Serum ferritin level of transfusion dependent thalassaemia patients- A Single Centre Study

The aim of the study was to determine serum ferritin level in transfusion dependent thalassaemia patients. A total of 64 transfusion dependent thalassaemia (TDT) patients was included in this cross sectional study from April, 2018 to September, 2019 according to selection criteria. Body iron load was estimated by serum ferritin level. The study sample consisted of 43 male and 21 female TDT patients, with a mean age of 25.5 years. Most of the patients (43.8%) patients had serum ferritin level in between 1000-2500 ng/ml. 12 patients (18.7%) had serum ferritin level >5000 ng/ml and 3 patients (4.7%) had serum ferritin in between 2501-5000 ng/ml. The mean serum ferritin was found 2462.6 ± 2792.7ng/ml with range from 207.0 -11891.2ng/m.

Post-injury ventricular enlargement associates with iron in choroid plexus but not with seizure susceptibility nor lesion atrophy—6-month MRI follow-up after experimental traumatic brain injury

Ventricular enlargement is one long-term consequence of a traumatic brain injury, and a risk factor for memory disorders and epilepsy. One underlying mechanisms of the chronic ventricular enlargement is disturbed cerebrospinal-fluid secretion or absorption by choroid plexus. We set out to characterize the different aspects of ventricular enlargement in lateral fluid percussion injury (FPI) rat model by magnetic resonance imaging (MRI) and discovered choroid plexus injury in rats that later developed hydrocephalus. We followed the brain pathology progression for 6 months and studied how the ventricular growth was associated with the choroid plexus injury, cortical lesion expansion, hemorrhagic load or blood perfusion deficits. We correlated MRI findings with the seizure susceptibility in pentylenetetrazol challenge and memory function in Morris water-maze. Choroid plexus injury was validated by ferric iron (Prussian blue) and cytoarchitecture (Nissl) stainings. We discovered choroid plexus injury that accumulates iron in 90% of FPI rats by MRI. The amount of the choroid plexus iron remained unaltered 1-, 3- and 6-month post-injury. During this time, the ventricles kept on growing bilaterally. Ventricular growth did not depend on the cortical lesion severity or the cortical hemorrhagic load suggesting a separate pathology. Instead, the results indicate choroidal injury as one driver of the post-traumatic hydrocephalus, since the higher the choroid plexus iron load the larger were the ventricles at 6 months. The ventricle size or the choroid plexus iron load did not associate with seizure susceptibility. Cortical hypoperfusion and memory deficits were worse in rats with greater ventricular growth.

Frequency, Pattern, and Associations of Renal Iron Accumulation in Sickle Beta-Thalassemia

Background: Chronically transfused homozygous sickle cell disease (HbSS) patients were shown to have higher kidney iron deposition than thalassemia major patients, not associated to total body iron and mainly caused by chronic hemolysis. Kidney iron deposition has not been explored in sickle beta-thalassemia (Sβ-thal), resulting from the inheritance of both sickle cell and beta-thalssemia genes. Aim: This multi center study aimed to study frequency, pattern, and associations of renal iron accumulation in sickle beta-thalassemia. Methods: Thirty-three Sβ-thal patients (36.49±14.72 years; 13 females) consecutively enrolled in the Extension-Myocardial Iron Overload in Thalassemia (E-MIOT) network were considered. Moreover, 20 healthy subjects, 14 HbSS patients and 71 thalassemia major (TM) patients were included as comparison groups. Hepatic, cardiac, pancreatic, and renal iron overload was quantified by the gradient-echo T2* technique. In each kidney T2* was measured in anterior, posterolateral, and posteromedial parenchymal regions and the global T2* value was calculated as the average of the two kidneys T2* values. Results. Global renal T2* were significantly higher in healthy subjects versus both Sβ-thal patients (49.68±10.09 ms vs 43.19±8.07 ms; P=0.013) and HbSS patients (49.68±10.09 ms vs 26.21±17.07 ms; P<0.0001). Sβ-thal patients showed comparable age, sex, frequency of regular transfusion, hematochemical parameters, and hepatic, cardiac and pancreatic iron load than HbSS patients, but they had a significant lower frequency of renal iron overload (global renal T2*<31 ms) (9.1% vs 57.1%; P=0.001). Regularly transfused patients (16 Sβ-thal and 10 HbSS) were compared with TM patients, homogeneous for age and sex, but TM started regular transfusions significantly earlier and they were more frequently chelated. No significant difference was detected in terms of hepatic and cardiac iron levels, but TM patients had significantly lower pancreas T2* values than both the other two groups and significantly higher global renal T2* values than HbSS patients (42.87±9.43 ms vs 24.39±15.74 ms; P=0.001). In Sβ-thal patients no significant difference was detected between T2* values in left and right kidneys, and global renal T2* values were not associated to age, gender, splenectomy, and they were comparable between regularly transfused and non transfused patients. No correlation was detected between renal T2* values and serum ferritin levels or iron load in the other organs. Global renal T2* values were not associated with serum creatinine levels but showed a significant inverse correlation with serum lactate dehydrogenase (Figure 1). Conclusion. Renal iron deposition is not common in Sβ-thal patients, with a prevalence significantly lower compared to that of HbSS patients, but with a similar underlying mechanism due to the chronic hemolysis. Figure 1 Figure 1. Disclosures Pepe: Bayer S.p.A.: Other: no profit support; Chiesi Farmaceutici S.p.A: Other: no profit support. Maggio: Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene Corp: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Membership on an entity's Board of Directors or advisory committees.

