Inflammation-responsive drug delivery nanosystems for treatment of bacterial-induced sepsis.

Sepsis, a complication of dysregulated host immune systemic response to an infection, is life threatening and causes multiple organ injuries. Sepsis is recognized by WHO as a big contributor to global morbidity and mortality. The heterogeneity in sepsis pathophysiology, antimicrobial resistance threat, the slowdown in the development of antimicrobials, and limitations of conventional dosage forms jeopardize the treatment of sepsis. Drug delivery nanosystems are promising tools to overcome some of these challenges. Among the drug delivery nanosystems, inflammation-responsive nanosystems have attracted considerable interest in sepsis treatment due to their ability to respond to specific stimuli in the sepsis microenvironment to release their payload in a precise, targeted, controlled, and rapid manner compared to non-responsive nanosystems. These nanosystems posit superior therapeutic potential to enhance sepsis treatment. This review critically evaluates the recent advances in the design of drug delivery nanosystems that are inflammation responsive and their potential in enhancing sepsis treatment. The sepsis microenvironment's unique features, such as acidic pH, upregulated receptors, overexpressed enzymes, and enhanced oxidative stress, that form the basis for their design have been adequately discussed. These inflammation-responsive nanosystems have been organized into five classes namely: Receptor-targeted nanosystems, pH-responsive nanosystems, redox-responsive nanosystems, enzyme-responsive nanosystems, and multi-responsive nanosystems. Studies under each class have been thematically grouped and discussed with an emphasis on the polymers used in their design, nanocarriers, key characterization, loaded actives, and key findings on drug release and therapeutic efficacy. Further, this information is concisely summarized into tables and supplemented by inserted figures. Additionally, this review adeptly points out the strengths and limitations of the studies and identifies research avenues that need to be explored. Finally, the challenges and future perspectives on these nanosystems have been thoughtfully highlighted.

Reticulocyte Hemoglobin Content (Ret He): A Simple Tool for Evaluation of Iron Status in Childhood Cancer.

BACKGROUND: Cancer-related anemia is a common complication of cancer and its treatment that may be mediated by nutritional deficiency or inflammatory cytokines inhibiting erythropoiesis. AIM: We evaluated the value of reticulocyte hemoglobin content (Ret He) as a marker of iron availability for erythropoiesis in childhood cancer and the impact of oral iron supplementation on hematologic parameters in patients with low Ret He. MATERIALS AND METHODS: This prospective study included 100 pediatric patients with cancer on chemotherapy who were screened for the presence of anemia. Patients with anemia underwent testing for complete blood count including Ret He on Sysmex XE 2100 and assessment of reticulocyte count, serum iron, serum ferritin, transferrin saturation, total iron-binding capacity, and C-reactive protein. Patients were classified according to their level of Ret He into normal or low Ret He using a cutoff level of 28 pg. Patients with low Ret He were subjected to 6 weeks' treatment with oral ion and were followed up with complete blood count and iron profile. RESULTS: Thirty-one (77.5%) patients had normal Ret He, and 9 (22.5%) had low Ret He. Ret He was positively correlated with red cell indices, but not with iron parameters. After oral iron supplementation, a significant increase in hemoglobin, reticulocyte count, and iron was found. CONCLUSIONS: We suggest that Ret He could be used as an easy and affordable tool for the assessment of iron deficiency anemia in childhood cancer during chemotherapy treatment. A trial of oral iron in patients with low Ret He may be useful to correct the associated anemia.

Evaluation of continuous glucose monitoring system for detection of alterations in glucose homeostasis in pediatric patients with ß-thalassemia major.

