Transferrin Ratio Research Articles

Optimization of Transcardiac Perfusion for More Accurately Evaluating Biodistribution of Large Molecules.

The accurate assessment of drug concentrations in biodistribution studies is crucial for evaluating the efficacy and toxicity of compounds in drug development. As the concentration of biologics in plasma can be higher than in tissue due to their potentially low volume of distribution, transcardiac perfusion is commonly employed to reduce the influence of excess drugs in residual blood. However, there is a lack of consistency in the literature on the conditions and methods of perfusion. To enhance blood removal during transcardiac perfusion, sodium nitrite (NaNO2), a vasodilator, has been widely used with concentrations up to 5% in publications. However, we found that such high NaNO2 could disrupt the BBB during perfusion, which should be avoided in experiments. In this study, we examined the impact of various vasodilators on blood-brain barrier integrity and vascular permeability using the ratio of FITC-Dextran to Texas Red-Dextran (FITC/Texas Red). Additionally, we optimized perfusion conditions-including euthanasia method and perfusion flow rate-based on hemoglobin levels and the FITC/Texas Red ratio in tissues. Despite the superiority of NaNO2 in terms of solubility and cost over other vasodilators, we found that 2% NaNO2 disrupted blood-brain barrier integrity, significantly altering the FITC/Texas Red ratio. In contrast, 100 mM NaNO2 did not significantly affect this ratio. Moreover, under Ketamine/Xylazine (Ket/Xyl) anesthesia, which reduced blood clot formation compared to CO2 euthanasia, 100 mM NaNO2 achieved the lowest hemoglobin levels in the brain. Compared to other vasodilators and the PBS control group, 100 mM NaNO2 decreased the tissue/plasma ratio (Kp,t) but not brain/plasma ratio (Kp,b) of hIgG1 and human transferrin. We have developed a method to efficiently evaluate blood-brain barrier integrity during transcardiac perfusion. The combination of Ket/Xyl anesthesia and 100 mM NaNO2 effectively removes residual blood from tissues without significantly affecting blood vessel permeability.

Choroidal Vascularity Index and Choroidal Structural Changes in Children With Nephrotic Syndrome.

To investigate the choroidal vascularity index (CVI) and choroidal structural changes in children with nephrotic syndrome. This was a cross-sectional study involving 45 children with primary nephrotic syndrome and 40 normal controls. All participants underwent enhanced depth imaging-optical coherence tomography examinations. An automatic segmentation method based on deep learning was used to segment the choroidal vessels and stroma, and the choroidal volume (CV), vascular volume (VV), and CVI within a 4.5mm diameter circular area centered around the macular fovea were obtained. Clinical data, including blood lipids, serum proteins, renal function, and renal injury indicators, were collected from the patients. Compared with normal controls, children with nephrotic syndrome had a significant increase in CV (nephrotic syndrome: 4.132 ± 0.464 vs. normal controls: 3.873 ± 0.574; P = 0.024); no significant change in VV (nephrotic syndrome: 1.276 ± 0.173 vs. normal controls: 1.277 ± 0.165; P = 0.971); and a significant decrease in the CVI (nephrotic syndrome: 0.308 [range, 0.270-0.386] vs. normal controls: 0.330 [range, 0.288-0.387]; P < 0.001). In the correlation analysis, the CVI was positively correlated with serum total protein, serum albumin, serum prealbumin, ratio of serum albumin to globulin, and 24-hour urine volume and was negatively correlated with total cholesterol, low-density lipoprotein cholesterol, urinary protein concentration, and ratio of urinary transferrin to creatinine (all P < 0.05). The CVI is significantly reduced in children with nephrotic syndrome, and the decrease in the CVI parallels the severity of kidney disease, indicating choroidal involvement in the process of nephrotic syndrome. Our findings contribute to a deeper understanding of how nephrotic syndrome affects the choroid.

Development and Validation of a Nomogram for Predicting Survival Based on Ferritin and Transferrin Ratio in Breast Cancer Patients.

