Quantifying non-transferrin-bound iron (NTBI) in human plasma: incorporating BODIPY-pyridylhydrazone (BODIPY-PH) within a thin green film linked to a portable fluorescence-based device.

Free iron in human serum or non-transferrin-bound iron (NTBI) can generate free radicals and lead to oxidative damage. Moreover, it is highly toxic to various tissues and a vital biomarker related to the iron-loading status of thalassemia and Alzheimer's patients. In NTBI in healthy individuals, NTBI levels are typically less than 1 µM; current NTBI analysis usually requires advanced instrumentation and many-step sample pretreatment. To address this issue, we employed our invented BODIPY derivative, BODIPY-PH, as a fluorescence probe and trapped it onto the microcentrifuge tube lid using tapioca starch. The fluorescence intensity of BODIPY-PH increased with increasing NTBI concentration (turn-on). The developed portable reaction chamber facilitates rapid analysis (∼5 min) using small sample volumes (10 µL sample in a total volume of 600 µL). Under optimum conditions, using the sample-developed portable fluorescence device and fluorescence spectrometer, we achieved impressive limits of detection (LOD) of 0.003 and 0.0015 µM, respectively. Furthermore, the developed sensors show relatively high selectivity toward Fe3+ over other metal ions and biomolecules (i.e., Fe2+, Cr3+, Cu2+, and glucose). The sensor performance in serum samples of thalassemia patients exhibited no significant difference compared to the labeled value (obtained from standard methods). Overall, the developed fluorescence sensor is suitable for determining NTBI and offers high sensitivity, high selectivity, and a short incubation time (5 min). Moreover, the method requires a limited number of reagents, is simple to use, and uses low-cost equipment to determine NTBI in human serum samples.

Intravenous iron therapy results in rapid and sustained rise in myocardial iron content through a novel pathway.

BACKGROUND AND AIMS: Intravenous iron therapies contain iron-carbohydrate complexes, designed to ensure iron becomes bioavailable via the intermediary of spleen and liver reticuloendothelial macrophages. How other tissues obtain and handle this iron remains unknown. This study addresses this question in the context of the heart. METHODS: A prospective observational study was conducted in 12 patients receiving ferric carboxymaltose (FCM) for iron deficiency. Myocardial, spleen, and liver magnetic resonance relaxation times and plasma iron markers were collected longitudinally. To examine the handling of iron taken up by the myocardium, intracellular labile iron pool (LIP) was imaged in FCM-treated mice and cells. RESULTS: In patients, myocardial relaxation time T1 dropped maximally 3 h post-FCM, remaining low 42 days later, while splenic T1 dropped maximally at 14 days, recovering by 42 days. In plasma, non-transferrin-bound iron (NTBI) peaked at 3 h, while ferritin peaked at 14 days. Changes in liver T1 diverged among patients. In mice, myocardial LIP rose 1 h and remained elevated 42 days after FCM. In cardiomyocytes, FCM exposure raised LIP rapidly. This was prevented by inhibitors of NTBI transporters T-type and L-type calcium channels and divalent metal transporter 1. CONCLUSIONS: Intravenous iron therapy with FCM delivers iron to the myocardium rapidly through NTBI transporters, independently of reticuloendothelial macrophages. This iron remains labile for weeks, reflecting the myocardium's limited iron storage capacity. These findings challenge current notions of how the heart obtains iron from these therapies and highlight the potential for long-term dosing to cause cumulative iron build-up in the heart.

Hypoferremia of inflammation: Innate host defense against infections.

Iron is an essential nutrient for microbes, plants and animals. Multicellular organisms have evolved multiple strategies to control invading microbes by restricting microbial access to iron. Hypoferremia of inflammation is a rapidly-acting organismal response that prevents the formation of iron species that would be readily accessible to microbes. This review takes an evolutionary perspective to explore the mechanisms and host defense function of hypoferremia of inflammation and its clinical implications.

Plasma non-transferrin-bound iron uptake by the small intestine leads to intestinal injury and intestinal flora dysbiosis in an iron overload mouse model and Caco-2 cells.

