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Deep tissue abscesses represent a significant source of morbidity and hospital stay, with standard of care drainage failing in many cases. We investigated photodynamic therapy (PDT) as an adjunct to standard of care, to reduce or eliminate bacterial burden. A Phase 1 clinical trial was performed to evaluate safety and feasibility of methylene blue (MB) PDT at the time of abscess drainage. Immediately following drainage, MB-PDT was performed. Diffuse reflectance spectroscopy was performed to evaluate abscess wall optical properties. No study-related adverse events were noted, and no side effects were observed. PDT was well tolerated by all subjects, and infused MB was recovered in all cases. Optical property measurements showed variability in hemoglobin concentration and oxygenation, as well as MB uptake, between subjects. MB-PDT at the time of percutaneous abscess drainage was safe and feasible, and optical property measurements showed wide variance between subjects. [ABSTRACT FROM AUTHOR]

The archaeological applications of optimization theory that were applied to resource use are reviewed. A study that modeled agricultural productivity among the 18th-early 19th century Muscogee Creek Indians showed that the residents of Cussetuh were risk minimizers and were not maximizing long-term average rate of corn yield in their gardens.

Purpose: To investigate whether accessory vein embolization (AVE) improves long-term performance of salvaged nonmaturing arteriovenous fistulae (AVFs).Materials and Methods: This retrospective review included 72 patients who underwent percutaneous balloon angioplasty for salvage of nonmaturing AVFs between 2008 and 2014. AVE was performed on 32 patients between 2008 and 2011 (mean age, 59 y [range, 33-85 y]; men, n = 21; women, n = 11; upper arm, n = 17; forearm, n = 15), whereas the procedure was not performed on 40 patients after 2011 (mean age, 62 y [range, 28-85 y]; men, n = 26; women, n = 14; upper arm, n = 26; forearm, n = 14). Endpoints compared between groups included number of procedures required to achieve maturation, time to maturation, number of procedures required to maintain patency, and duration of primary and secondary patency after intervention.Results: There was no statistically significant difference in number of procedures to achieve maturation (2.1 ± 1.4 vs 2.4 ± 1.2; P = .24) or time to maturation (26.1 d ± 56.2 vs 41.1 d ± 54.6; P = .072) between AVE and no embolization groups. Primary (P = .21) and secondary patency (P = .14) after intervention were not significantly different between groups. The number of procedures performed to maintain patency after maturation was significantly greater in the AVE group for patients with forearm AVFs (0.11 ± 0.098 vs 0.04 ± 0.064 per patient year; P = .039) but not for patients with upper arm AVFs.Conclusions: AVE of AVFs after balloon angioplasty does not lead to significantly improved long-term outcomes. Percutaneous salvage of nonmaturing AVFs in the forearm without AVE resulted in a decreased number of interventions to maintain patency. [ABSTRACT FROM AUTHOR]

We present an in vivo fluorescence microscopic evaluation of intratumor distribution of the photosensitizer mono-L-aspartylchlorin-e6 (NPe6) in an intradermal mouse EMT6 tumor model. Although the identification of favorable photophysical and pharmacological properties has led to the development of new photosensitizers in photodynamic therapy, their intratumor distribution kinetics have remained relatively understudied. In this study, we used confocal fluorescence microscopy to follow the transport of NPe6 in vivo after systemic administration through the tail vein. Labeling of vasculature using fluorophore-conjugated anti-CD31 antibodies allows visualization of the uptake of NPe6 in tumor and normal vessels and its partitioning kinetics into the adjacent parenchyma for 3 hours after injection. During the initial 60 minutes after injection, the drug is predominantly confined to the vasculature. Subsequently, it significantly redistributes throughout the extravascular regions with no discernable difference in its extravasation rate between tumor and normal tissues. Further, we investigate the sensitizer's altered intratumor distribution in response to photodynamic therapy irradiation and observe that treatment-induced changes in vessel permeability caused enhanced accumulation of NPe6 in the extravascular space. Our findings are of immediate clinical relevance and demonstrate the importance of an in vivo imaging approach to examine the dynamic process of intratumor drug distribution. [ABSTRACT FROM AUTHOR]

Abstract: Patients who receive a left ventricular assist device (LVAD) are prone to develop end-stage renal disease. Primary arteriovenous fistula (AVF) maturation in these patients may be unsuccessful secondary to the nonpulsatile flow with an LVAD. Two patients with LVADs are described in whom assisted maturation aided long-term AVF patency. [Copyright &y& Elsevier]

