Ingested soluble CD14 contributes to the functional pool of circulating sCD14 in mice

Soluble CD14 (sCD14) is a pattern recognition receptor and Toll-like co-receptor observed in human milk (5–26 μg/mL) and other bodily fluids such as blood (3 μg/mL). The most well defined role of sCD14 is to recognize lipopolysaccharide of Gram-negative bacteria and signal an immune response through Toll-like receptor 4 (TLR4). Previous research has shown ingested sCD14 to transfer from the gastrointestinal tract and into the blood stream in neonatal rats. The contribution of human milk sCD14 to circulating levels in the infant and the functionality of the protein, however, remained unknown. Using CD14^−/− mouse pups fostered to wild type (WT) mothers expressing sCD14 in their milk, we show herein that ingestion of sCD14 resulted in blood sCD14 levels up 0.16 ± 0.09 μg/mL. This represents almost one-third (26.7%) of the circulating sCD14 observed in WT pups fostered to WT mothers (0.60 ± 0.14 μg/mL). We also demonstrate that ingested-sCD14 transferred to the blood remains functional in its ability to recognize lipopolysaccharide as demonstrated by a significant increase in immune response (IL-6 and TNF-α) in CD14^−/− pups fostered to WT mothers in comparison to control animals (P = 0.002 and P = 0.007, respectively). Using human intestinal cells (Caco-2), we also observed a significant decrease in sCD14 transcytosis when TLR4 was knocked down (P < 0.001), suggesting sCD14 transfer involves TLR4. The bioavailability of human milk sCD14 established in this report confirms the importance of human milk proteins for the infant and demonstrates the need to improve infant formulas which are lacking in immune proteins such as sCD14.     

Burden of iron overload among non-chronically blood transfused preschool children with sickle cell anaemia

BackgroundSickle cell disease is the commonest genetic disorder of haemoglobin due to inheritance of mutant haemoglobin genes from both parents. The disorder is characterized by chronic haemolysis which results in increased availability of iron from red blood cell destructions.ObjectiveTo determine the prevalence of iron overload among non-chronically blood transfused preschool children with sickle cell anaemia.MethodsSerum ferritin was assayed and transferrin saturation derived in 97 steady state sickle cell anaemia children. Elevated iron stores were defined as serum ferritin level >300ng/ml, and transferrin saturation >45%.ResultsSerum ferritin level was greater than 300 mg/ml in 14 (14.4%) subjects and transferrin saturation >45% in six (6.2%) subjects with sickle cell anaemia. The prevalence of iron overload was 20.6%. The prevalence of iron overload was higher among subjects in older age group, female, with history of blood transfusion, and with single blood transfusion sessionConclusionIron overload is prevalent in older children; the number of blood transfusion sessions notwithstanding. Regular assessment of serum ferritin is recommended.     

Short-time lower leg ischemia reduces plantar foot sensitivity

The aim of this study was to investigate the effects of short-time blood flow occlusion on plantar foot vibration sensitivity of healthy young adults. 39 subjects (20 female; 19 male) participated in the study. Blood flow reduction was evoked with a pneumatic tourniquet, placed about 10 cm above the popliteus cavity. Vibration thresholds (200 Hz) were measured at three anatomical locations of the plantar foot (heel, first metatarsal head and hallux) in three different cuff pressure conditions: baseline (0 mmHg), low (50 mmHg) and high (150 mmHg). Each pressure condition was held for 4 min prior to vibration threshold measurements. No reperfusion time was allowed between conditions. The results show a significant increase in vibration thresholds measured at all anatomical locations in the high pressure condition (150 mmHg), whereas low pressure (50 mmHg) caused a significant threshold increase only at the hallux, compared to baseline (0 mmHg) measurements. Short-time blood flow occlusion seems to affect the afferent transmission of vibration stimuli from Vater–Pacini corpuscles, resulting in decreased plantar foot sensitivity. The present study provides an insight into initial adaptations caused by reduced blood flow in plantar foot sensitivity of healthy young adults.     