Safety and Efficacy of Early-Start Deferiprone in Infants and Young Children with Beta-Thalassemia (START study)

Background: Patients with beta-thalassemia may need to start receiving regular red blood cell transfusions as early as infancy. In the absence of iron chelation therapy, frequent transfusions cause iron to accumulate in the body, which can lead to morbidity, organ damage, and death. However, in very young children, current practice is to delay chelation therapy until receipt of 10-20 transfusions, or until the patient's serum ferritin (SF) level has reached 1000 μg/L, due to concerns over excessive iron depletion observed with the parenteral iron chelator deferoxamine. Unfortunately, this delay may increase the risk of iron accumulation in endocrine glands such as the pancreas, pituitary, and thyroid, where toxicities could manifest later in life. The START study (NCT03591575) evaluated the safety and efficacy of the oral iron chelator deferiprone (DFP) in children with transfusion-dependent beta-thalassemia who did not yet meet the criteria for starting chelation therapy as per standard practice. Methods: Infants and children who had started on a regular blood transfusion regimen, received a minimum of 2 transfusions, and whose SF level was between 200 and 600 μg/L were randomly assigned 1:1 to receive either (DFP) oral solution or a matching volume of placebo until their SF levels exceeded 1000 μg/L at 2 consecutive visits or they completed 12 months of therapy, whichever occurred first. The dosage of DFP was initiated at 25 mg/kg/day and increased to 50 mg/kg/day after 2 weeks; based on iron load, the dosage was then increased to 75 mg/kg/day for some patients. All adverse events (AEs) were reported and assessed for causality. Efficacy was assessed by monthly SF measurements to monitor iron load, with the primary efficacy endpoint being the percentage of patients in each group whose SF was still below the 1000 μg/L threshold. Once withdrawn, the patients were to receive standard chelation therapy, as recommended by their primary care physician. Results: The study enrolled 64 patients; 32 in each group. The mean (SD) age was 3.03 (2.42) years in the DFP group and 2.63 (1.70) years in the placebo group; the participants were 62.5% and 65.6% male in the DFP and placebo groups, respectively. There were no statistical group differences in the baseline demographics. The primary reason for withdrawal was SF levels that exceeded 1000 μg/L at 2 consecutive visits, which occurred in 25% of patients receiving DFP compared with 63% of patients receiving placebo (P=0.0051). After completing 12 months of treatment, 65.6% of patients receiving DFP had a SF level <1000 mg/L compared with 37.5% receiving placebo (P=0.0446). The percentage of patients who reached the 1000 mg/L SF threshold increased more rapidly in the placebo group compared with the DFP group, and the difference in rates between the 2 groups was significant (P=0.0407). A summary of adverse events (AEs) is shown in Table 1. There were no significant group differences in the number of overall AEs (P=1.0000), serious AEs (P=0.4258), or the number of AEs that were considered to be at least possibly related to the study treatment (P=1.0000). Two patients receiving DFP withdrew from the study due to AEs: 1 patient experienced agranulocytosis and 1 patient experienced neutropenia of moderate severity and both patients recovered. Conclusions: Initiation of DFP chelation therapy at a lower threshold of SF values than currently recommended was safe and efficacious in preventing iron overload in most transfusion-dependent children. After 12 months of treatment, the number of patients below the SF threshold was significantly higher in the DFP group compared with the placebo group. Moreover, there was a significant difference in the number of patients who withdrew due to elevated SF levels in the placebo group (62.5%) compared with the DFP group (25%). The safety and tolerability profile of DFP administered for up to 12 months in infants and young children was comparable to the profile established in older age groups and there were no instances of iron depletion. Disclosures: This study was sponsored by Chiesi Global Rare Diseases, and medical writing support was provided by Kelsey Hodge-Hanson, PhD, of Oxford PharmaGenesis Inc., Newtown, PA, and funded by Chiesi. Figure 1 Figure 1. Disclosures Fradette: Chiesi Canada Corp: Current Employment. Lee: Chiesi Canada Corp: Current Employment. Temin: Chiesi Canada Corp: Current Employment. Tricta: Chiesi Canada Corp: Current Employment. Rozova: Chiesi Canada Corp: Current Employment. Hamdy: Novartis: Honoraria; Roche: Honoraria; NovoNordisk: Honoraria; Bayer: Honoraria; Takeda: Honoraria; Amgen: Honoraria; ApoPharma: Honoraria.

