Antioxidant mesoporous Ce-doped bioactive glass nanoparticles with anti-inflammatory and pro-osteogenic activities

Mesoporous bioactive glass nanoparticles (MBGNs) are emerging biomaterials for bone repair/regeneration, considering their favorable pro-osteogenic and proangiogenic activities. To further improve their therapeutic effects, the endowment of MBGNs with additional antioxidant properties is of particular interest to target oxidative stress related to bone remodeling and diseases. To this end, we developed antioxidant cerium-containing MBGNs (Ce-MBGNs) (particle size of 100–300 ​nm) by using a postimpregnation strategy to incorporate Ce, through which the shape, pore structure, and dispersity of the nanoparticles were preserved. The incorporated amount of Ce could be tailored by adjusting the concentration of the Ce precursor solution. When impregnated at a relatively low temperature (20 ​°C), Ce-MBGNs containing either 1.8 or 2.8 ​mol% of Ce were produced, while the formation of by-product cerium oxide nanoparticles (nanoceria) could be avoided. In both developed Ce-MBGNs, the concentration of Ce4+ was higher than that of Ce3+, while the relative molar percentage of Ce4+ was similar (∼74%) in both Ce-MBGNs. The obtained Ce-MBGNs were evidenced to be non-cytotoxic against fibroblasts at the concentration of 1 ​mg/mL. Moreover, the incorporation of Ce into MBGNs significantly reduced the expression of oxidative stress–related genes in macrophages (J774a.1). Particularly in the presence of pro-oxidation agents, Ce-MBGNs could downregulate the expression of oxidative stress–related genes in comparsion with the polystyrene plates (control). When cultured with Ce-MBGNs, the expression of proinflammatory-related genes in macrophages could also be downregulated in comparsion with MBGNs and the control. Ce-MBGNs also exhibited pro-osteogenic activities through suppressing pro-osteoclastogenic responses. The obtained results highlight the great potential of the developed Ce-MBGNs in a variety of biomedical applications, particularly in treating bone defects under inflammatory conditions, considering their antioxidant, anti-inflammatory, and pro-osteogenesis activities

A Multicenter Retrospective Survey regarding Diabetic Ketoacidosis Management in Italian Children with Type 1 Diabetes

We conducted a retrospective survey in pediatric centers belonging to the Italian Society for Pediatric Diabetology and Endocrinology. The following data were collected for all new-onset diabetes patients aged 0-18 years: DKA (pH < 7.30), severe DKA (pH < 7.1), DKA in preschool children, DKA treatment according to ISPAD protocol, type of rehydrating solution used, bicarbonates use, and amount of insulin infused. Records (n = 2453) of children with newly diagnosed diabetes were collected from 68/77 centers (87%), 39 of which are tertiary referral centers, the majority of whom (n = 1536, 89.4%) were diagnosed in the tertiary referral centers. DKA was observed in 38.5% and severe DKA in 10.3%. Considering preschool children, DKA was observed in 72%, and severe DKA in 16.7%. Cerebral edema following DKA treatment was observed in 5 (0.5%). DKA treatment according to ISPAD guidelines was adopted in 68% of the centers. In the first 2 hours, rehydration was started with normal saline in all centers, but with different amount. Bicarbonate was quite never been used. Insulin was infused starting from third hour at the rate of 0.05-0.1 U/kg/h in 72% of centers. Despite prevention campaign, DKA is still observed in Italian children at onset, with significant variability in DKA treatment, underlying the need to share guidelines among centers

Mathematical Modeling and Simulation of Ventricular Activation Sequences: Implications for Cardiac Resynchronization Therapy

Next to clinical and experimental research, mathematical modeling plays a crucial role in medicine. Biomedical research takes place on many different levels, from molecules to the whole organism. Due to the complexity of biological systems, the interactions between components are often difficult or impossible to understand without the help of mathematical models. Mathematical models of cardiac electrophysiology have made a tremendous progress since the first numerical ECG simulations in the 1960s. This paper briefly reviews the development of this field and discusses some example cases where models have helped us forward, emphasizing applications that are relevant for the study of heart failure and cardiac resynchronization therapy

Quantifying the effect of uncertainty in input parameters in a simplified bidomain model of partial thickness ischaemia

Reduced blood flow in the coronary arteries can lead to damaged heart tissue (myocardial ischaemia). Although one method for detecting myocardial ischaemia involves changes in the ST segment of the electrocardiogram, the relationship between these changes and subendocardial ischaemia is not fully understood. In this study, we modelled ST-segment epicardial potentials in a slab model of cardiac ventricular tissue, with a central ischaemic region, using the bidomain model, which considers conduction longitudinal, transverse and normal to the cardiac fibres. We systematically quantified the effect of uncertainty on the input parameters, fibre rotation angle, ischaemic depth, blood conductivity and six bidomain conductivities, on outputs that characterise the epicardial potential distribution. We found that three typical types of epicardial potential distributions (one minimum over the central ischaemic region, a tripole of minima, and two minima flanking a central maximum) could all occur for a wide range of ischaemic depths. In addition, the positions of the minima were affected by both the fibre rotation angle and the ischaemic depth, but not by changes in the conductivity values. We also showed that the magnitude of ST depression is affected only by changes in the longitudinal and normal conductivities, but not by the transverse conductivities

Chronic treatment with rosuvastatin modulates nitric oxide synthase expression and reduces ischemia-reperfusion injury in rat hearts.

Di Napoli P, Taccardi AA, Grilli A, De Lutiis MA, Barsotti A, Felaco M, De Caterina R. Chronic treatment with rosuvastatin modulates nitric oxide synthase expression and reduces ischemia-reperfusion injury in rat hearts. Cardiovasc Res. 2005 Jun 1;66(3):462-71. Epub 2005 Mar 2. Laboratory of Experimental Cardiology, Department of Clinical Sciences and Bioimaging, and Center of Excellence of Aging, G. d'Annunzio University, Chieti, Italy. OBJECTIVE: Due to reported modulatory effects of statins on nitric oxide synthase (NOS) expression, we tested the hypothesis of protective effects of in vivo chronic treatment with rosuvastatin, a novel 3-hydroxy-3-methyl-glutaryl coenzyme A-reductase inhibitor, on ischemia-reperfusion injury, and investigated mechanisms involved. METHODS: After 3 weeks of in vivo treatment with rosuvastatin (0.2-20 mg/kg/day) or placebo, excised hearts from Wistar rats were subjected to 15 min global ischemia and 22-180 min reperfusion. We evaluated creatine-phosphokinase and nitrite levels in the coronary effluent, heart weight changes, microvascular permeability (extravasation of fluoresceine-labeled albumin), ultrastructural alterations, and the expression of endothelial (e) and inducible (i) nitric oxide synthase (NOS) (by reverse-transcription polymerase chain reaction and Western blotting). RESULTS: Rosuvastatin 0.2 and 2 mg/kg/day significantly reduced myocardial damage and vascular hyperpermeability, concomitant with a reduction in endothelial and cardiomyocyte lesions. At 2 mg/kg/day, rosuvastatin significantly increased eNOS mRNA and protein compared with untreated hearts, and conversely decreased iNOS mRNA and protein, as well as nitrite production after ischemia-reperfusion. The addition of the NOS inhibitor N(omega)-nitro-L-arginine methylester (L-NAME, 30 micromol/L) significantly reduced cardioprotection against ischemia-reperfusion. CONCLUSIONS: Chronic treatment with rosuvastatin before ischemia reduces ischemia-reperfusion injury and prevents coronary endothelial cell and cardiomyocyte damage by NO-dependent mechanisms