Evaluation of a web-based network for reproducible T2* MRI assessment of iron overload in thalassemia

Purpose

To build and evaluate a national network able to improve the care of thalassemia, a genetic disorder in haemoglobin synthesis often associated with iron accumulation in a variety of organs, due to the continuous blood transfusions.

Methods

The MIOT (Myocardial Iron Overload in Thalassemia) network is constituted by thalassemia and magnetic resonance imaging (MRI) centers. Thalassemia centers are responsible for patient recruitment and collection of anamnestic and clinical data. MRI centers have been equipped with a standardized acquisition technique and an affordable workstation for image analysis. They are able to perform feasible and reproducible heart and liver iron overload assessments for a consistent number of thalassemia patients in a robust manner. All centers are linked by a web-based network, configured to collect and share patient data.

Results

On 30th March 2008, 695 thalassemia patients were involved in the network. The completion percentage of the patient records in the database was 85 ± 6.5%. Six hundred and thirteen patients (88%) successfully underwent MRI examination. Each MRI center had a specific absorption capacity that remained constant over time, but the network was capable of sustaining an increasing number of patients due to continuous enrollment of new centers. The patient's comfort, assessed as the mean distance from the patient home locations to the MRI centers, significantly increased during the network's evolution.

Conclusion

The MIOT network seems to be a robust and scalable system in which T2* MRI-based cardiac and liver iron overload assessment is available, accessible and reachable for a significant and increasing number of thalassemia patients in Italy (about 420 per year), reducing the mean distance from the patient locations to the MRI sites from 951 km to 387 km. A solid, wide and homogeneous database will constitute an important scientific resource, shortening the time scale for diagnostic, prognostic and therapeutical evidence-based research on the management of thalassemia disease.     

Pathophysiology and classification of iron overload diseases; update 2018

Iron overload pathophysiology has benefited from significant advances in the knowledge of iron metabolism and in molecular genetics. As a consequence, iron overload nosology has been revisited. The hematologist may be confronted to a number of iron overload syndromes, from genetic or acquired origin. Hemochromatoses, mostly but not exclusively related to the HFE gene, correspond to systemic iron overload of genetic origin in which iron excess is the consequence of hepcidin deficiency, hepcidin being the hormone regulating negatively plasma iron. Iron excess develops following hypersideremia and the formation of non-transferrin-bound iron, which targets preferentially parenchymal cells (hepatocytes). The ferroportin disease has a totally different iron overload mechanism consisting of defective egress of cellular iron into the plasma, iron deposition taking place mostly within the macrophages (spleen). Hereditary aceruloplasminemia is peculiar since systemic iron overload involves the brain. Two main types of acquired iron overload can be seen by the hematologist, one related to dyserythropoiesis (involving hypohepcidinemia ), the other related to multiple transfusions (thalassemias, myelodysplasia, hematopoietic stem cell transplantation). Congenital sideroblastic anemias, either monosyndromic (anemia) or polysyndromic (anemia plus extra-hematological syndromes), develop both compartimental iron excess within the erythroblast mitochondria, and systemic iron overload (through dyserythropoiesis and/or transfusions).     

Effect of a group-based rehabilitation programme on glycaemic control and cardiovascular risk factors in type 2 diabetes patients: The Copenhagen Type 2 Diabetes Rehabilitation Project

Objective

To compare the effectiveness of a group-based rehabilitation programme with an individual counselling programme at improving glycaemic control and cardiovascular risk factors among patients with type 2 diabetes.

Methods

We randomised 143 adult type 2 diabetes patients to either a 6-month multidisciplinary group-based rehabilitation programme or a 6-month individual counselling programme. Outcome measures included glycated haemoglobin (HbA_1c), blood pressure, lipid profile, weight, and waist circumference.

Results

Mean HbA_1c decreased 0.3%-point (95% confidence interval [CI] = −0.5, −0.1) in the rehabilitation group and 0.6%-point (95% CI = −0.8, −0.4) among individual counselling participants (p < 0.05). Within both groups, equal reductions occurred in body weight, waist circumference, systolic blood pressure and diastolic blood pressure, but no significant between-group differences between occurred for any of the cardiovascular outcomes. The group-based rehabilitation programme consumed twice as many personnel resources.

