Iron and Sphingolipids as Common Players of (Mal)Adaptation to Hypoxia in Pulmonary Diseases

Hypoxia, or lack of oxygen, can occur in both physiological (high altitude) and pathological conditions (respiratory diseases). In this narrative review, we introduce high altitude pulmonary edema (HAPE), acute respiratory distress syndrome (ARDS), Chronic Obstructive Pulmonary Disease (COPD), and Cystic Fibrosis (CF) as examples of maladaptation to hypoxia, and highlight some of the potential mechanisms influencing the prognosis of the affected patients. Among the specific pathways modulated in response to hypoxia, iron metabolism has been widely explored in recent years. Recent evidence emphasizes hepcidin as highly involved in the compensatory response to hypoxia in healthy subjects. A less investigated field in the adaptation to hypoxia is the sphingolipid (SPL) metabolism, especially through Ceramide and sphingosine 1 phosphate. Both individually and in concert, iron and SPL are active players of the (mal)adaptation to physiological hypoxia, which can result in the pathological HAPE. Our aim is to identify some pathways and/or markers involved in the physiological adaptation to low atmospheric pressures (high altitudes) that could be involved in pathological adaptation to hypoxia as it occurs in pulmonary inflammatory diseases. Hepcidin, Cer, S1P, and their interplay in hypoxia are raising growing interest both as prognostic factors and therapeutical targets

Pseudographs and Lax-Oleinik semi-group: a geometric and dynamical interpretation

Let H be a Tonelli Hamiltonian defined on the cotangent bundle of a compact and connected manifold and let u be a semi-concave function defined on M. If E (u) is the set of all the super-differentials of u and (\phi t) the Hamiltonian flow of H, we prove that for t > 0 small enough, \phi-t (E (u)) is an exact Lagrangian Lipschitz graph. This provides a geometric interpretation/explanation of a regularization tool that was introduced by P.~Bernard to prove the existence of C 1,1 subsolutions

The physics models of FLUKA: status and recent development

A description of the intermediate and high energy hadronic interaction models used in the FLUKA code is given. Benchmarking against experimental data is also reported in order to validate the model performances. Finally the most recent developments and perspectives for nucleus-nucleus interactions are described together with some comparisons with experimental data.Comment: talk from the 2003 Computing in High Energy and Nuclear Physics (CHEP03), La Jolla, Ca, USA, March 2003, 10 pages, p

Modelling the influence of shielding on physical and biological organ doses.

Distributions of "physical" and "biological" dose in different organs were calculated by coupling the FLUKA MC transport code with a geometrical human phantom inserted into a shielding box of variable shape, thickness and material. While the expression "physical dose" refers to the amount of deposited energy per unit mass (in Gy), "biological dose" was modelled with "Complex Lesions" (CL), clustered DNA strand breaks calculated in a previous work based on "event-by-event" track-structure simulations. The yields of complex lesions per cell and per unit dose were calculated for different radiation types and energies, and integrated into a version of FLUKA modified for this purpose, allowing us to estimate the effects of mixed fields. As an initial test simulation, the phantom was inserted into an aluminium parallelepiped and was isotropically irradiated with 500 MeV protons. Dose distributions were calculated for different values of the shielding thickness. The results were found to be organ-dependent. In most organs, with increasing shielding thickness the contribution of primary protons showed an initial flat region followed by a gradual decrease, whereas secondary particles showed an initial increase followed by a decrease at large thickness values. Secondary particles were found to provide a substantial contribution, especially to the biological dose. In particular, the decrease of their contribution occurred at larger depths than for primary protons. In addition, their contribution to biological dose was generally greater than that of primary protons

Arginine-calcium carbonate professional treatment for tubules occlusion in hypersensitive dentin