Our objective is to develop a predictive model utilizing the ferritin and transferrin ratio (FTR) and clinical factors to forecast overall survival (OS) in breast cancer (BC) patients. We conducted a retrospective analysis of clinical data from 2858 BC patients diagnosed between 2013 and 2021. Subsequently, the cohort of 2858 BC patients underwent random assignment into distinct subsets: a training cohort comprising 2002 patients and a validation cohort comprising 856 patients, maintaining a proportional ratio of 7:3. Employing multivariable Cox regression analysis within the training cohort, we derived a prognostic nomogram. The predictive performance was assessed using calibration curves, C-index, and decision curve analysis. The final prognostic model included the TNM stage, subtype, hemoglobin levels, and the ferritin-transferrin ratio. The nomogram achieved a C-index of .794 (95% CI: .777-.810). The nomogram demonstrated superior predictive accuracy for OS at 3, 5, and 7 years for BC, with area under the time-dependent curves of .812, .782, and .773, respectively. These values notably outperformed those of the conventional TNM stage. Decision curve analysis reaffirmed the greater net benefit of our nomogram compared to the TNM stage. These findings were subsequently validated in the independent validation cohort. The FTR-based prognostic model may predict a patient's OS better than the TNM stage in a clinical setting. The nomogram can provide an early, affordable, and reliable tool for survival prediction, as well as aid clinicians in treatment option-making and prognosis evaluation. However, further multi-center prospective trials are required to confirm the reliability of the existing nomogram.

Analysis of transferrin in urine in patients with bladder cancer using nanobodies

It is known that the saturation ratio of transferrin (Tf) with iron in human blood is an important clinical parameter. Specific antibodies can be used to analyze subtle changes in the relative abundance of different forms of transferrin potentially associated with a pathological process. Recently, the authors of this study were able to obtain and characterize highly specific single-domain antibodies (nanobodies) that predominantly recognize the iron-saturated (holo-Tf) or iron-unsaturated (apo-Tf) form of transferrin. In this work, under conditions closer to physiological than in previous experiments, we further demonstrated that these unique nanobodies have extremely high differential binding specificity for different forms of Tf in different human biological fluids. Using these nanobodies, we were able to analyze for the first time the relative abundance of transferrin forms in urine samples from patients with bladder cancer (BC). We have shown that an increase in the concentration of total Tf in urine samples normalized for creatinine is associated with the degree of progress and growth of malignancy of BC. In the samples of healthy donors and in the early stages of BC (G1), Tf is detected in much smaller amounts (compared to later stages) and only with additional concentration of the studied samples. For most of the studied urine samples from BC patients, it is expected (as previously shown in the case of Tf in the blood of terminal ovarian cancer patients) that the concentration of apo-Tf is clearly higher than holo-Tf, especially in the case of the most advanced muscle-invasive BC. It was a surprise for us that approximately equal amounts of apo-Tf and “holo-Tf” were found in the urine samples of some patients with BC. We hypothesized that the “holo-Tf” fraction in this case can be largely represented by “secondary complexes” formed by apo-Tf in combination with ions other than Fe3+, which accumulate in the urine of some cancer patients and are able to bind to apo-Tf, changing its conformation towards holo-Tf. Using inductively coupled plasma ionization mass spectroscopy (ICP-MS), we obtained the first results confirming our hypothesis. The “holo-Tf” preparation in these urine samples was found to be highly enriched in zinc and nickel. Also in this preparation, a relative enrichment in cadmium is observed, but it is present in much lower concentrations. The data obtained indicate that the nanobody used, recognizing predominantly the iron-saturated form of transferrin (holo-Tf), is also capable of binding transferrin in association with other metal ions that are different from iron. This ability could potentially open up new possibilities in studies of the relative abundance of various metal ions in association with transferrin in human biological fluids in normal and pathological conditions.

Diagnostic and Monitoring Value of β-2 Transferrin and Transferrin for Intracranial Infection After Neurosurgery.