Conclusion

The group-based rehabilitation programme resulted in changes in glycaemic control and cardiovascular risk factor reduction that were equivalent or inferior to those of an individual counselling programme.

Practice implications

The group-based rehabilitation programme, tested in the current design, did not offer additionally improved outcomes and consumed more personnel resources than the individual counselling programme; its broad implementation is not supported by this study.Trial registration Clinicaltrials.gov NCT00284609.     

Melatonin: Potential avenue for treating iron overload disorders

Iron overload as a highly risk factor, can be found in almost all human chronic and common diseases. Iron chelators are often used to treat iron overload; however, patient adherence to these chelators is poor due to obvious side effects and other disadvantages. Numerous studies have shown that melatonin has a high iron chelation ability and direct free radical scavenging activity, and can inhibit the lipid peroxidation process caused by iron overload. Therefore, melatonin may become potential complementary therapy for iron overload-related disorders due to its iron chelating and antioxidant activities. Here, the research progress of iron overload is reviewed and the therapeutic potential of melatonin in the treatment of iron overload is analyzed. In addition, studies related to the protective effects of melatonin on oxidative damage induced by iron overload are discussed. This review provides a foundation for preventing and treating iron homeostasis disorders with melatonin.     

Mitochondrial DNA acquires immunogenicity on exposure to nitrosative stress in patients with vitiligo

Vitiligo is a common pigmentary skin disorder of unknown etiology. Many studies show the defective mitochondrial functionality in vitiligo patients, but the potential role of mitochondrial DNA (mtDNA) in the pathogenesis of vitiligo remains to be investigated. Recent evidences demonstrate that mitochondria possess their own nitric-oxide-synthase and can produce endogenous peroxynitrite (ONOO⁻). This study was undertaken to investigate the role of ONOO⁻-modified-mitochondrial-DNA (ONOO⁻-mtDNA) in vitiligo autoimmunity. Our data revealed that ONOO⁻-induced modifications in mtDNA caused structural alterations. Specificity of immunoglobulin G (IgG) from vitiligo patients (n = 26) and controls (n = 25) were analysed towards ONOO⁻-mtDNA. Vitligo-IgG samples (Vt-IgG) show preferential binding to ONOO⁻-mtDNA in comparison with native mtDNA (p < 0.01). Anti-ONOO⁻-mtDNA–IgG show cross-reactivity with isolated DNA from vitiligo patients. Furthermore, levels of anti-ONOO⁻-mtDNA–IgG, inducible-nitric-oxide-synthase (iNOS), nitric oxide (NO) and nitrotyrosine were higher among vitiligo patients whose disease durations (DD) were ?5 years as compared to patients with lower DD (DD < 5 years). In conclusion, this is the first study to demonstrate the role of ONOO⁻-modified mtDNA in vitiligo patients. Our data provide an important insight into the immunological mechanisms occur in vitiligo. The ONOO⁻-mtDNA may be useful in elucidating the mechanisms of disease pathogenesis.     

Exercise improves cardiovascular control in a model of dislipidemia and menopause

The present study investigated the effects of exercise training on arterial pressure, baroreflex sensitivity, cardiovascular autonomic control and metabolic parameters on female LDL-receptor knockout ovariectomized mice. Mice were divided into two groups: sedentary and trained. Trained group was submitted to an exercise training protocol. Blood cholesterol was measured. Arterial pressure (AP) signals were directly recorded in conscious mice. Baroreflex sensitivity was evaluated by tachycardic and bradycardic responses to AP changes. Cardiovascular autonomic modulation was measured in frequency (FFT) and time domains. Maximal exercise capacity was increased in trained as compared to sedentary group. Blood cholesterol was diminished in trained mice (191 ± 8 mg/dL) when compared to sedentary mice (250 ± 9 mg/dL, p < 0.05). Mean AP and HR were reduced in trained group (101 ± 3 mmHg and 535 ± 14 bpm, p < 0.05) when compared with sedentary group (125 ± 3 mmHg and 600 ± 12 bpm). Exercise training induced improvement in bradycardic reflex response in trained animals (−4.24 ± 0.62 bpm/mmHg) in relation to sedentary animals (−1.49 ± 0.15 bpm/mmHg, p < 0.01); tachycardic reflex responses were similar between studied groups. Exercise training increased the variance (34 ± 8 vs. 6.6 ± 1.5 ms² in sedentary, p < 0.005) and the high-frequency band (HF) of the pulse interval (IP) (53 ± 7% vs. 26 ± 6% in sedentary, p < 0.01). It is tempting to speculate that results of this experimental study might represent a rationale for this non-pharmacological intervention in the management of cardiovascular risk factors in dyslipidemic post-menopause women.     