Iron overload often occurs during blood transfusion and iron supplementation, resulting in the presence of non-transferrin-bound iron (NTBI) in host plasma and damage to multiple organs, but effects on the intestine have rarely been reported. In this study, an iron overload mouse model with plasma NTBI was established by intraperitoneal injection of iron dextran. We found that plasma NTBI damaged intestinal morphology, caused intestinal oxidative stress injury and reactive oxygen species (ROS) accumulation, and induced intestinal epithelial cell apoptosis. In addition, plasma NTBI increased the relative abundance of Ileibacterium and Desulfovibrio in the cecum, while the relative abundance of Faecalibaculum and Romboutsia was reduced. Ileibacterium may be a potential microbial biomarker of plasma NTBI. Based on the function prediction analysis, plasma NTBI led to the weakening of intestinal microbiota function, significantly reducing the function of the extracellular structure. Further investigation into the mechanism of injury showed that iron absorption in the small intestine significantly increased in the iron group. Caco-2 cell monolayers were used as a model of the intestinal epithelium to study the mechanism of iron transport. By adding ferric ammonium citrate (FAC, plasma NTBI in physiological form) to the basolateral side, the apparent permeability coefficient (Papp) values from the basolateral to the apical side were greater than 3×10-6 cm s-1. Intracellular ferritin level and apical iron concentration significantly increased, and SLC39A8 (ZIP8) and SLC39A14 (ZIP14) were highly expressed in the FAC group. Short hairpin RNA (shRNA) was used to knock down ZIP8 and ZIP14 in Caco-2 cells. Transfection with ZIP14-specific shRNA decreased intracellular ferritin level and inhibited iron uptake. These results revealed that plasma NTBI may cause intestinal injury and intestinal flora dysbiosis due to the uptake of plasma NTBI from the basolateral side into the small intestine, which is probably mediated by ZIP14.

Effect of Deferoxamine on Post-Transfusion Iron, Inflammation, and In Vitro Microbial Growth in a Canine Hemorrhagic Shock Model: A Randomized Controlled Blinded Pilot Study.

Red blood cell (RBC) transfusion is associated with recipient inflammation and infection, which may be triggered by excessive circulating iron. Iron chelation following transfusion may reduce these risks. The aim of this study was to evaluate the effect of deferoxamine on circulating iron and inflammation biomarkers over time and in vitro growth of Escherichia coli (E. coli) following RBC transfusion in dogs with atraumatic hemorrhage. Anesthetized dogs were subject to atraumatic hemorrhage and transfusion of RBCs, then randomized to receive either deferoxamine or saline placebo of equivalent volume (n = 10 per group) in a blinded fashion. Blood was sampled before hemorrhage and then 2, 4, and 6 h later. Following hemorrhage and RBC transfusion, free iron increased in all dogs over time (both p < 0.001). Inflammation biomarkers interleukin-6 (IL6), CXC motif chemokine-8 (CXCL8), interleukin-10 (IL10), and keratinocyte-derived chemokine (KC) increased in all dogs over time (all p < 0.001). Logarithmic growth of E. coli clones within blood collected 6 h post-transfusion was not different between groups. Only total iron-binding capacity was different between groups over time, being significantly increased in the deferoxamine group at 2 and 4 h post-transfusion (both p < 0.001). In summary, while free iron and inflammation biomarkers increased post-RBC transfusion, deferoxamine administration did not impact circulating free iron, inflammation biomarkers, or in vitro growth of E. coli when compared with placebo.

Labile plasma iron and echocardiographic parameters are associated with cardiac events in ß-thalassemic patients.