Objective: To test the tubules occlusion of an arginine-based professional treatment for hypersensitive dentin. Method: Dentin segments/discs were prepared from erupted sound molars. Elmex sensitive professional desensitizing paste (GABA Int. by Colgate Oral Pharmaceuticals, Dallas, USA) containing arginine 8% and calcium carbonate was applied on EDTA-treated dentin for 20s at 1000rpm using a prophy cup, following the manufacturer directions. The excess was removed using a microbrush then the dentin disc was gently rinsed and immersed in 20mL of simulated body fluid (Hank\u2019s Balanced Salt Solution, HBSS) at 37\ub0C. After 24h, 7 and 28d the dentin surface was analyzed by ESEM-EDX to evaluate the tubules occlusion and the mineral content. Elmex paste mixed with calcein solution 1% was used to evaluate its penetration depth into the tubules by confocal microscopy. Result: After 24h in HBSS, ESEM-EDX analyses on Elmex-treated dentin showed the presence of precipitates on dentin surface and in the dentinal tubules, relevant amount of N(16-19 wt%, demonstrating the presence of arginine and Ca/P molar ratio 653.0. Confocal microscopy showed a penetration of the paste into the dentinal tubules to a mean depth of approx 50 microns (maximum depth penetration 100 microns). ESEM showed the presence of many tubules still obturated by material after 7d in HBSS; EDX found N (approx 19 wt%) and Ca/P molar ratio was 2.43. After 28d in HBSS a coating of calcium phosphate deposits covered the dentin surface so tubules were not visible; EDX detected N (6-7 wt%) and showed a Ca/P molar ratio of 2.14. Conclusion: Elmex sensitive professional paste can obturate the dentinal tubules and adhere to the dentin surface. Evidences of mineralizing properties have been found by the deposition of calcium and phosphate-containing minerals within the dentinal tubules and the formation of a calcium phosphate protective layer on the dentin surface

Arginine-Based Toothpaste Induces Calcium-Phosphates Deposits on Dentin Surface and Tubules

Objective: To test the ability of a calcium carbonate-containing toothpaste for dentinal hypersensitivity to occlude the exposed open tubules of dentin surface. Method: Dentine slices (0.9±0.1 thick) and crown segments (1.5±0.3 cm thick) from human third molars were used. Elmex Sensitive Professional toothpaste (GABA Int AG, Therwill, Switzerland) containing as main active ingredients arginine (8%), sodium monofluorophosphate (1450 ppm Fˉ) and calcium carbonate, was applied (3 min) on coronal dentin surface. Fluid flow/permeation through the dentin thickness (i.e. permeability or hydraulic conductance, Lp in microliters/min) was evaluated using a digital fluid flow-meter after smear layer formation, after EDTA treatment, after Elmex toothpaste treatment (t=0) and after soaking for 1, 7, 28 days in simulated body fluid (HBSS). Tubules occlusion, elemental analysis and mineral content were studied by ESEM-EDX. Toothpaste penetration inside dentinal tubules was analyzed by laser confocal microscopy using calcein as tracer. Result: Lp of EDTA-treated dentin significantly decreased after treatment with Elmex toothpaste (-73,32% at t=0) and after soaking in HBSS the Lp values further decreased (-77,69% at 24h, -78,18% at 7d, -83,01% at 28d). After 24h and 7d in HBSS, ESEM on Elmex-treated dentin showed the presence of precipitates on dentin surface and in the dentinal tubules; EDX revealed N (from arginine) and F (from monofluorophosphate) of the toothpaste. Lp remained significantly lower (-78,18%) than EDTA- treated control dentin. After 28d in HBSS, a calcium phosphate layer was detected on dentin surface so tubules were not visible. EDX detected F and no N. No CaP deposits were found on EDTA-treated dentin soaked in HBSS. Confocal microscopy showed an average penetration depth of the toothpaste into the dentinal tubules of ~85 microns. Conclusion: Elmex sensitive toothpaste can reduce the fluid movement into the exposed dentinal tubules and favour the formation of calcium phosphate minerals

Oxidative Stress Markers to Investigate the Effects of Hyperoxia in Anesthesia

Oxygen (O-2) is commonly used in clinical practice to prevent or treat hypoxia, but if used in excess (hyperoxia), it may act as toxic. O-2 toxicity arises from the enhanced formation of Reactive Oxygen Species (ROS) that exceed the antioxidant defenses and generate oxidative stress. In this study, we aimed at assessing whether an elevated fraction of inspired oxygen (FiO(2)) during and after general anesthesia may contribute to the unbalancing of the pro-oxidant/antioxidant equilibrium. We measured five oxidative stress biomarkers in blood samples from patients undergoing elective abdominal surgery, randomly assigned to FiO(2) = 0.40 vs. 0.80: hydroperoxides, antioxidants, nitrates and nitrites (NOx), malondialdehyde (MDA), and glutathionyl hemoglobin (HbSSG). The MDA concentration was significantly higher 24 h after surgery, and the body antioxidant defense lower, in the FiO(2) = 0.80 group with respect to both the FiO(2) = 0.40 group and the baseline values (p <= 0.05, Student's t-test). HbSSG in red blood cells was also higher in the FiO(2) = 0.80 group at the end of the surgery. NOx was higher in the FiO(2) = 0.80 group than the FiO(2) = 0.40 group at t = 2 h after surgery. MDA, the main end product of the peroxidation of polyunsaturated fatty acids directly influenced by FiO(2), may represent the best marker to assess the pro-oxidant/antioxidant equilibrium after surgery