Concentration of iron and distribution of iron and transferrin after experimental iron overload in rat tissues in vivo: study of the liver, the spleen, the central nervous system and other organs

The purpose of this study was to estimate the iron concentration in the liver, spleen and brain of control rats and rats overloaded with iron and to determine the distribution of iron and of transferrin (TF). Iron was administered to Wistar rats by food supplemented with 3% carbonyl iron for 3 months, or intraperitoneally, or intraveneously as iron polymaltose for 4 months (total administered dose: 300 or 350 mg/rat, respectively). Iron concentration was estimated by atomic absorption spectrophotometry and iron- and TF-distribution histochemically and immunohistochemically, respectively. In control rats the organ with the highest iron content was the spleen, followed by the liver and brain. After iron loading the increase of iron in the liver was greater than that of the spleen; iron concentration in the brain did not change significantly. Distribution of iron in the liver was in Kupffer cells throughout the lobule and in hepatocytes at its periphery. No difference in the number of positive cells or staining intensity for TF was observed between control rats and iron overloaded animals in the liver or central nervous system (CNS); the spleen was negative for TF. Distribution of TF in the liver showed a centrilobular localisation in hepatocytes. TF reaction in the brain occurred in oligodendrocytes, vessel walls, choroid plexus epithelial cells and some neurons. In conclusion, experimental iron overload in rats leads to iron uptake mainly by reticuloendothelial (RE) cells and hepatocytes, indicating that hepatocytes are of particular importance for iron metabolism. Iron uptake by the brain was not significant, probably because the brain is protected against iron overload. Iron overload did not influence location and quantity of TF in the liver and CNS, whereas the visualisation of iron and TF did not coincide. This indicates that TF may have other functions beyond iron transport.     

Real-time monitoring of blood carbon dioxide tension by fluorosensor

A new intravascular fluorosensor was developed and validated for inline PCO₂ monitoring. The PCO₂ sensor was based on the fluorescent indicator 1-hydroxypyrene-3,6,8-trisulfonate. The PCO₂ sensor was then immersed in various solutions in vitro and carotid artery bypass of rabbits in vivo for testing. Changes of PCO₂ in solutions and blood were created by bubbling CO₂/N₂ and hyperventilation/hypoventilation, respectively. The changes of fluorescent intensity over PCO₂ range of 14-150 mmHg was linear. The resolution of the whole sensor system was 1 mmHg, with a bias ± SD of −0.1 ± 2.9 mmHg and precision ± SD of 2.1 ± 1.9 mmHg. The sensor signal has been stable during measurement for at least 25 h and was insensitive to fluctuations of ions concentration and osmosis at pathophysiological limits. The performance of the sensor is in agreement with blood gas analyzer in a wide range of PCO₂ and it is qualified for continuous intravascular measurement of blood PCO₂ at various conditions.     

Self-help interventions for symptoms of depression,anxiety and psychological distress in patients with physical illnesses: A systematic review and meta-analysis

