VEGF188 promotes corneal reinnervation after injury

Vascular endothelial growth factor A (VEGF) induces angiogenesis and vascular hyperpermeability in ocular tissues and is therefore a key therapeutic target for eye conditions in which these processes are dysregulated. In contrast, the therapeutic potential of VEGF's neurotrophic roles in the eye has remained unexploited. In particular, it is not known whether modulating levels of any of the 3 major alternatively spliced VEGF isoforms might provide a therapeutic approach to promote neural health in the eye without inducing vascular pathology. Here, we have used a variety of mouse models to demonstrate differences in overall VEGF levels and VEGF isoform ratios across tissues in the healthy eye. We further show that VEGF isoform expression was differentially regulated in retinal versus corneal disease models. Among the 3 major isoforms - termed VEGF120, VEGF164, and VEGF188 - VEGF188 was upregulated to the greatest extent in injured cornea, where it was both necessary and sufficient for corneal nerve regeneration. Moreover, topical VEGF188 application further promoted corneal nerve regeneration without inducing pathological neovascularization. VEGF isoform modulation should therefore be explored further for its potential in promoting neural health in the eye

Techniques of ozone monitoring in a mountain forest region: passive and continuous sampling, vertical and canopy profiles

Ozone is the most harmful air pollutant for plant ecosystems in the Mediterranean and Alpine areas due to its biological and economic damage to crops and forests. In order to evaluate the relation between ozone exposure and vegetation injury under on-field conditions, suitable ozone monitoring techniques were investigated. In the framework of a 5-year research project aimed at ozone risk assessment on forests, both continuous analysers and passive samplers were employed during the summer seasons (1994-1998) in different sites of a wide mountain region (80 x 40 km2) on the southern slope of the European Alps. Continuous analysers allowed the recording of ozone hourly concentration means necessary both to calculate specific exposure indexes (such as AOT, SUM, W126) and to record daily time-courses. Passive samplers, even though supplied only weekly mean concentration values, made it possible to estimate the altitude concentration gradient useful to correct the altitude dependence of ozone concentrations to be inserted into exposure indexes. In-canopy ozone profiles were also determined by placing passive samplers at different heights inside the forest canopy. Vertical ozone soundings by means of tethered balloons (kytoons) allowed the measurement of the vertical concentration gradient above the forest canopy. They also revealed ozone reservoirs aloft and were useful to explain the ozone advection dynamic in mountain slopes where ground measurement proved to be inadequate. An intercomparison between passive (PASSAM, CH) and continuous measurements highlighted the necessity to accurately standardize all the exposure operations, particularly the pre- and postexposure conservation at cold temperature to avoid dye (DPE) activity. Advantages and disadvantages from each mentioned technique are discussed

Farmaci orfani e malattie rare: un confronto internazionale delle normative di riferimento

Orphan drugs are defined as medicines with low economic returns, so that their production is not a profitable business far pharmaceutical companies. The present study analyses the main characteristics and the role of orphan drugs in four countries (United States of America, .Japan, Australia and European Union), by considering the regulation and the market situation of each State. All countries have introduced a specific legislation on orphan drugs to stimulate the research activity of pharmaceutical industry. The first law was the Orphan Drug Act of the United States of America in 1982. A common limit of all regulations is the strict correlation between “orphan drugs” and “rare diseases”. In fact, the term “orphan” does not refer only to rare disease, but also to other elements that can determine low economic returns for the industry (e.g. drugs with high cost of research and development, drugs that cannot be patented)

Population pharmacokinetics of lopinavir and ritonavir in combination with rifampicin-based antitubercular treatment in HIV-infected children

Children with HIV associated tuberculosis often require co-formulated lopinavir/ritonavir (LPV/RTV)-based antiretroviral treatment with rifampicin-based antitubercular treatment (ATT). Rifampicin (RIF), a potent inducer of drug-metabolizing systems, profoundly reduces the bioavailability of LPV. The aims of this study were to develop an integrated population pharmacokinetic (PK) model describing LPV and RTV PK in children with and without concomitant ATT using two different dosing approaches and to estimate doses of LPV/RTV achieving target exposures during ATT in young children