After neurosurgery, intracranial infection is a common complication with high rates of clinical impairment and death. Traditional diagnostic approaches are time-consuming. Early and correct diagnosis improves infection control, treatment success, and survival. Novel markers are used to diagnose and classify post-neurosurgical meningitis (PNM) to overcome the difficulties of diagnosing postoperative intracranial infections and avoid the drawbacks of existing diagnostic measures. The objective was to investigate the diagnostic value of β-2 transferrin (β-2TF) and transferrin (TF) in the cerebrospinal fluid (CSF) for the identification of intracranial infection after neurosurgery. Owing to their symptoms and laboratory results, 168 patients with suspected intracranial infection after neurosurgery were divided into 3 groups: post-neurosurgical bacterial meningitis (PNBM; n = 61), post-neurosurgical aseptic meningitis (PNAM; n = 45), and non-PNM (n = 62). We measured lactate (LA), β-2TF, and TF levels in the CSF. CSF LA levels were significantly higher in the PNM, PNBM, and PNAM groups compared with the non-PNM group ( P < .05). The CSF β-2TF level in PNM, PNBM, and PNAM were statistically higher than those in non-PNMs ( P < .05). CSF TF levels in the PNBM group were statistically higher than those in the PNAM and non-PNM groups ( P < .05). The PNBM and non-PNM receiver operating curve (ROC) analysis indicates that the cutoff values for the combination (LA, β-2TF, TF) was 0.349, and the area under the curve (AUC) was 0.945 ( P < .0001), with 92.86% sensitivity and 92.98% specificity. The PNAM and non-PNM ROC analysis indicates that the cutoff values for the combination (LA, β-2TF, TF) was 0.346, and the AUC was 0.962 ( P < .0001), with 89.29% sensitivity and 90.24% specificity. The PNM and non-PNM ROC analysis indicates that the cutoff values for the combination (LA, β-2TF, TF) was 0.609, and the AUC was 0.941 ( P < .0001), with 96.36% sensitivity and 82.83% specificity. A Glasgow Coma Scale score ≤8, LA, β-2TF/TF ratio, length of hospital stay, intensive care unit admission, poor surgical wound, and craniotomy were associated with poor outcomes ( P < .05). LA and β-2TF were independent risk factors for intracranial infection. Postoperative cerebral infections can be identified using CSF β-2TF as a particular marker protein. CSF TF helps distinguish PNBM from PNAM. Combining CSF LA with them improves diagnostic speed, sensitivity, and accuracy. LA and β-2TF were independent risk factors for cerebral infection.

Analysis of Transferrin in the Urine of Patients with Bladder Cancer Using Nanobodies.

It is known that the saturation ratio of transferrin (Tf) with iron in human blood is an important clinical parameter. Specific antibodies can be used to analyze subtle changes in the relative abundance of different forms of transferrin potentially associated with a pathological process. Recently, the authors of this study were able to obtain and characterize highly specific single-domain antibodies (nanobodies) that predominantly recognize the iron-saturated (holo-Tf) or iron-unsaturated (apo-Tf) form of transferrin. In this work, under conditions closer to physiological than in the previous experiments, we further demonstrated that these unique nanobodies have extremely high differential binding specificity for different forms of Tf in different human biological fluids. Using these nanobodies, we were able to analyze for the first time relative abundance of the transferrin forms in urine samples from the patients with bladder cancer (BC). We have shown that increase in the concentration of total Tf in the urine samples normalized for creatinine is associated with the degree of progress and growth of malignancy of BC. In the samples of healthy donors and in the early stages of BC (G1), Tf is detected in much smaller amounts (compared to the later stages) and only with additional concentration of the studied samples. For most of the studied urine samples from the BC patients, it is expected (as previously shown in the case of Tf in the blood of terminal ovarian cancer patients) that the concentration of apo-Tf is clearly higher than holo-Tf, especially in the case of the most advanced muscle-invasive BC. It was a surprise for us that approximately equal amounts of apo-Tf and holo-Tf were found in the urine samples of some patients with BC. We hypothesized that the holo-Tf fraction in this case could be largely represented by the "secondary complexes" formed by apo-Tf in combination with ions other than Fe3+, which accumulate in the urine of some cancer patients and are able to bind to apo-Tf, changing its conformation towards holo-Tf. By using inductively coupled plasma mass spectroscopy (ICP-MS), we obtained first results confirming our hypothesis. Preparation of the holo-Tf in these urine samples was found to be highly enriched in zinc and nickel. Also, relative enrichment in cadmium has been observed in this preparation, but at much lower concentrations. The obtained data indicate that the used nanobody, while recognizing predominantly the iron-saturated form of transferrin (holo-Tf), is also capable of binding transferrin in association with other metal ions that are different from iron. This ability could potentially open up new possibilities for investigation of relative abundance of various metal ions in association with transferrin in human biological fluids in normal and pathological conditions.