BACKGROUND AND AIM: Notwithstanding the improvement in therapies, patients affected by thalassemia major (TM) and intermedia (TI) are still at high risk of cardiac complications. This study aimed at evaluating the incidence and predictive factors for developing cardiac events in adult ß-TM and TI patients. POPULATION AND METHODS: Data on diagnosis and clinical history were collected retrospectively; prospective data on new-onset cardiac failure and arrhythmias, echocardiographic parameters, biochemical variables including non-transferrin-bound iron (NTBI) and labile plasma iron (LPI), magnetic resonance imaging (MRI) T2* measurement of hepatic and cardiac iron deposits, and iron chelation therapy were recorded during a 6-year follow-up. RESULTS: Thirty-seven patients, 29 TM and 8 TI, were included. At baseline, 8 TM patients and 1 TI patient had previously experienced a cardiac event (mainly heart failure). All patients were on chelation therapy and only 3 TM patients had mild-to-severe cardiac siderosis. During follow-up, 11 patients (29.7%) experienced a new cardiac event. The occurrence of cardiac events was correlated to high LPI levels (OR 12.0, 95% CI 1.56-92.3, p .017), low mean pre-transfusion haemoglobin (OR 0.21, 95% C.I. 0.051-0.761, p .21) and echocardiographic parameters suggestive of myocardial hypertrophy. Multivariate analysis disclosed high LPI and left ventricle mass index (LVMI) as independent variables significantly associated with cardiac events. Cardiac iron deposits measured by MRI T2* failed to predict cardiac events. CONCLUSION: LPI, Hb levels and echocardiographic parameters assessing cardiac remodelling are associated with cardiac events in adult TM and TI patients. LPI might represent both a prognostic marker and a potential target for novel treatment strategies. Further studies are warranted to confirm our findings on larger populations.

Low-temperature Mössbauer spectroscopy of organs from 57Fe-enriched HFE(-/-) hemochromatosis mice: an iron-dependent threshold for generating hemosiderin.

Hereditary hemochromatosis is an iron-overload disease most often arising from a mutation in the Homeostatic Fe regulator (HFE) gene. HFE organs become overloaded with iron which causes damage. Iron-overload is commonly detected by NMR imaging, but the spectroscopic technique is insensitive to diamagnetic iron. Here, we used Mössbauer spectroscopy to examine the iron content of liver, spleen, kidney, heart, and brain of 57Fe-enriched HFE(-/-) mice of ages 3-52 wk. Overall, the iron contents of all investigated HFE organs were similar to the same healthy organ but from an older mouse. Livers and spleens were majorly overloaded, followed by kidneys. Excess iron was generally present as ferritin. Iron-sulfur clusters and low-spin FeII hemes (combined into the central quadrupole doublet) and nonheme high-spin FeII species were also observed. Spectra of young and middle-aged HFE kidneys were dominated by the central quadrupole doublet and were largely devoid of ferritin. Collecting and comparing spectra at 5 and 60 K allowed the presence of hemosiderin, a decomposition product of ferritin, to be quantified, and it also allowed the diamagnetic central doublet to be distinguished from ferritin. Hemosiderin was observed in spleens and livers from HFE mice, and in spleens from controls, but only when iron concentrations exceeded 2-3 mM. Even in those cases, hemosiderin represented only 10-20% of the iron in the sample. NMR imaging can identify iron-overload under non-invasive room-temperature conditions, but Mössbauer spectroscopy of 57Fe-enriched mice can detect all forms of iron and perhaps allow the process of iron-overloading to be probed in greater detail.

NTBI levels in C282Y homozygotes after therapeutic phlebotomy.

C282Y homozygotes exposed to sustained elevated transferrin saturation (TS) may develop worsening clinical symptoms. This might be related to the appearance of non-transferrin bound iron (NTBI) when TS≥50% and labile plasma iron (LPI) when TS levels reach 75-80%. In this study, NTBI levels were examined in 219 randomly selected untreated and treated C282Y homozygotes. Overall, 161 of 219 had TS ≥ 50%, 124 of whom had detectable NTBI (≥0.47 µM, 1.81 µM [0.92-2.46 µM]) with a median serum ferritin 320 µg/L (226-442 µg/L). Ninety of 219 homozygotes had TS ≥ 75%, and all had detectable NTBI (2.21 µM [1.53-2.59 µM] with a median ferritin 338 µg/L [230-447 µg/L]). Of 125 homozygotes who last had phlebotomy ≥12 months ago (42 months [25-74 months], 92 had TS levels ≥ 50%, and 70 of these had NTBI ≥ 0.47 µM (2.06 µM [1.23-2.61µM]). Twenty-six of these 70 had a normal ferritin. Fifty-five of 125 had TS ≥ 75%, and NTBI was detected in all of these (2.32 µM [1.57-2.77 µM]) with a median ferritin 344 µg/L (255-418 µg/L). Eighteen of these 55 had a normal ferritin. In summary, NTBI is frequently found in C282Y homozygotes with TS ≥ 50%. Furthermore, C282Y homozygotes in the maintenance phase often have TS ≥ 50% together with a normal ferritin. Therefore, monitoring the TS level during the maintenance phase is recommended as an accessible clinical marker of the presence of NTBI.