BACKGROUND: Disturbances of glucose metabolism are common in ß-thalassemia major (ß-TM). AIM: This study was conducted to assess the pattern of glucose homeostasis in pediatric ß-TM patients comparing oral glucose tolerance test (OGTT) and continuous glucose monitoring system (CGMS). METHODS: Two-hundred ß-TM patients were studied and those with random blood glucose (RBG) ≥7.8 mmol/L (140 mg/dL) were subjected to OGTT, insertion of CGMS and measurement of fasting C peptide, fasting insulin, and hemoglobin A1c (HbA1c). RESULTS: Twenty patients (10%) had RBG ≥ 7.8 mmol/L. Using OGTT, 6 out of 20 patients (30%) had impaired glucose tolerance (IGT) while 7 (35%) patients were in the diabetic range. CGMS showed that 7/20 (35%) patients had IGT and 13 (65%) patients had diabetes mellitus (DM); 10 of the latter group had HbA1c readings within diabetic range. The percentage of diabetic patients diagnosed by CGMS was significantly higher than that with OGTT (P = 0.012). Serum ferritin was the only independent variable related to elevated RBG. All ß-TM patients with DM were non-compliant to chelation therapy. CONCLUSIONS: The use of CGMS in the diagnosis of early glycemic abnormalities among pediatric patients with ß-TM appears to be superior to other known diagnostic modalities.

Role of vitamin C as an adjuvant therapy to different iron chelators in young ß-thalassemia major patients: efficacy and safety in relation to tissue iron overload.

BACKGROUND: Vitamin C, as antioxidant, increases the efficacy of deferoxamine (DFO). AIM: To investigate the effects of vitamin C as an adjuvant therapy to the three used iron chelators in moderately iron-overloaded young vitamin C-deficient patients with ß-thalassemia major (ß-TM) in relation to tissue iron overload. METHODS: This randomized prospective trial that included 180 ß-TM vitamin C-deficient patients were equally divided into three groups (n = 60) and received DFO, deferiprone (DFP), and deferasirox (DFX). Patients in each group were further randomized either to receive vitamin C supplementation (100 mg daily) or not (n = 30). All patients received vitamin C (group A) or no vitamin C (group B) were followed up for 1 yr with assessment of transfusion index, hemoglobin, iron profile, liver iron concentration (LIC) and cardiac magnetic resonance imaging (MRI) T2*. RESULTS: Baseline vitamin C was negatively correlated with transfusion index, serum ferritin (SF), and LIC. After vitamin C therapy, transfusion index, serum iron, SF, transferrin saturation (Tsat), and LIC were significantly decreased in group A patients, while hemoglobin and cardiac MRI T2* were elevated compared with baseline levels or those in group B without vitamin C. The same improvement was found among DFO-treated patients post-vitamin C compared with baseline data. DFO-treated patients had the highest hemoglobin with the lowest iron, SF, and Tsat compared with DFP or DFX subgroups. CONCLUSIONS: Vitamin C as an adjuvant therapy possibly potentiates the efficacy of DFO more than DFP and DFX in reducing iron burden in the moderately iron-overloaded vitamin C-deficient patients with ß-TM, with no adverse events.

CD144+ endothelial microparticles as a marker of endothelial injury in neonatal ABO blood group incompatibility.

BACKGROUND: ABO antigens are expressed on the surfaces of red blood cells and the vascular endothelium. We studied circulating endothelial microparticles (EMP) in ABO haemolytic disease of the newborn (ABO HDN) as a marker of endothelial activation to test a hypothesis of possible endothelial injury in neonates with ABO HDN, and its relation with the occurrence and severity of haemolysis. MATERIAL AND METHODS: Forty-five neonates with ABO HDN were compared with 20 neonates with Rhesus incompatibility (Rh HDN; haemolytic controls) and 20 healthy neonates with matched mother and infant blood groups (healthy controls). Laboratory investigations were done for markers of haemolysis and von Willebrand factor antigen (vWF Ag). EMP (CD144(+)) levels were measured before and after therapy (exchange transfusion and/or phototherapy). RESULTS: vWF Ag and pre-therapy EMP levels were higher in infants with ABO HDN or Rh HDN than in healthy controls, and were significantly higher in babies with ABO HDN than in those with Rh HDN (p<0.05). In ABO HDN, pre-therapy EMP levels were higher in patients with severe hyperbilirubinaemia than in those with mild and moderate disease or those with Rh HDN (p<0.001). Post-therapy EMP levels were lower than pre-therapy levels in both the ABO HDN and Rh HDN groups; however, the decline in EMP levels was particularly evident after exchange transfusion in ABO neonates with severe hyperbilirubinaemia (p<0.001). Multiple regression analysis revealed that the concentrations of haemoglobin, lactate dehydrogenase and indirect bilirubin were independently correlated with pre-therapy EMP levels in ABO HDN. DISCUSSION: Elevated EMP levels in ABO HDN may reflect an IgG-mediated endothelial injury parallel to the IgG-mediated erythrocyte destruction and could serve as a surrogate marker of vascular dysfunction and disease severity in neonates with this condition.