GENETIC BASES FOR IMPROVING THE REPRODUCTIVE AND PRODUCTIVE QUALITIES OF THE SOUTH-KAZAKH MERINOES BRED IN THE DESERT CONDITIONS CHU-ILI LOW MOUNTAINS AND THE MOIYN-KUM SANDS

The article reflects the data of scientific research that can serve the practice of selection and breeding work under conditions of various forms of ownership, as well as the improvement of selection and breeding work and the technology of production of high-quality and competitive sheep products in the conditions of year-round use of the foothill-steppe and desert pastures of the south of Kazakhstan. The research of polymorphism systems of serum proteins of sheep's blood of different intra-breed types by gender and age groups revealed the presence of certain allele combinations and the ratio of transferrin and hemoglobin genotypes. It has been established that these animals have their own specific range of frequencies of occurrence of alleles and combinations of genotypes. Based on the results obtained, the possibility of using genetic blood markers in the early assessment of the productive qualities of animals has been established. As a result of scientifically based breeding methods, in the “Batai-Shu” LLP in Zhambyl region created a breeding australized herd of the South Kazakh Merino breed with a white wool yolk, a cut of washed wool of 3.1 kg with a yield of 48-50%.

Carbohydrate-deficient transferrin is a sensitive marker of alcohol consumption in fatty liver disease.

The prevalence of nonalcoholic fatty liver disease (NAFLD) and alcohol-associated/related liver disease (ALD) with metabolic syndrome is increasing globally. Metabolic syndrome and excessive alcohol consumption synergically exacerbate liver pathologies; therefore, drinking-specific serum markers unaffected by liver injury or metabolic syndrome are essential for assessing alcohol consumption. We evaluated the ratio of carbohydrate-deficient transferrin to total transferrin (%CDT) in patients with fatty liver disease, particularly focusing on its correlation with metabolic factors (UMIN000033550). A total of 120 patients with fatty liver disease, including ALD and NAFLD, were screened for alcohol misuse using the Alcohol Use Disorders Identification Test. Associations of metabolic syndrome-related factors and hepatic steatosis/liver stiffness with drinking markers, such as %CDT, gamma-glutamyl transferase (GGT), and mean corpuscular volume (MCV), were assessed using multiple linear regression analyses. %CDT significantly increased with 3-4 drinks/day. The optimal cutoff value for identifying non- to light drinkers was 1.78% (sensitivity, 71.8%; specificity, 83.7%; and area under the receiver operating characteristic curve [AUROC], 0.851), which was significantly higher than that for GGT. The cutoff value for identifying heavy drinkers was 2.08% (sensitivity, 65.5%; specificity, 86.8%; and AUROC, 0.815). Multiple regression analysis revealed that this proportion was negatively correlated with body mass index, whereas GGT and MCV were influenced by multiple factors involved in liver injury and dyslipidemia. %CDT showed a strong correlation with alcohol consumption, independent of liver damage, steatosis/stiffness, or metabolic syndrome-related factors, indicating that it is a useful drinking marker for the accurate diagnosis of NAFLD and ALD.

