The radiosensitizing effect of platinum nanoparticles in proton irradiations is not caused by an enhanced proton energy deposition at the macroscopic scale.

Objective.Due to the radiosensitizing effect of biocompatible noble metal nanoparticles (NPs), their administration is considered to potentially increase tumor control in radiotherapy. The underlying physical, chemical and biological mechanisms of the NPs' radiosensitivity especially when interacting with proton radiation is not conclusive. In the following work, the energy deposition of protons in matter containing platinum nanoparticles (PtNPs) is experimentally investigated.Approach.Surfactant-free monomodal PtNPs with a mean diameter of (40 ± 10) nm and a concentration of 300 µg ml-1, demonstrably leading to a substantial production of reactive oxygen species (ROS), were homogeneously dispersed into cubic gelatin samples serving as tissue-like phantoms. Gelatin samples without PtNPs were used as control. The samples' dimensions and contrast of the PtNPs were verified in a clinical computed tomography scanner. Fields from a clinical proton machine were used for depth dose and stopping power measurements downstream of both samples types. These experiments were performed with a variety of detectors at a pencil beam scanning beam line as well as a passive beam line with proton energies from about 56-200 MeV.Main results.The samples' water equivalent ratios in terms of proton stopping as well as the mean proton energy deposition downstream of the samples with ROS-producing PtNPs compared to the samples without PtNPs showed no differences within the experimental uncertainties of about 2%.Significance.This study serves as experimental proof that the radiosensitizing effect of biocompatible PtNPs is not due to a macroscopically increased proton energy deposition, but is more likely caused by a catalytic effect of the PtNPs. Thus, these experiments provide a contribution to the highly discussed radiobiological question of the proton therapy efficiency with noble metal NPs and facilitate initial evidence that the dose calculation in treatment planning is straightforward and not affected by the presence of sensitizing PtNPs.

The projected costs and benefits of a supervised injection facility in Seattle, WA, USA.

BACKGROUND: As one strategy to improve the health and survival of people who inject drugs, the King County Heroin & Opioid Addiction Task Force recommended the establishment of supervised injection facilities (SIF) where people can inject drugs in a safe and hygienic environment with clinical supervision. Analyses for other sites have found them to be cost-effective, but it is not clear whether these findings are transferable to other settings. METHODS: We utilized local estimates and other data sources deemed appropriate for our setting to implement a mathematical model that assesses the impact of a hypothetical SIF on overdose deaths, non-fatal overdose health service utilization, skin and soft tissue infections, bacterial infections, viral infections, and enrollment in medication assisted treatment (MAT). We estimated the costs and savings that would occur on an annual basis for a small-scale pilot site given current overdose rates, as well as three other scenarios of varying scale and underlying overdose rates. RESULTS: Assuming current overdose rates, a hypothetical Seattle SIF in a pilot phase is projected to annually reverse 167 overdoses and prevent 6 overdose deaths, 45 hospitalizations, 90 emergency department visits, and 92 emergency medical service deployments. Additionally, the site would facilitate the enrollment of 41 SIF clients in medication assisted treatment programs. These health benefits correspond to a monetary value of $5,156,019. The annual estimated cost of running the SIF is $1,222,332. The corresponding cost-benefit ratio suggests that the pilot SIF would generate $4.22 for every dollar spent on SIF operational costs. The pilot SIF is projected to save the healthcare system $534,453. If Seattle experienced elevated overdose rates and Seattle SIF program were scaled up, the health benefits and financial value would be considerably greater. CONCLUSION: This analysis suggests that a SIF program in Seattle would save lives and result in considerable health benefits and cost savings.

Activation of the complement attack mechanism in the fluid phase and its control by C567-INH: lysis of normal erythrocytes initiated by zymosan, endotoxin, and immune complexes.