Psychological distress, depression and anxiety are common in most physical diseases, and self-help interventions, if effective, might be an important approach to improve outcomes as they are inexpensive to provide to large numbers of patients. The primary aim of this review was to assess randomised controlled trials examining the impact of self-help interventions on symptoms of depression, anxiety and psychological distress in patients with physical illness. Systematic searches of electronic databases resulted in twenty-five eligible studies for meta-analysis (n = 4211). The results of the primary meta-analyses revealed a significant improvement in depression symptoms, in favour of the intervention group (SMD = − 0.13, 95% CI: − 0.25, − 0.02, p = 0.02, I² = 50%). There were no significant differences in symptoms of anxiety (SMD = − 0.10, 95% CI: − 0.24, 0.05, p = 0.20, I² = 63%) or psychological distress (SMD = − 0.14, 95% CI: − 0.40, 0.12, p = 0.30, I² = 72%) between intervention and control conditions. Several subgroup and sensitivity analyses improved effect sizes, suggesting that optimal mental health outcomes may be obtained in patients without neurological conditions, and with interventions based on a therapeutic model (such as cognitive behavioural therapy), and with stress management components. This review demonstrates that with appropriate design and implementation, self-help interventions may potentially improve symptoms of depression in patients with physical conditions.     

Acute iron overload in mice: pathogenesis of Salmonella typhimurium infection.

The bacterial growth in the tissues of C3D2F1 male mice was measured during an experimental infection with two Salmonella typhimurium strains (high virulence, strain 2386/74; low virulence, strain L15403). This experimental model was used for evaluation of the pathogenesis in normal and iron-overloaded animals. Acute iron overload was accomplished by intramuscular injections of chelated iron (with 2,3-dihydroxybenzoic acid and citrate) with a single dose of 100 micrograms of iron per mouse. Bacteria were given intraperitoneally 1 h after the iron injection. Serum iron levels, transferrin levels, and the bacteria counts in blood and liver were measured simultaneously in all animals. There was a significant increase of bacterial growth in all tissues in the iron-treated animals. Iron abolished the normal clearance of the bacteria with low virulence from the blood. This study demonstrates that a general iron overload, as determined by an increased serum iron level, resulting from preinjection of iron, enhances bacterial growth.     

Ramp rate of blood pressure changes does not affect aortic afferent sensitivity in anesthetized rats

To investigate whether the rate of change in blood pressure affects the sensitivity of the aortic baroreceptor afferent response, the change in aortic nerve activity (ANA) to two different rates of ramp increase in mean blood pressure (MBP), elicited by phenylephrine administration, was determined in the rat under urethane (1.5 g kg⁻¹) anesthesia. The sensitivity of the increase in ANA following a rapid (average ramp rate, 9.14 ± 0.60 mmHg s⁻¹, n = 11) or gradual (1.78 ± 0.24 mmHg s⁻¹, n = 11) increase in MBP was 2.03 ± 0.14% and 1.81 ± 0.20% of baseline mmHg⁻¹, respectively. These values were not significantly different from each other (P = 0.16). Furthermore, we found no correlation between the rate of ramp increase in MBP and the sensitivity of the increase in ANA (r = 0.24, P = 0.29, n = 22). These results suggest that, at least within the normal physiological range of MBP, the rate of the ramp change in blood pressure does not affect aortic baroreceptor afferent sensitivity in the anesthetized rat.     

A meta-analysis about the association between −1082G/A and −819C/T polymorphisms of IL-10 gene and risk of type 2 diabetes

The present meta-analysis was conducted to investigate the association between the −1082G/A and −819C/T polymorphisms of the IL-10 gene and risk of type 2 diabetes mellitus (T2DM). Relevant articles were identified by searching PubMed, Embase, and Web of Science. Pooled odds ratios (ORs) were used to assess the strength of the association between target polymorphisms and the risk of T2DM. Significant associations between the −1082G/A polymorphism and T2DM were found for the allele contrast (OR = 0.90, 95% CI: [0.83, 0.98], P = 0.02), homozygote contrast (OR = 0.82, 95% CI: [0.69, 0.97], P = 0.02), and recessive genetic model (OR = 0.85, 95% CI: [0.74, 0.96], P = 0.01). However, no significant association was found for the dominant genetic model (OR = 0.91, 95% CI: [0.80, 1.05], P = 0.08). The association between −819C/T polymorphism and T2DM was significant for the allele contrast (OR = 0.73, 95% CI: [0.64, 0.84], P < 0.01); however, no significant associations were found for −819C/T in the homozygote contrast (OR = 1.01, 95% CI: [0.38, 2.67], P = 0.99), dominant genetic model (OR = 0.94, 95% CI: [0.50, 1.77], P = 0.86), and recessive genetic model (OR = 0.92, 95% CI: [0.50, 1.68], P = 0.78). No significant publication bias was detected. This meta-analysis suggests that allele A of −1082G/A and allele C of −819C/T in the IL-10 gene have potentially protective effects in terms of risk of T2DM.     