Calculation of cut-off value of carbohydrate deficiency transferrin ratio in Japanese in medical examination business: Cut-off value to detect daily drinking habits

Calculation of cut-off value of carbohydrate deficiency transferrin ratio in Japanese in medical examination business: Cut-off value to detect daily drinking habits

Urine transferrin as an early endothelial dysfunction marker in type 2 diabetic patients without nephropathy: a case control study

BackgroundAlbumin, along with other proteins, is abnormally eliminated via the urine during early stages of diabetic nephropathy. Moreover, endothelial dysfunction (ED) accompanying early diabetic nephropathy may develop even before microalbuminuria is detectable. Transferrin has a molecular weight comparable to albumin, whereas transferrinuria and microalbuminuria in a 24-h urine sample may comparably reflect early diabetic nephropathy. Whereas transferrin metabolism is related with ED during very early diabetic nephropathy has not been elucidated yet. This case–control study aimed to evaluate the relation between ED and urine transferrin, even before early diabetic nephropathy is present.MethodsPatients were enrolled from two study sites in Mexico City: Ticomán General Hospital (healthy controls); and a Specialized Clinic for the Management of the Diabetic Patient (cases). All patients provided written informed consent. The primary endpoint was the correlation between urinary transferrin concentration and ED measured in type 2 diabetic patients without albuminuria. ED was evaluated by ultrasonographic validated measurements, which included carotid intima-media thickness (CIMT) and flow mediated dilation (FMD). Plasma biomarkers included glycated hemoglobin, creatinine, cholesterol and triglycerides, as well as urine albumin, transferrin and evidence of urinary tract infection.ResultsSixty patients with type 2 Diabetes Mellitus (t2DM; n = 30) or without t2DM (n = 30), both negative for microalbuminuria, were recruited. The group with t2DM were older, with higher values of HbA1c and higher ED. This group also showed significant differences in urine transferrin and urine/plasma transferrin ratio, as compared with healthy controls (14.4 vs. 18.7 mg/mL, p = 0.04, and 74.2 vs. 49.5; p = 0.01; respectively). Moreover, urine transferrin correlated with higher CIMT values (r = 0.37, p = 0.04), being particularly significant for t2DM population. CIMT also correlated with time from t2DM diagnosis (r = 0.48, p < 0.001) and HbA1c (r = 0.48; p < 0.001).ConclusionUrine transferrin correlated with subclinical atherogenesis in patients with t2DM without renal failure, suggesting its potential to identify cardiovascular risk in patients at very early nephropathy stage without microalbuminuria.

Acute monocyte pro inflammatory response predicts higher positive to negative acute phase reactants ratio and severe hemostatic derangement in dengue fever

PurposeThe present study was intended to investigate whether monocyte immune activation shapes plasma positive to negative acute phase reactants (APRs) ratio and predicts disease severity in dengue infection. MethodsSerum level of ferritin, ceruloplasmin and transferrin was measured by means of electrochemiluminescence and immunoturbidimetry, respectively. Gene expression and plasma level for TNF-α, IL-6 and IL1-β was measured by means of RT-qPCR and ELISA. ResultsA significant increased serum ferritin to transferrin [6.6 (3–11.7) vs 3.4 (1.9–6.1)] and ceruloplasmin to transferrin ratio [0.48 (0.21–0.87) vs 0.22 (0.13–0.43)] has been detected among the subjects with secondary dengue infection (SDENI) compared to primarily infected (PDENI) subjects (P < 0.001). Significant increased expression for CD14+ monocyte TNF-α, IL-6 and IL-1β has been detected in SDENI patients (vs PDENI and control, P < 0.001). Plasma ferritin to transferrin ratio was found in a significant association with high level of plasma TNF-α [ρ = 0.6522, 95% CI (0.4714–0.7805)], IL-6 [ρ = 0.6181, 95% CI (0.4257–0.7571)] and IL- 1β [ρ = 0.4119, 95% CI (0.1689–0.6077)] level among SDENI patients at 5th day time point after progression of the disease, with significantly low platelet [P < 0.001] and prolonging prothrombin time [P < 0.001] compared to control and PDENI subjects, respectively. ConclusionAcute proinflammatory cytokine response is significantly associated with increased positive to negative APRs ratio in SDENI patients, which predicts intense immune activation, and renders SDENI patients extremely susceptible to hemostatic derangement.