Manufacturing of PAV-ONE, a Permeator against Vacuum Mock-Up with Niobium Membrane

The Permeator Against Vacuum (PAV) is one of the proposed technologies for the Tritium Extraction System of the WCLL BB (Water-Cooled Lithium-Lead Breeding Blanket) of the EU DEMO reactor. In this paper, the manufacturing of the first PAV mock-up with a niobium membrane with a cylindrical configuration is presented. This work aimed to demonstrate the possibility of manufacturing a relevant-size PAV to be later tested in the TRIEX-II facility. The adopted prototypical solutions are described in detail, starting with the methodology developed to join the Nb tubes with a 10CrMo9-10 (A182 F22) plate. Dedicated manufacturing and welding procedures, based on vacuum brazing with a nickel-based brazing alloy, were developed to solve the problem. This new kind of brazing was first analyzed to check the morphology of the joint and then tested to check its capability to withstand the TRIEX-II operative conditions. In parallel, the compatibility with a lithium-lead environment was analyzed by exposing samples of niobium and 10CrMo9-10 (A335 P22) to a flow of the eutectic alloy at 500 °C up to 4000 h. Finally, the PAV mock-up was installed in the TRIEX-II facility

Le valutazioni economiche in Italia: una revisione sistematica della letteratura esistente

Aim of this paper is to provide some systematic information about Economic Evaluation studies published on national and international journals by Italian authors. All studies are in Italian or English language and published between 1994 and 2000. The main source is the CESAV database, according to these keywords: “Economic Evaluation”, “Cost-Benefit Analysis”, “Cost-Efficacy Analysis”, “Cost-Utility Analysis”, Cost of Illness” and “Italy”. The study investigated the following variables: methods of analysis, illness, kind of therapy, source of data on efficacy, modelling, source of data on health resources, source of data on unit cost, type of costs, sensitivity analysis. A comparison with the main international reviews (“The U .K. NHS Economic Evaluation Database” and “The Health Economic Evaluation Database”) showed that the approach to the Economic Evaluation in Italy is consistent to the European model, even though the number of studies is still less than in other States

Linezolid population pharmacokinetic model in plasma and cerebrospinal fluid among patients with tuberculosis meningitis

BACKGROUND: Linezolid is evaluated in novel treatment regimens for tuberculous meningitis (TBM). Linezolid pharmacokinetics have not been characterized in this population, particularly in cerebrospinal fluid (CSF) where exposures may be affected by changes in protein concentration. Linezolid co-administration with high-dose rifampicin, has also not been studied. We aimed to characterize linezolid plasma and CSF pharmacokinetics in adults with TBM. METHODS: In LASER-TBM pharmacokinetic-substudy, the intervention groups received high-dose rifampicin (35mg/kg) plus linezolid 1200mg/day for 28days, then reduced to 600mg/day. Plasma sampling was done on day 3 (intensive) and on day 28 (sparse). A lumbar CSF sample was obtained on both visits. RESULTS: 30-participants, median(min-max) age and weight of 40(27-56)years and 58(30-96)kg, contributed 247 plasma and 28 CSF observations. Plasma pharmacokinetics was described by one-compartment model with first-order absorption and saturable elimination. Maximal clearance was 7.25L/h, and Km was 27.2mg/L. Rifampicin co-treatment duration did not affect linezolid pharmacokinetics. CSF-Plasma partitioning correlated with CSF total-protein upto 1.2g/L where the partition-coefficient reached maximal value of 37%. Plasma-CSF equilibration half-life was ∼3.5hours. CONCLUSION: Linezolid was readily detected in CSF despite high-dose rifampicin co-administration. These findings support continued clinical evaluation of linezolid plus high-dose rifampicin for the treatment of TBM in adults