Bioactive nutraceutical ligands and their efficiency to chelate elemental iron of varying dynamic oxidation states to mitigate associated clinical conditions.

The natural bioactive or nutraceuticals exhibit several health benefits, including anti-inflammatory, anti-cancer, metal chelation, antiviral, and antimicrobial activity. The inherent limitation of nutraceuticals or bioactive ligand(s) in terms of poor pharmacokinetic and other physicochemical properties affects their overall therapeutic efficiency. The excess of iron in the physiological compartments and its varying dynamic oxidation state [Fe(II) and Fe(III)] precipitates various clinical conditions such as non-transferrin bound iron (NTBI), labile iron pool (LIP), ferroptosis, cancer, etc. Though several natural bioactive ligands are proposed to chelate iron, the efficiency of bioactive ligands is limited due to poor bioavailability, denticity, and other related physicochemical properties. The present review provides insight into the relevance of studying the dynamic oxidation state of iron(II) and iron(III) in the physiological compartments and its clinical significance for selecting diagnostics and therapeutic regimes. We suggested a three-pronged approach, i.e., diagnosis, selection of therapeutic regime (natural bioactive), and integration of novel drug delivery systems (NDDS) or nanotechnology-based principles. This systematic approach improves the overall therapeutic efficiency of natural iron chelators to manage iron overload-related clinical conditions.

Iron-Induced Oxidative Stress in Human Diseases.

Iron is responsible for the regulation of several cell functions. However, iron ions are catalytic and dangerous for cells, so the cells sequester such redox-active irons in the transport and storage proteins. In systemic iron overload and local pathological conditions, redox-active iron increases in the human body and induces oxidative stress through the formation of reactive oxygen species. Non-transferrin bound iron is a candidate for the redox-active iron in extracellular space. Cells take iron by the uptake machinery such as transferrin receptor and divalent metal transporter 1. These irons are delivered to places where they are needed by poly(rC)-binding proteins 1/2 and excess irons are stored in ferritin or released out of the cell by ferroportin 1. We can imagine transit iron pool in the cell from iron import to the export. Since the iron in the transit pool is another candidate for the redox-active iron, the size of the pool may be kept minimally. When a large amount of iron enters cells and overflows the capacity of iron binding proteins, the iron behaves as a redox-active iron in the cell. This review focuses on redox-active iron in extracellular and intracellular spaces through a biophysical and chemical point of view.

Indices of iron homeostasis in asymptomatic subjects with HFE mutations and moderate ferritin elevation during iron removal treatment.