Flow cytometric assessment of circulating platelet and erythrocytes microparticles in young thalassemia major patients: relation to pulmonary hypertension and aortic wall stiffness.

Heart disease is the leading cause of mortality and morbidity in ß-thalassemia major (ß-TM). Aggregability of abnormal red cells and membrane-derived microparticles (MPs) stemming from activated platelets and erythrocytes are responsible for thrombotic risk. We measured platelet and erythrocyte MPs (PMPs and ErMPs) in 60 young ß-TM patients compared with 40 age- and sex-matched healthy controls and assessed their relation to clinicopathological characteristics and aortic elastic properties. Patients were studied stressing on transfusion history, splenectomy, thrombotic events, chelation therapy, hematological and coagulation profiles, flow cytometric measurement of PMPs (CD41b(+) ) and ErMPs (glycophorin A(+) ) as well as echocardiographic assessment of aortic elastic properties. Aortic stiffness index and pulmonary artery pressure were significantly higher, whereas aortic strain and distensibility were lower in TM patients than controls (P < 0.001). Both PMPs and ErMPs were significantly elevated in TM patients compared with controls, particularly patients with risk of pulmonary hypertension, history of thrombosis, splenectomy or serum ferritin >2500 µg/L (P < 0.001). Compliant patients on chelation therapy had lower MPs levels than non-compliant patients (P < 0.001). PMPs and ErMPs were positively correlated to markers of hemolysis, serum ferritin, D-dimer, vWF Ag, and aortic stiffness, whereas negatively correlated to hemoglobin level and aortic distensibility (P < 0.05). We suggest that increased MPs may be implicated in vascular dysfunction, pulmonary hypertension risk, and aortic wall stiffness observed in thalassemia patients. Their quantification could provide utility for early detection of cardiovascular abnormalities and monitoring the biological efficacy of chelation therapy.

Clinicopathological and radiological study of Egyptian ß-thalassemia intermedia and ß-thalassemia major patients: relation to complications and response to therapy.

The clinico epidemiological characteristics, frequency of complications, and response to various therapeutic modalities in 80 Egyptian ß-thalassemia intermedia (ß-TI) patients were compared with 70 ß-thalassemia major (ß-TM) patients. ß-Thalassemia intermedia patients had a higher incidence of left atrium dilatation, right ventricular dilatation and pulmonary hypertension, whereas, ß-TM patients showed a higher incidence of left ventricular (LV) dilatation, restrictive LV filling and impaired LV contractility, with an overall higher incidence of heart disease (p <0.001). Short stature, delayed puberty, osteoporosis, bone fractures, diabetes mellitus and viral hepatitis was frequently observed in ß-TM patients compared with ß-TI patients (p <0.05). Administration of hydroxyurea (HU) alone was associated with significant improvement in hematological parameters and quality of life for ß-TI patients. In conclusion, the risk of complications still burdens the life of Egyptian thalassemia patients and their frequency varies between ß-TI and ß-TM. We provide evidence that calls for the use of HU in ß-TI patients.