Evaluation of Ferritin and Transferrin Ratio as a Prognostic Marker for Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) has tripled in incidence over the past 20years and now ranks as the third leading cause of mortality attributed to cancer. Underlying pathophysiology is sustained hepatic inflammation which results in hepatocellular dysplasia and thus an environment prone to HCC. Considering the essential role of inflammation in the pathogenesis of HCC, we evaluated the prognostic utility of ferritin-transferrin ratio (FTR) in HCC. We retrospectively reviewed the electronic medical records of patients with HCC (diagnosed on radiographic criteria and/or biopsy) from 2000 through 2015. We collected data regarding the patient demographics, laboratory investigations at the time of HCC diagnosis and prior to the initiation of treatment. Overall survival was calculated from the time of diagnosis, cases were censored at the date of last follow-up, if date of death was not known. Kaplan-Meier curves were estimated to evaluate the prognostic significance of FTR. Receiver operating characteristics (ROC) curve was plotted for FTR to predict mortality and identify cut-off value by optimized Youden's index. Among the 176 patients identified by initial screening, 116 patients were eventually included for analysis. Overall median survival was 11.9months. FTR, of note, was significantly lower in alive (6.9, p < 0.001). In univariate analysis, alfa-fetoprotein (AFP), aspartate aminotransferase (AST), serum ferritin (SF), transferrin (TFS), and FTR were significantly associated with mortality. On multivariate analysis for mortality, FTR, AFP, and epidemiologic factors predictive of mortality including male gender and advanced HCC were significant. The ferritin-transferrin ratio (FTR), calculated at the time of HCC diagnosis could predict mortality in our cohort of patients. With an optimal cut-off of 7.7 for FTR were stratified into high- and low-risk groups. The hazard ratio between the two groups was 2.36 (p < 0.003). Future studies with longitudinal follow-up of FTR at intervals and important time points (e.g., perioperative) might provide more insights to its prognostic value.

The Ceruloplasmin Transferrin Ratio in the Blood of Patients at Different Stages of Parkinson’s Disease

The ratio of the concentrations of Cu2+-ceruloplasmin/Fe3+-transferrin in the blood plasma of 54 patients at different stages of Parkinson’s disease treated and not treated with L-DOPA was estimated by EPR-spectroscopy. It was established that in patients who suffer from Parkinson’s disease, the value of ceruloplasmin/ transferrin increased by 157% in comparison with the control group of clinically healthy people of the same age group. In patients with Parkinson’s disease, the ratio of ceruloplasmin/transferrin increased at stage 1 of the disease by 119%, at stage 2 by 117%, and at stage 3 by 135% in comparison with the control group. There was no statistically significant difference between the ratio of ceruloplasmin/transferrin in patients who received and did not recive L-DOPA replacement therapy. These data reveal changes in the functioning of the ceruloplasmin: transferrin system, which decreases the content of toxic ions of Fe2+ in the plasma of patients with Parkinson’s disease. These changes are a pathogenetically significant factor of Parkinson’s disease at all stages of the disease.

Role of soluble transferrin receptor and soluble transferrin receptor index in diagnosing iron deficiency anemia in patients with chronic kidney disease