Effect of powder recycling in laser-based powder bed fusion of Ti-6Al-4V

Additive manufacturing (AM) has shown promise to process parts for end-use applications, however stringent requirements must be fulfilled in terms of reliability and predictability. The expensiveness of raw materials for AM, especially for metal-based Powder Bed Fusion (PBF), brings about the need for a careful recycling of powder, but the effect of powder reuse on both processing conditions and final part performance is still the focus of intensive research in the open literature. Although ASTM F2924-14 specifies the virgin-to-used powder ratio to be introduced to manufacture titanium-6aluminum-4vanadium (Ti-6Al-4V) components by PBF, a deeper understanding of the effect of powder recycling on the mechanical properties of finished parts is expected to foster a more efficient and safe reuse. The present contribution is therefore addressed to investigate the consequence of Ti- 6Al-4V powder recycling on the flowability, particle size distribution and morphology of the feedstock material as well as on the density and tensile performance of built parts. In order to quantify the recyclability of powders, a new "average usage time" (AUT) parameter is defined to account for both the real usage time of the powder and the virgin-to-used powder mixing ratio. The new parameter, whose applicability can be readily extended to any kind of feedstock powder, offers a significant contribution to achieve a more consistent and economical recycling of raw materials for PBF processing

Exploring the dusty Universe

Dust is an ubiquitous inhabitant of the interstellar medium, and leaves an unmistakable signature in its optical properties, and physico-chemical evolution. Although there is little direct knowledge of the true nature of interstellar dust grains, strong evidences point toward the possibility that such grains are composites of many small monomers (mainly made of silicates and carbonaceous materials). We consider two different models of fluffy dust aggregates, occurring as result of ballistic particle-cluster and cluster-cluster aggregation, and a cluster with a Gaussian-like sphere size distribution. We study the optical properties of such composite structures through the multipole fields and the Transition Matrix approach. Our results show the severe limits of applicability of the effective medium theories. By comparing radiation and gravitational forces, we also infer some relevant insights into the dynamical evolution of composite grains in the Solar System. We finally explore the possible role of composite fluffy dust grains in igniting an extraterrestrial prebiotic chemistry

A comparison of the population pharmacokinetics of rifampicin, isoniazid and pyrazinamide between hospitalized and non-hospitalized tuberculosis patients with or without HIV

Background. Early mortality among hospitalized HIV-associated tuberculosis (TB/HIV) patients is high despite treatment. The pharmacokinetics of rifampicin, isoniazid, and pyrazinamide were investigated in hospitalized TB/HIV patients and a cohort of outpatients with TB (with or without HIV) to determine whether drug exposures differed between groups. Methods. Standard first-line TB treatment was given daily as per national guidelines, which consisted of oral 4-drug fixed-dose combination tablets containing 150 mg rifampicin, 75 mg isoniazid, 400 mg pyrazinamide, and 275 mg ethambutol. Plasma samples were drawn on the 3rd day of treatment over eight hours post-dose. Rifampicin, isoniazid, and pyrazinamide in plasma were quantified and NONMEM® was used to analyze the data. Results. Data from 60 hospitalized patients (11 of whom died within 12 weeks of starting treatment) and 48 outpatients were available. Median (range) weight and age were 56 (35 - 88) kg, and 37 (19 - 77) years, respectively. Bioavailability and clearance of the three drugs were similar between TB/HIV hospitalized and TB outpatients. However, rifampicin’s absorption was slower in hospitalized patients than in outpatients; mean absorption time was 49.9% and 154% more in hospitalized survivors and hospitalized deaths, respectively, than in outpatients. Higher levels of conjugated bilirubin correlated with lower rifampicin clearance. Isoniazid’s clearance estimates were 25.5 L/h for fast metabolizers and 9.76 L/h for slow metabolizers. Pyrazinamide’s clearance was more variable among hospitalized patients. The variability in clearance among patients was 1.70 and 3.56 times more for hospitalized survivors and hospitalized deaths, respectively, than outpatients. Conclusion. We showed that the pharmacokinetics of first-line TB drugs are not substantially different between hospitalized TB/HIV patients and TB (with or without HIV) outpatients. Hospitalized patients do not seem to be underexposed compared to their outpatient counterparts