We analysed iron biomarkers and their relationships in 30 subjects with HFE mutations and moderate hyperferritinaemia undergoing iron removal at our blood donation centre. Body mass index (BMI) and liver enzymes were assessed. Serum iron (SI), ferritin, transferrin saturation (TSAT), hepcidin and non-transferrin bound iron (NTBI) were measured serially. Seventeen subjects had p.C282Y/p.C282Y, nine p.C282Y/p.H63D, four p.H63D/p.H63D. Median age (p = 0.582), BMI (p = 0.500) and ferritin (p = 0.089) were comparable. At baseline, 12/17 p.C282Y/p.C282Y and 2/9 p.C282Y/p.H63D had measurable NTBI (p = 0.003). The p.C282Y/p.C282Y had higher TSAT (p < 0.001), lower hepcidin (p = 0.031) and hepcidin/ferritin ratio (p = 0.073). After treatment, iron indices were similar among groups, except TSAT (higher in p.C282Y/p.C282Y; p = 0.06). Strong relationships were observed between ferritin and TSAT (R = 0.71), NTBI and TSAT (R = 0.61), NTBI and SI (R = 0.54) in p.C282Y/p.C282Y. Hepcidin correlated weakly with ferritin in p.C282Y/p.C282Y (R = 0.37) but strongly in p.C282Y/p.H63D (R = 0.66) and p.H63D/p.H63D (R = 0.72), while relationships with TSAT were weak (R = 0.27), moderate (R = 0.55) and strong (R = 0.61), respectively. Low penetrance p.C282Y/p.C282Y phenotype displays hepcidin dysregulation and biochemical risk for iron toxicity.

Rhabdomyolysis after Intravenous Ferric Gluconate: A Case Report.

Patients with severe iron deficiency, malabsorption or intolerance to oral iron are frequently treated with intravenous iron replacement. We report the case of a 42-year-old woman with non-erosive oligoarticular arthritis with antiparietal cell antibodies and iron deficiency anemia secondary to menorrhagia and unresponsive to oral iron preparations. She was treated with an intravenous infusion of ferric gluconate. After the first infusion of 125 mg (in 250 mL saline), she developed transient pain in her knee and wrist joints. When the dose was subsequently halved, the patient showed no adverse symptoms in the next four infusions and had normalized hemoglobin levels and iron indices. However, after a subsequent 125 mg ferric gluconate infusion she developed severe leg pain, muscular and joint stiffness, and functional impairment of her hands, right foot, and ankle. Laboratory tests showed a progressive increase in creatine kinase, transaminase, and C-reactive protein that normalized several days after the infusion. Although rhabdomyolysis is not reported among endovenous iron-induced adverse events, our findings suggest that intravenous iron infusions might have increased free iron generation promoting oxidative joint and muscular injury, which would explain the joint pain and stiffness, and rhabdomyolysis. Greater attention should be paid to the more frequent cases of myalgia occurring after iron infusion, which may underlie a rhabdomyolytic event requiring clinical observation. LEARNING POINTS: Rhabdomyolysis can occur not only after intramuscular injection of iron dextran but also after infusion of ferric gluconate.The generation of increased free iron following iron administration can promote oxidative joint and muscular injury.Leg cramps and myalgia, which are relatively common adverse events after iron infusions, might represent undiagnosed events of mild to moderate rhabdomyolysis requiring further investigation.

Non-transferrin bound iron.

Non-transferrin-bound iron (NTBI) is an important biomarker related to the iron loading status of patients with certain diseases. NTBI is a highly toxic form of iron capable of generating free radicals and can lead to oxidative damage of various tissues. It is critical to quantify NTBI in blood to ensure personalised patient chelation management and to prevent high iron concentrations that can lead to toxicity and organ failure. Different analytical methods for the direct quantification of NTBI are described in the literature, but none have been translated for use in clinical laboratories. This review provides a critical discussion on the recent breakthroughs and remaining challenges for the direct quantification of NTBI. Most of the developed methods involve lengthy and complex sample preparation, use of expensive reagents and equipment while lacking the required accuracy and reproducibility. Collectively, these factors have limited the clinical translation of the developed methods, and therefore, the need for a reliable and widely accepted analytical method to quantify NTBI remains. Finally, this review explores the potential of rapid and accurate electrochemical techniques that have been demonstrated for environmental samples but are yet to be applied to detect NTBI in human blood plasma/serum and translation to widespread routine clinical use.

Verapamil downregulates iron uptake and upregulates divalent metal transporter 1 expression in H9C2 cardiomyocytes.