Background: Approximately 25–38% of chronic kidney disease (CKD) patients with anemia suffer absolute or functional iron deficiency. This deficiency is estimated and monitored primarily through two iron indices, viz., transferrin saturation (TSAT) and serum ferritin. However, both these parameters suffer from several lacunae and search continues to establish more true measures. This study enquires into the role of soluble transferrin receptors (sTfR) and ratio of sTfR and log ferritin index (sTfR index) as potential measures of the true iron status in patients. Material and Methods: This prospective cross-sectional study comprised a total of 126 CKD patients with anemia on erythropoietin (EPO) undergoing hemodialysis (HD). Of these 126 patients, 55 had iron deficiency anemia (IDA). Estimations of serum iron, TSAT, serum ferritin, and sTfR and sTfR, indices were performed in each patient. Bone marrow aspiration (BMA) was carried out to determine cellularity, cytomorphology, and myeloid: erythroid (M/E) ratio, and was stained with Prussian blue stain. The results of the bone marrow iron status were taken as the gold standard. Subsequently, receiver operating characteristic (ROC) curve analysis was carried out to assess the discriminative power of the sTfR and sTfR indices for evaluation of iron status in patients with CKD. Results: The cut-off value of sTfR index at its maximum sensitivity (71.8%) and specificity (62%) was found to be 1.39, whereas that of sTfR at its maximum sensitivity (63.6%) and specificity (64.8%) was 3.00. Statistically significant correlations were found between sTfR index (Pearson correlation (r) = –0.379) and serum iron (r = –0.38; P < 0.01), TSAT (r = –0.31; P < 0.01), and serum ferritin (r = –0.399; P < 0.01). sTfR was found to correlate significantly (r = –0.445) with serum iron (P < 0.01), TSAT (r = –0.365; P < 0.01), and hemoglobin (r = –0.179; P = 0.04) but not with serum ferritin (r = 0.12; P = 0.153). Conclusion: sTfR and sTfR index values are useful tools for assessment of iron status in patients with CKD, however, they are at best complementary to the existing indices of serum ferritin and TSAT. Between sTfR and sTfR index, the latter has a greater discriminating power.

Testosterone Induces Erythrocytosis via Increased Erythropoietin and Suppressed Hepcidin: Evidence for a New Erythropoietin/Hemoglobin Set Point

The mechanisms by which testosterone increases hemoglobin and hematocrit remain unclear. We assessed the hormonal and hematologic responses to testosterone administration in a clinical trial in which older men with mobility limitation were randomized to either placebo or testosterone gel daily for 6 months. The 7%-10% increase in hemoglobin and hematocrit, respectively, with testosterone administration was associated with significantly increased erythropoietin (EPO) levels and decreased ferritin and hepcidin levels at 1 and 3 months. At 6 months, EPO and hepcidin levels returned toward baseline in spite of continued testosterone administration, but EPO levels remained nonsuppressed even though elevated hemoglobin and hematocrit higher than at baseline, suggesting a new set point. Consistent with increased iron utilization, soluble transferrin receptor (sTR) levels and ratio of sTR/log ferritin increased significantly in testosterone-treated men. Hormonal and hematologic responses were similar in anemic participants. The majority of testosterone-treated anemic participants increased their hemoglobin into normal range. Testosterone-induced increase in hemoglobin and hematocrit is associated with stimulation of EPO and reduced ferritin and hepcidin concentrations. We propose that testosterone stimulates erythropoiesis by stimulating EPO and recalibrating the set point of EPO in relation to hemoglobin and by increasing iron utilization for erythropoiesis.

Ceruloplasmin/Transferrin Ratio Changes in Alzheimer′s Disease

The link between iron and Alzheimer's disease (AD) has been mainly investigated with a focus on the local accumulation of this metal in specific areas of the brain that are critical for AD. In the present study, we have instead looked at systemic variations of markers of iron metabolism. We measured serum levels of iron, ceruloplasmin, and transferrin and calculated the transferrin saturation and the ceruloplasmin to transferrin ratio (Cp/Tf). Cp/Tf and transferrin saturation increased in AD patients. Cp/Tf ratios also correlated positively with peroxide levels and negatively with serum iron concentrations. Elevated values of ceruloplasmin, peroxides, and Cp/Tf inversely correlated with MMSE scores. Isolated medial temporal lobe atrophy positively correlated with Cp/Tf and negatively with serum iron. All these findings indicate that the local iron accumulation found in brain areas critical for AD should be viewed in the frame of iron systemic alterations.