Compound heterozygosity for haemochromatosis gene mutations and hepatic iron overload in allogeneic bone marrow transplant recipients

Iron overload has been proposed as a cause of liver dysfunction after BMT Factors which could be relevant to iron overload include the number of red cell transfusions and mutations within the haemochromatosis gene (HFE). Two point mutations, Cys282Tyr and His63Asp, have been described within HFE. Cys282Tyr homozygosity is associated with haemochromatosis; the effect of compound heterozygosity, Cys282Tyr/His63Asp, on iron status is variable. We analysed HFE status in 52 allograft patients surviving more than 6 months. Compound heterozygosity was identified in three patients (Cases 1-3). Iron status and liver function were evaluated and, in Cases 1 and 2, liver histology and iron content as well. Case 3 who received 12 units of red cells had a normal ferritin and liver function. Cases 1 and 2 received 29 and 59 units, respectively, and had high serum ferritins and transferrin saturations, abnormal liver function and significant hepatic iron overload on biopsy. Iron overload in Case 1 patient progressed in the context of GVHD and in the absence of further transfusion, suggesting that liver GVHD may increase hepatic iron accumulation. These cases demonstrate the variable phenotypic expression of HFE compound heterozygosity in BMT recipients, which may be only partly explained by transfusional iron loading. Venesection or chelation therapy should be considered in patients with coexistent hepatic GVHD and iron overload.     

The effect of maintenance and reversal of DOCA-Salt hypertension on extravasation of macromolecules and serum nitric oxide concentration in male rats

Objective: Previous studies indicated that there are some functional and morphological changes of endothelial cells in hypertension. The aim of this study was to investigate the effect of DOCA-Salt hypertension and its reversal on extravasation of macromolecules (endothelial permeability) and serum Nitric Oxide (NO) concentrations in male rats. Method: Male rats were divided into four groups as follows: Group (i): DOCA-Salt for 12 weeks; Group (ii): Solvent of DOCA injection for 12 weeks; Group (iii): DOCA-Salt for 12 weeks and DOCA-Salt withdrawal for 12 weeks; Group (iv): Solvent of DOCA injection for 12 weeks and its withdrawal for 12 weeks. At the end of experiment, serum NO concentrations were measured and vascular permeability in aorta and coronary circulation were evaluated using Evans Blue dye method. Results: Results showed that systolic blood pressure was significantly higher in DOCA-Salt hypertensive rats compared to normotensive group (150.1 ± 2.42 vs. 97.7 ± 2.32 mmHg, respectively). DOCA-Salt withdrawal completely reduced blood pressure in hypertensive rats to normotensive level (150.1 ± 2.42 vs. 98.1 ± 3.68 mmHg, respectively). Coronary vascular and aortic endothelial permeability were not different between DOCA-Salt hypertensive and normotensive rats and reversal of blood pressure did not alter it. Serum NO level was significantly lower in the hypertensive animals compared to normotensive group (3.87 ± 0.97 vs. 7.71 ± 0.67 μmol/l) and blood pressure reduction returned serum NO level to normotensive level (7.25 ± 0.96 vs. 7.71 ± 0.67 μmol/l). Conclusion: DOCA-Salt hypertension and its reversal did not alter coronary vascular and aortic endothelial permeability. However, serum NO level was significantly reduced during hypertension and reversal of hypertension completely reduced blood pressure together with the restoration of serum NO concentration. This may suggest that biological marker of endothelial function do not behave uniformly at least in this model of hypertension.     