Belgrade rats have a defect in divalent metal transport 1 (DMT1) with a reduced heart iron, indicating that DMT1 plays a physiological role in non-transferrin-bound iron (NTBI) uptake by cardiomyocytes. However, L-type voltage-dependent Ca2+ channel (LVDCC) blockers were recently demonstrated to significantly reduce NTBI uptake by cardiomyocytes, implying that LVDCC plays a dominant role in NTBI uptake by cardiomyocytes under iron-overloaded conditions. These findings led us to hypothesize that the LVDCC blocker-induced reduction in NTBI uptake might result not only from the inhibition of LVDCC-mediated NTBI uptake but also from the suppression of DMT1-mediated NTBI uptake. We therefore investigated the effects of the LVDCC blocker verapamil on NTBI uptake as well as DMT1 expression in H9C2 cells by the measurement of radio-labeled 55 Fe(II), reverse transcription polymerase chain reaction (RT-PCR) and western blot analysis. We demonstrated that verapamil induced a significant reduction in NTBI uptake by H9C2 cells but also unexpectedly a remarkable increase rather than decrease in the expression of DMT1 mRNA and protein in H9C2 cells. Our findings imply that the verapamil-induced reduction in NTBI uptake by H9C2 cells is not associated with DMT1 and also indicate that verapamil stimulates rather than inhibits DMT1 expression and DMT1-mediated iron uptake by heart cells.

The (Bio)Chemistry of Non-Transferrin-Bound Iron.

In healthy individuals, virtually all blood plasma iron is bound by transferrin. However, in several diseases and clinical conditions, hazardous non-transferrin-bound iron (NTBI) species occur. NTBI represents a potentially toxic iron form, being a direct cause of oxidative stress in the circulating compartment and tissue iron loading. The accumulation of these species can cause cellular damage in several organs, namely, the liver, spleen, and heart. Despite its pathophysiological relevance, the chemical nature of NTBI remains elusive. This has precluded its use as a clinical biochemical marker and the development of targeted therapies. Herein, we make a critical assessment of the current knowledge of NTBI speciation. The currently accepted hypotheses suggest that NTBI is mostly iron bound to citric acid and iron bound to serum albumin, but the chemistry of this system remains fuzzy. We explore the complex chemistry of iron complexation by citric acid and its implications towards NTBI reactivity. Further, the ability of albumin to bind iron is revised and the role of protein post-translational modifications on iron binding is discussed. The characterization of the NTBI species structure may be the starting point for the development of a standardized analytical assay, the better understanding of these species' reactivity or the identification of NTBI uptake mechanisms by different cell types, and finally, to the development of new therapies.

Comparisons of serum non-transferrin-bound iron levels and fetal cardiac function between fetuses affected with hemoglobin Bart's disease and normal fetuses.

Objective: To compare the levels of Non-transferrin bound iron (NTBI) in fetuses with anemia, using Hb Bart's disease as a study model, and those in unaffected fetuses and to determine the association between fetal cardiac function and the levels of NTBI. Patients and methods: A prospective study was conducted on pregnancies at risk of fetal Hb Bart's disease. All fetuses underwent standard ultrasound examination at 18-22 weeks of gestation for fetal biometry, anomaly screening and fetal cardiac function. After that, 2 ml of fetal blood was taken by cordocentesis to measure NTBI by Labile Plasma Iron (LPI), serum iron, hemoglobin and hematocrit. The NTBI levels of both groups were compared and the correlation between NTBI and fetal cardiac function was determined. Results: A total of 50 fetuses, including 20 fetuses with Hb Bart's disease and 30 unaffected fetuses were recruited. There was a significant increase in the level of serum iron in the affected group (median: 22.7 vs. 9.7; p-value: 0.013) and also a significant increase in NTBI when compared with those of the unaffected fetuses (median 0.11 vs. 0.07; p-value: 0.046). In comparisons of fetal cardiac function, myocardial performance (Tei) index of both sides was significantly increased in the affected group (left Tei: p = 0.001, Right Tei: p = 0.008). Also, isovolumetric contraction time (ICT) was also significantly prolonged (left ICT: p = 0.00, right ICT: p = 0.000). Fetal LPI levels were significantly correlated inversely with fetal hemoglobin levels (p = 0.030) but not significantly correlated with the fetal serum iron levels (p = 0.138). Fetal LPI levels were also significantly correlated positively with myocardial performance index (Tei) of both sides (right Tei: R = 0.000, left Tei: R = 0.000) and right ICT (R = 0.013), but not significantly correlated with left ICT (R = 0.554). Conclusion: Anemia caused by fetal Hb Bart's disease in pre-hydropic stage is significantly associated with fetal cardiac dysfunction and increased fetal serum NTBI levels which are significantly correlated with worsening cardiac dysfunction. Nevertheless, based on the limitations of the present study, further studies including long-term data are required to support a role of fetal anemia as well as increased fetal serum NTBI levels in development of subsequent heart failure or cardiac compromise among the survivors, possibly predisposing to cardiovascular disease in adult life.

