa meningococcal outer membrane transferrin binding protein 1 (TbpA) from strain B385 was cloned and sequenced. Sequence comparison among its deduced aminoacid sequence and those from TbpA and the closely related LbpA (lactoferrin binding protein) gene from three different meningococcal strains, and four isolates from two other bacterial pathogens, showed that TbpA variability is confined to five specific segments, designated VR1 (199–287), VR2 (306–381), VR3 (480–546), VR4 (618–651) and VR5 (681–708). The third VR was the most variable among strains both at the nucleotide and amino acid levels. Six additionaltbpAgenes from different meningococcal strains were cloned and its VR3 sequence determined. On the basis of this data we were able to clustertbpAgenes in two groups: D (bearing a deletion in VR3) and N (nondeleted); all N and D strains belonging to the groups of high or low molecular weight transferrin receptor isotype, respectively. However, by phenogram analysis, the prototypical strain M982 (Group II) was clustered with M990 (B16B6 isotype, Group I). These results point to the existence of important exposed regions as well as to the possibility of horizontal gene exchange involving this locus. A topology model with 14 exposed loops and 28 membrane spanning segments was postulated. According to this tentative analysis, TbpA as well as LbpA proteins should form a gated channel in the neisserial outer membrane. The variable regions were located in the fifth, sixth, eighth, 10th and 11th loops respectively. Among TbpAs VR1, VR2, and VR3 resulted the most relevant regions.

Nontransferrin-bound Iron in Serum of Patients Receiving Bone Marrow Transplants

Nontransferrin-bound iron (NTBI) and other parameters of iron status were measured in 40 patients undergoing bone marrow transplantation (BMT) prior to conditioning therapy (between day −10 and −7), at the time of BMT (day 0), and 2 weeks later (day +14). Serum iron and transferrin saturation values were normal before conditioning therapy. At day 0 serum iron values were high and median transferrin saturation was 98% (changes in the values of both serum iron and transferrin saturation, p < .0001). Transferrin saturation values were still elevated 2 weeks posttransplant (day +14 vs. baseline values, p = .0001). Starting at low NTBI levels pretransplant (median 0.4 μmol/l, range 0–4.2 μmol/l, controls: ≤ 0.4 μmol/l), all patients revealed high levels on day 0 (median 4.0 μmol/l, range 1.9–6.9 μmol/l, p < .0001) and 2 weeks posttransplant (median 2.7 μmol/l, range 0–6.2 μmol/l, p < .0001). These observations indicate that the plasma iron pool in patients undergoing BMT increases to a level at which the normal ability to sequestrate iron becomes exhausted and considerable amounts of NTBI appear in serum. This “free” form of iron can mediate the production of reactive oxygen species and may cause organ toxicity in the early posttransplantation period. © 1997 Elsevier Science Inc.

Pruritus in chronic hepatitis C: association with high serum bile acids, advanced pathology, and bile duct abnormalities.

Pruritus is a common symptom of chronic cholestatic liver diseases but is considered rare in chronic hepatitis. We observed pruritus to be an unusually common complaint in patients with advanced chronic hepatitis C. We reviewed the records of 175 chronic hepatitis C patients to identify patients with severe, diffuse, unexplained pruritus; 12 consecutive prospective patients undergoing liver biopsy for chronic hepatitis C served as controls. Assessment included laboratory biochemical tests and assessment of liver pathology by stage, grade, hepatic activity index, and a bile duct score. Pruritus was present in nine (5.1%) patients. Serum AST, ALT, alkaline phosphatase, GGTP, total bilirubin, and ferritin were similar in pruritics and controls. Pruritics had higher serum bile acids (2028.4 +/- 223.1 mmol/liter vs 423.1 +/- 194.3, P < 0.001), higher transferrin saturation (57.5 +/- 6.8% vs 33.2 +/- 3.3, P < 0.01), and lower HCV RNA by bDNA (24.5 +/- 12.7 x 10(5) vs 172.7 +/- 54.1 x 10(5), P < 0.05). Pathology revealed cirrhosis in 6/9 (66.6%) pruritics vs 1/12 (8.3%) controls (P < 0.01). Pruritics had higher pathologic stage (3.7 +/- 0.2 vs 2.2 +/- 0.4, P < 0.01), grade (4.4 +/- 0.2 vs 2.1 +/- 0.2, P < 0.001), activity index (14.3 +/- 1.9 vs 8.6 +/- 1.9, P < 0.025), and bile duct score (7.6 +/- 0.6 vs 4.7 +/- 0.4, P < 0.01). Of eight pruritics treated with IFN-alpha2b, two had complete ALT response and one relapsed. Pruritus followed a relapsing course and only three patients partially responded despite a variety of interventions. In conclusion, pruritus is a common complication of advanced CHC. Its presence is associated with high serum bile acids, advanced pathology and bile duct abnormalities. The clinical course of pruritus is relapsing and response to therapy is inconsistent. These features suggest that pruritus in CHC has a pathogenesis that may vary from that of chronic cholestatic diseases.