Effects of psychological stress on neutrophil phagocytosis and bactericidal activity in humans — a meta-analysis

Several authors have reviewed the effects of psychological stress on lymphocyte activity. However the effect of psychological stress on neutrophil functions has not been reviewed. The present meta-analysis summarizes evidence of the effects of psychological stress on neutrophil phagocytosis and bactericidal activity collated from a MEDLINE search of the English literature. We searched the database to identify the relevant studies through April 30, 2013. Eleven studies met our inclusion criteria and we divided them into those addressing transient acute stress (3 studies, n = 74), academic examinations (4 studies n = 101) and chronic stress/life events (4 studies, n = 193). We performed a meta-analysis of the data and calculated total standardized mean differences (SMD) to evaluate the effects of chronic stress. Transient acute stressors might both enhance and decrease these neutrophil functions. Academic examinations tended to elevate neutrophil functions. On the other hand, the total SMDs of neutrophil phagocytosis and bactericidal activity altered by chronic stress/life events were − 0.589 (95% CI: − 0.908 to − 0.270, p < 0.05) and − 0.547 (95% CI: − 0.845 to − 0.248, p < 0.05), respectively, indicating suppressive effects on these neutrophil functions. Further systematic review of more pooled studies is warranted to confirm that academic examinations might enhance, whereas chronic stress/life events might suppress these neutrophil functions.     

Management of iron overload in hemoglobinopathies

Hemoglobinopathies, thalassemia and sickle cell disease are among the most frequent monogenic diseases in the world. Transfusion has improved dramatically their prognosis, but provokes iron overload, which induces multiple organ damages. Iron overload is related to accumulation of iron released from hemolysis and transfused red cell, but also, in thalassemic patients, secondary to ineffective erythropoiesis, which increases intestinal iron absorption via decreased hepcidin production. Transfusion-related cardiac iron overload remains a main cause of death in thalassemia in well-resourced countries, and is responsible for severe hepatic damages in sickle cell disease. Regular monitoring by Magnetic Resonance Imaging (MRI) using myocardial T2* (ms) and Liver Iron Content (LIC) (mg of iron/g dry weight) are now standards of care in chronically transfused patients. Serum ferritin level measurements and record of the total number of transfused erythrocyte concentrates are also helpful tools. Three iron chelators are currently available, deferoxamine, which must be injected subcutaneously or intravenously, and two oral chelators, deferiprone and deferasirox. We will review the main characteristics of these drugs and their indications.     

Effects of iron overload on the immune system

Iron and its binding proteins have immunoregulatory properties, and shifting of immunoregulatory balances by iron excess or deficiency may produce severe, deleterious physiological effects. Effects of iron overload include decreased antibody-mediated and mitogen-stimulated phagocytosis by monocytes and macrophages, alterations in T-lymphocyte subsets, and modification of lymphocyte distribution in different compartments of the immune system. The importance of iron in regulating the expression of T-lymphocyte cell surface markers, influencing the expansion of different T-cell subsets, and affecting immune cell functions can be demonstrated in vitro and in vivo. The poor ability of lymphocytes to sequester excess iron in ferritin may help to explain the immune system abnormalities in iron-overloaded patients. Iron overload as seen in hereditary hemochromatosis patients enhances suppressor T-cell (CD8) numbers and activity, decreases the proliferative capacity, numbers, and activity of helper T cells (CD4) with increases in CD8/CD4 ratios, impairs the generation of cytotoxic T cells, and alters immunoglobulin secretion when compared to treated hereditary hemochromatosis patients or controls. A correlation has recently been found between low CD8+ lymphocyte numbers, liver damage associated with HCV positivity, and severity of iron overload in beta-thalassemia major patients. Iron overload, with its associated increases of serum iron levels and transferrin saturation, may cause a poor response to interferon therapy. Iron overload with hyperferremia is associated with suppressed functions of the complement system (classic or alternative types). High plasma ferritin content in patients with chronic, diffuse diseases of the liver (cirrhosis, chronic hepatitis), beta-thalassemia major, dyserythropoiesis, and hereditary hemochromatosis may induce the development of anti-ferritin antibodies with the production of circulating immune complexes. Increased body stores of iron in various clinical situations may tip the immunoregulatory balance unfavorably to allow increased growth rates of cancer cells and infectious organisms, and complicate the clinical management of preexisting acute and chronic diseases.