Red blood cell transfusion-induced non-transferrin-bound iron promotes Pseudomonas aeruginosa biofilms in human sera and mortality in catheterized mice.

Transfusion of storage-damaged red blood cells (RBCs) increases non-transferrin-bound iron (NTBI) levels in humans. This can potentially enhance virulence of microorganisms. In this study, Pseudomonas aeruginosa replication and biofilm production in vitro correlated with NTBI levels of transfused subjects (R2 = 0·80; P < 0·0001). Transfusion of stored RBCs into catheterized mice enhanced P. aeruginosa virulence and mortality in vivo, while pre-administration of apotransferrin reduced NTBI levels improving survival (69% vs 27% mortality; P < 0·05). These results suggest that longer RBC storage, by modulating the bioavailability of iron, may increase the risk of P. aeruginosa biofilm-related infections in transfused patients.

Early detection of ventricular dysfunction by tissue Doppler echocardiography related to cardiac iron overload in patients with thalassemia.

Cardiac T2* MRI is used as a gold standard for cardiac iron quantification in patients with transfusion-dependent thalassemia (TDT). We hypothesized that left ventricular (LV) diastolic dysfunction would reflect the severity of iron overload and can serve as an early detection of cardiac iron deposits. A study was conducted on all patients with TDT. Hemoglobin, serum ferritin and non-transferrin bound iron, together with a complete echocardiography and cardiac T2* MRI, were performed on all patients. Seventy-seven patients with TDT were enrolled (median age 14 years). In the patient group with a mean serum ferritin of > 2500 ng/mL during the past 12 months, there were more patients with severe cardiac iron deposits than in the group with a mean serum ferritin of ≤ 2500 ng/mL. Diastolic dysfunction was absent in all patients with a serum ferritin of < 1000 ng/mL. All patients with cardiac T2* ≤ 20 ms had grade III LV diastolic dysfunction. However, twenty-one percent of patients with cardiac T2* > 20 ms had LV diastolic dysfunction. The differences observed in pulmonary vein atrial reversal duration and mitral A-wave (PVAR-MVA) duration ≥ - 1 ms and an E/E' ratio ≥ 11 were proven to be the associated factors with the cardiac T2* ≤ 20 ms. Increased PVAR-MVA duration and increased E/E' ratio reliably reflected a severe iron overload, according to a cardiac T2* in patients with TDT. LV diastolic dysfunction can occur prior to severe cardiac iron deposition. Tissue Doppler echocardiography has the potential for the early detection of cardiac involvement in patients with TDT .

Iron Through the Prism of Haematology.

Since the inception of the British Society for Haematology (BSH) 60 years ago, our increased scientific understanding of iron metabolism, together with clinical developments, have changed the way we diagnose and treat its disorders. In the UK, perhaps the most notable contributions relate to iron overload, some of which I will outline from personal experience. Diagnostically, this began with the identification of serum ferritin as a marker of iron overload and continued later with the application of MRI-based imaging techniques for iron and its distribution. Therapeutically, the first trials of both parenteral and oral chelation, which have radically changed the outcomes of transfusional iron-overloaded patients, took place in the UK and are now part of standard clinical practice. During this time, our scientific understanding of iron metabolism at a cellular and systemic level have advanced the diagnosis and treatment of inherited disorders of iron metabolism. There are potential novel applications related to our recent understanding of hepcidin metabolism and manipulation.