Sensitivity and specificity of decreased CSF asialotransferrin for eIF2B-related disorder

This is a study estimating diagnostic accuracy of CSF asialotransferrin to transferrin ratio measurement in eIF2B related disorders by using clinical evaluation and EIF2B mutation analysis as the reference standard. eIF2B-related disorder is a relatively common leukodystrophy with broad phenotypic variation that is caused by mutations in any of the five EIF2B genes. There is a need for a simple and clinically valid screening tool for physicians evaluating patients with an unclassified leukodystrophy. CSF two-dimensional gel (2DG) electrophoresis analyses to measure asialotransferrin to transferrin ratios were performed in 60 subjects including 6 patients with documented EIF2B gene mutations, patients with other types of leukodystrophy, and patients with no leukodystrophy. All six patients with mutation proven eIF2B-related disease showed low to nearly undetectable amounts of asialotransferrin in their CSF when compared to 54 unaffected controls by CSF 2DG analyses in this study. eIF2B-like patients, with clinically similar presentations but no mutations in EIF2B1-5, were distinguished from patients with mutations in EIF2B1-5 by this biomarker. Patients with mutations in EIF2B1-5 had asialotransferrin/transferrin ratio levels significantly different from the group as a whole (p < 0.001). Using 8% asialotransferrin/transferrin ratio as a cutoff, this biomarker has a 100% sensitivity (95% CI = 52-100%) and 94% specificity (95% CI = 84-99%). Decreased asialotransferrin/transferrin ratio in the CSF of patients with eIF2B-related disorder is highly sensitive and specific. This rapid (<48 hours) and inexpensive diagnostic tool for eIF2B-related disorders has the potential to identify patients with likely eIF2B-related disorder for mutation analysis.

Comparison of plasma ferritin concentration versus the ratio of plasma transferrin receptor/ferritin to estimate total body iron stores: results of four intervention trials

Comparison of plasma ferritin concentration versus the ratio of plasma transferrin receptor/ferritin to estimate total body iron stores: results of four intervention trials

Biochemical model for inflammation of the brain: the effect of iron and transferrin on monocytes and lipid peroxidation.

Cerebral inflammation plays a role in diseases such as multiple sclerosis (MS), Alzheimer's disease (AD), and depression. Iron is involved in infection and inflammation through free radical production. Theoretically transferrin should prohibit iron from participating in oxidative reactions, but transferrin has also been found to promote free radical damage. We reported previously that isolation of transferrin from plasma by ion exchange column chromatography produced a broad pink protein band that subsequently separated on a gel filtration column into three proteins containing many metals. In this study some properties of the three proteins were studied in 20 volunteers. Protein 3 (identified as transferrin by nephelometry) contained the most iron while Protein 1 (called "toxiferrin") contained significantly less iron (p < 0.00001). Plasma from volunteers obtained under conditions of infection/inflammation with fever (n = 5) had a significantly increased toxiferrin to transferrin ratio compared to healthy volunteers (n = 15; p < 0.001). In vitro, Protein 2 and transferrin inhibited lipid peroxidation, while toxiferrin (possibly a protease degradation product of transferrin), enhanced lipid peroxidation. Also, toxiferrin (1 mg/mL) caused a significant increase in viability of monocytes as measured by the 3-(4,5-dimethyl-thiazol-2-yl) 2,5-diphenyl tetrazolium bromide (MTT) reduction test, as well as the morphological transformation of monocytes to macrophages.

The orchestration of body iron intake: how and where do enterocytes receive their cues?

Our understanding of how iron transverses the intestinal epithelium has improved greatly in recent years, although the mechanism by which body iron demands regulate this process remains poorly understood. By critically examining the earlier literature in this field and considering it in combination with recent advances we have formulated a model explaining how iron absorption could be regulated by body iron requirements. In particular, this analysis suggests that signals to alter absorption exert a direct effect on mature enterocytes rather than influencing the intestinal crypt cells. We propose that the liver plays a central role in the maintenance of iron homeostasis by regulating the expression of hepcidin in response to changes in the ratio of diferric transferrin in the circulation to the level of transferrin receptor 1. Such changes are detected by transferrin receptor 2 and the HFE/transferrin receptor 1 complex. Circulating hepcidin then directly influences the expression of Ireg1 in the mature villus enterocytes of the duodenum, thereby regulating iron absorption in response to body iron requirements. In this manner, the body can rapidly and appropriately respond to changes in iron demands by adjusting the release of iron from the duodenal enterocytes and, possibly, the macrophages of the reticuloendothelial system. This model can explain the regulation of iron absorption under normal conditions and also the inappropriate absorption seen in pathological states such as hemochromatosis and thalassemia.