MANAGEMENT OF GESTASIONAL DIABETES MELLITUS IN A BETA MAJOR THALASSEMIA PATIENT

Gestational diabetes mellitus (GDM) is a hyperglycemic condition that is first discovered during pregnancy. GDM is a high-risk condition during pregnancy, for both mother and fetus. GDM affects about 1–14% of pregnancies. In the last 20 years, the incidence of gestational diabetes has been increasing. High iron load and disorders of iron metabolism have been associated with glucose metabolism. The beta thalassemias are a group of hereditary hemoglobinopathies. Treatment for beta thalassemias patients is transfusion, but intensive transfusion can aggravate iron overload in patients. In this study, a case of GDM in a pregnant woman with beta-thalassemia was reported.

Intracerebral Iron Accumulation may be Associated with Secondary Brain Injury in Patients with Poor Grade Subarachnoid Hemorrhage

Background The amount of intracranial blood is a strong predictor of poor outcome after subarachnoid hemorrhage (SAH). Here, we aimed to measure iron concentrations in the cerebral white matter, using the cerebral microdialysis (CMD) technique, and to associate iron levels with the local metabolic profile, complications, and functional outcome. Methods For the observational cohort study, 36 patients with consecutive poor grade SAH (Hunt & Hess grade of 4 or 5, Glasgow Coma Scale Score ≤ 8) undergoing multimodal neuromonitoring were analyzed for brain metabolic changes, including CMD iron levels quantified by graphite furnace atomic absorption spectrometry. The study time encompassed 14 days after admission. Statistical analysis was performed using generalized estimating equations. Results Patients were admitted in a poor clinical grade (n = 26, 72%) or deteriorated within 24 h (n = 10, 28%). The median blood volume in the subarachnoid space was high (SAH sum score = 26, interquartile range 20–28). Initial CMD iron was 44 µg/L (25–65 µg/L), which significantly decreased to a level of 25 µg/L (14–30 µg/L) at day 4 and then constantly increased over the remaining neuromonitoring days (p < 0.01). A higher intraventricular hemorrhage sum score (≥ 5) was associated with higher CMD iron levels (Wald-statistic = 4.1, df = 1, p = 0.04) but not with the hemorrhage load in the subarachnoid space (p = 0.8). In patients developing vasospasm, the CMD iron load was higher, compared with patients without vasospasm (Wald-statistic = 4.1, degree of freedom = 1, p = 0.04), which was not true for delayed cerebral infarction (p = 0.4). Higher iron concentrations in the brain extracellular fluid (34 µg/L, 36–56 µg/L vs. 23 µg/L, 15–37 µg/L) were associated with mitochondrial dysfunction (CMD lactate to pyruvate ratio > 30 and CMD-pyruvate > 70 µM/L, p < 0.001). Brain extracellular iron load was not associated with functional outcome after 3 months (p > 0.5). Conclusions This study suggests that iron accumulates in the cerebral white matter in patients with poor grade SAH. These findings may support trials aiming to scavenger brain extracellular iron based on the hypothesis that iron-mediated neurotoxicity may contribute to acute and secondary brain injury following SAH.

Nanomaterials were formed into various shapes, with functionalization aimed at various internalization processes. Their nanoscale size allows drugs to reach cells or extracellular environments

Iron issues have been linked to a rising variety of refractory diseases, raising doubts about whether iron is the primary connection in etiology and pathology. Nanomaterials were transformed into diverse forms with functionalization aiming at diverse internalization processes. Their nanoscale size permits medications to penetrate cells or the extracellular environment. The original iron enrichment could be employed to fight diseases, including cancer. The effects of IONPs and intracellular iron load on macrophages is also unknown, giving the possibility for future alteration of macrophage phenotypes based on diverse situations.The data may be utilized to establish important patterns for disease risk prediction and prevention. Nano-sensing technology that reveals iron-regulating situations may deliver fresh insights into safety assessment of iron-based nanomaterials. Long-term stress caused by iron in cells and tissues does not create acute toxicity, but rather long-term damage. A better knowledge of iron homeostasis will result in further diagnostic and therapeutic applications employing nanotechnology.

Current and Emerging MR Methods and Outcome in Rodent Models of Parkinson’s Disease: A Review

Parkinson’s disease (PD) is a major neurodegenerative disease characterized by massive degeneration of the dopaminergic neurons in the substantia nigra pars compacta, α-synuclein-containing Lewy bodies, and neuroinflammation. Magnetic resonance (MR) imaging plays a crucial role in the diagnosis and monitoring of disease progression and treatment. A variety of MR methods are available to characterize neurodegeneration and other disease features such as iron accumulation and metabolic changes in animal models of PD. This review aims at giving an overview of how those physiopathological features of PD have been investigated using various MR methods in rodent models. Toxin-based and genetic-based models of PD are first described. MR methods for neurodegeneration evaluation, iron load, and metabolism alterations are then detailed, and the main findings are provided in those models. Ultimately, future directions are suggested for neuroinflammation and neuromelanin evaluations in new animal models.