Addition of zymosan-serum complexes to guinea pig erythrocytes in guinea pig complement-EDTA was found to result in substantial lysis of the bystander cells in the presence of polycations such as poly-L-lysine of 178,000 daltons. Involvement of the alternative C pathway was shown, and the optimum time, temperature, and eruthrocyte and polycation concentrations were defined; a surprising efficiency was observed at low temperature and high cell concentrations. Several lines of evidence indicated that this hemolysis was mediated via the C567 complex of the C system and modulated by serum inhibitors of C567 (C567-INH): lysis was observed only with zymosan-serum complexes possessing C-consuming activity; it was not observed in C5-depleted guinea pig serum but was restored upon addition of purified C5; the addition of partially purified C567-INH insubstantially depressed hemolysis; and poly-L-lysine which is known to neutralize C567-INH in solution resulted in substantial enhancement of hemolysis. We also sought to determine whether the addition of complement activators directly to erythrocyte-serum mixtures could result in the hemolysis of bystander erythrocytes. It was found that zymosan, endotoxin, antigen-antibody complexes, and aggregated human gamma-globulin each could initiate such bystander lysis under appropriate conditions. Lysis again was favored by increased erythrocyte concentrations, low temperatures, and the presence of polycations such as poly-L-lysine, and was found to be mediated via the C system. C567-INH blocked cytolysis whereas poly-L-lysine potentiated hemolysis by neutralization of C567-INH. These experiments emphasize the propensity for C567 formation and lysis of bystander erythrocytes during C activation generally, the role of C567-INH in the control of this lysis, and the susceptibility of these interactions to modulation by highly charged macromolecules.

Studies on the inhibition of C56-initiated lysis (reactive lysis). V. The roleof C567-INH in the regulation of complement-dependent haemolysis initiated by cobravenom factor.

Activation of the alternative pathway of complement by a factor from cobra venom (CVF) can lead to lysis of unsensitized erythrocytes (E) of some species. In these studies we observed that alterations in CVF-induced lysis could be produced by manipulation of C567-INH, a naturally occurring inhibitory activity which acts on fluid phase C567 complexes. Venom lysis of sheep and guinea-pig E was markedly inhibited by serum fractions having C567-INH activity. Microgram quantities of poly-L-lysine (PLL), molecular weight 180,000, a polycation which is a functional antagonist to C567-INH in serum, potentiated CVF lysis of sheep and guinea-pig E, and permitted the lysis of human E, which are otherwise not suscepticle to CVF lysis. The potentiation of venom lysis by PLL seemed not to be due to alterations in the target cell membrane; furthermore, it in turn was reversed by substances with C567-INH activity. This suggests that the generation of fluid phase C567 complexes contributes to the CVF-induced lysis of erythrocytes of these species, and that the haemolytic potential of fluid phase C567 generated during alternative pathway activation by this means is regulated by C567-INH.

Studies on the inhibition of C56-induced lysis (reactive lysis). VI. Modulation of C56-induced lysis polyanions and polycations.

Multiple polyanions and polycations were tested for their ability to influence formation of EC567 from C56, C7, and sheep erythrocytes. Six of 11 polyanions tested, including polyanethol sulfonate, heparin, and dextran sulfate, inhibited this reaction. By contrast, polycations (five or seven tested), including polybrene, protamine, and polyornithine, potentiated formation of EC567. The inhibition was similar to that previously described for anionic serum factors termed C567-INH, while the potentiation seemed to involve neutralization of serum C567-INH. Thus, this step of the complement attack mechanisms seems amenable to modulation by certain polyelectrolytes, and may thereby be susceptible to pharmacologic manipulation.

Studies of the inhibition of C56-initiated lysis (reactive lysis). IV. Antagonism of the inhibitory activity c567-INH by poly-L-lysine.

The stable intermediate complex C56 can initiate the lysis (reactive lysis) of unsensitized erythrocytes (E) by the membrane attack machanism of complement. Certain serum constituents designated C567-INH inhibit reactive lysis by preventing the C567 complex, once formed, from attaching to a membrane surface. It is shown here that microgram quantities of poly-L-lysine (PLL), a synthetic polycation of molecular weight 180,000, can reverse the effests of C567-INH, and thereby potentiate formation of EC567 by erythrocytes, C56 and C7 in whole serum. Erythrocytes exposed to PLL in a preincubation step did not show either increased susceptibility to C567 or resistance to C567-INH, and reversal of C567-IHN by given amounts of PLL was not diminished as cell concentrations were greatly increased, indicating that the effect of PLL was predominantly directed against fluid phase rather than against erythrocyte membrane substrates. The effects of PLL and C567-INH were quantitatively reciprocal. Thus, PLL-induced potentiation of C56-induced lysis is a solute effect which seems to involve direct neutralization of naturally occurring serum inhibitors of the C567 trimolecular complex of complement. The use of PLL thus provides a suitable antagonist for C567-INH in reaction mixtures, and allows evaluation of the role of C567 and C567-INH in a variety of situations involving C-mediated lysis.