Serum Transferrin Saturation, Stroke Incidence, and Mortality in Women and Men: The NHANES I Epidemiologic Followup Study

Several studies have examined relatively large body iron stores and the risk of coronary heart disease with conflicting results. No reports of studies that associated body iron stores with stroke were found. To test the hypothesis that relatively high transferrin saturation is associated with increased stroke incidence and mortality in women and men, data from a follow-up study of a national cohort were examined. A total of 5,033 women and men aged 45-74 years from the First National Health and Nutrition Examination Survey Epidemiologic Followup Study who were free of stroke at baseline were followed an average of 12 years. Transferrin saturation (serum iron concentration divided by total iron binding capacity) was used as a measure of the amount of circulating iron available to tissues. In white women aged 45-74, after adjusting for age or for age and other risk variables, the authors observed a significant U-shaped association of transferrin saturation with risk of incident stroke (> 44% vs. 30-36%, relative risk = 1.96, 95% confidence interval 1.15-3.36; < 20% vs. 30-36%, relative risk = 1.80, 95% confidence interval 1.20-2.71). However, no significant associations were found in white men aged 45-74 after adjusting for other risk variables. Similar findings were observed for stroke mortality in whites, but no significant associations were seen in blacks. The significantly increased risk of stroke that was seen at both high and low levels of transferrin saturation in white women should be confirmed in other cohorts of women and men.

Defective Iron Supply for Erythropoiesis and Adequate Endogenous Erythropoietin Production in the Anemia Associated With Systemic-Onset Juvenile Chronic Arthritis

Systemic-onset juvenile chronic arthritis (SoJCA) is associated with high levels of circulating interleukin-6 (IL-6) and is frequently complicated by severe microcytic anemia whose pathogenesis is unclear. Therefore, we studied 20 consecutive SoJCA patients with hemoglobin (Hb) levels <12 g/dL, evaluating erythroid progenitor proliferation, endogenous erythropoietin production, body iron status, and iron supply for erythropoiesis. Hb concentrations ranged from 6.5 to 11.9 g/dL. Hb level was directly related to mean corpuscular volume (r = .82, P < .001) and inversely related to circulating transferrin receptor (r = -.81, P < .001) suggesting that the severity of anemia was directly proportional to the degree of iron-deficient erythropoiesis. Serum ferritin ranged from 18 to 1,660 microgram/L and was unrelated to Hb level. Bone marrow iron stores wore markedly reduced in the three children investigated, and they also showed increased serum transferrin receptor and normal-to-high serum ferritin. All 20 patients had elevated IL-6 levels and normal in vitro growth of erythroid progenitors. Endogenous erythropoietin (epo) production was appropriate for the degree of anemia as judged by both the observed to predicted log (serum epo) ratio 10.95 +/- 0.12) and a comparison of the serum epo-Hb regression found in these subjects with that of thalassemia patients. Multiple regression analysis showed that serum transferrin receptor was the parameter most closely related to hemoglobin concentration: variation in circulating transferrin receptor explained 61% of the variation in Hb level (P < .001). In 10 severely anemic patients, amelioration of anemia following intravenous iron administration resulted in normalization of serum transferrin receptor. Defective iron supply to the erythron rather than blunted epo production is the major cause of the microcytic anemia associated with SoJCA. A true body-iron deficiency caused by decreased iron absorption likely complicates long-lasting inflammation in the most anemic children, and this can be recognized by high serum transferrin receptor levels. Although oral iron is of no benefit, intravenous iron saccharate is a safe and effective means for improving iron availability for erythropoiesis and correcting this anemia. Thus, while chronically high endogenous IL-6 levels do not appear to blunt epo production, they are probably responsible for the observed abnormalities in iron metabolism. Anemia of chronic disease encompasses a variety of anemic conditions whose peculiar features may specifically correlate with the type of cytokine(s) predominantly released.

Evaluation of patterns of urinary proteins by SDS-PAGE in rats of different ages

The patterns of urinary proteins in rats of different ages were examined on SDS gradient polyacrylamide gel electrophoresis coupled with silver staining. Proteins were fractionated into at least 26 bands. Densitometric measurements were used to characterize protein excretion patterns. The results showed that proteinuria in newborn, young and adult rats is predominantly tubular, consisting of low molecular-weight species. Conversely, late adults and old rats had a mixed glomerular pattern, with a steadily increasing excretion of albumin, IgG and transferrin, as was the case of other high molecular-weight proteins. Fragments of both immunoglobulins and albumin were found in all urine samples assayed. In 1 month old rats the percentage of Tamm-Hörsfall (T-H) protein was higher ( P<0.01) than in the remaining groups studied. In newborns, relatively high albumin, IgG and transferrin percentages were detected, as well as an α 1-acid glycoprotein and carbonic anhydrase excretion ( P < 0.05 and P < 0.01 respectively) higher than that observed in the other age groups studied.