Genetically-encoded photosensitizers produce reactive oxygen species (ROS) in response to light. Transgenic expression of fusion proteins can target the photosensitizers to specific cell regions and permit the spatial and temporal control of ROS production. These ROS-generating proteins (RGPs) are widely used for cell ablation, mutagenesis and chromophore-assisted light inactivation of target proteins. However, the species produced by RGPs are unclear due to indirect measures with confounding interpretations. Recently, the RGP mini “Singlet Oxygen Generator” (miniSOG) was engineered from Arabidopsis thaliana phototropin 2. While miniSOG produces singlet oxygen ( 1 O 2 ), the contribution of superoxide (O 2 • - ) to miniSOG-generated ROS remains unclear. We measured the light-dependent O 2 • - production of purified miniSOG using HPLC separation of dihydroethidium (DHE) oxidation products. We demonstrate that DHE is insensitive to 1 O 2 and establish that DHE is a suitable indicator to measure O 2 • - production in a system that produces both 1 O 2 and O 2 • - . We report that miniSOG produces both 1 O 2 and O 2 • - , as can its free chromophore, flavin mononucleotide. miniSOG produced O 2 • - at a rate of ~4.0 µmol O 2 • - /min/µmol photosensitizer for an excitation fluence rate of 5.9 mW/mm 2 at 470 ± 20 nm, and the rate remained consistent across fluences (light doses). Overall, the contribution of O 2 • - to miniSOG phenotypes should be considered. [ABSTRACT FROM AUTHOR]

Fluorescent proteins can generate reactive oxygen species (ROS) upon absorption of photons via type I and II photosensitization mechanisms. The red fluorescent proteins KillerRed and SuperNova are phototoxic proteins engineered to generate ROS and are used in a variety of biological applications. However, their relative quantum yields and rates of ROS production are unclear, which has limited the interpretation of their effects when used in biological systems. We cloned and purified KillerRed, SuperNova, and mCherry - a related red fluorescent protein not typically considered a photosensitizer - and measured the superoxide (O 2 •-) and singlet oxygen (1O 2) quantum yields with irradiation at 561 nm. The formation of the O 2 •--specific product 2-hydroxyethidium (2-OHE+) was quantified via HPLC separation with fluorescence detection. Relative to a reference photosensitizer, Rose Bengal, the O 2 •- quantum yield (ΦO 2 •-) of SuperNova was determined to be 1.5 × 10-3, KillerRed was 0.97 × 10-3, and mCherry 1.2 × 10-3. At an excitation fluence of 916.5 J/cm2 and matched absorption at 561 nm, SuperNova, KillerRed and mCherry made 3.81, 2.38 and 1.65 μM O 2 •-/min, respectively. Using the probe Singlet Oxygen Sensor Green (SOSG), we ascertained the 1O 2 quantum yield (Φ1O 2) for SuperNova to be 22.0 × 10-3, KillerRed 7.6 × 10-3, and mCherry 5.7 × 10-3. These photosensitization characteristics of SuperNova, KillerRed and mCherry improve our understanding of fluorescent proteins and are pertinent for refining their use as tools to advance our knowledge of redox biology. Image 1 • We report O 2 •- and 1O 2 quantum yields for KillerRed, SuperNova and mCherry. • O 2 •- generation was measured using HPLC separation of 2-OHE+ and 1O 2 with SOSG. • Supernova's O 2 •- and 1O 2 yields are larger than those of KillerRed and mCherry. • O 2 •- quantum yield of mCherry is comparable to those of KillerRed and SuperNova. [ABSTRACT FROM AUTHOR]

Abstract Oxidants play an important role in the cell and are involved in many redox processes. Oxidant concentrations are maintained through coordinated production and removal systems. The dysregulation of oxidant homeostasis is a hallmark of many disease pathologies. The local oxidant microdomain is crucial for the initiation of many redox signaling events; however, methods to control oxidant product are limited. Some fluorescent proteins, including GFP, TagRFP, KillerRed, miniSOG, and their derivatives, generate oxidants in response to light. These genetically-encoded photosensitizers produce singlet oxygen and superoxide upon illumination and offer spatial and temporal control over oxidant production. In this review, we will examine the photosensitization properties of fluorescent proteins and their application to redox biology. Emerging concepts of selective oxidant species production via photosensitization and the impact of light on biological systems are discussed. Graphical abstract fx1 Highlights • Some fluorescent proteins generate large quantities of oxidants upon illumination. • Genetically-encoded photosensitizers produce singlet oxygen and superoxide. • The contribution of each oxidant species for an application is often overlooked. • Advancements and limitations to these tools are highlighted. [ABSTRACT FROM AUTHOR]

Purpose: The present study investigates the efficacy of compartmental targeting in xenografted tumors treated by meta-tetra(hydroxyphenyl)chlorin (mTHPC)-mediated photodynamic therapy (PDT). The therapeutic efficacy was, furthermore, related to a regional photoinduced distribution of apoptosis and an mTHPC biodistribution profile.Methods and Materials: Mice bearing EMT6 tumors were subjected to a single irradiation (10 J/cm(2)) of red laser light (652 nm) at different intervals after a single- (0.3 mg/kg or 0.15 mg/kg) or double-intravenous (2 × 0.15 mg/kg) injection(s) of mTHPC. Efficiency of the treatment was evaluated by monitoring tumor regrowth. mTHPC pharmacokinetics were assessed by high-performance liquid chromatography analysis of excised organs. The regional distribution of apoptosis in tumor sections was investigated with a newly developed colabelling immunohistochemistry technique.Results: A fractionated double-injection protocol of mTHPC with 24-h and 3-h drug-light intervals (DLI) yielded 100% tumor cure, with tumors presenting a massive apoptosis of neoplastic cells along with a distortion of vessels. The best efficiency for a single injection (0.3 mg/kg) was about 54% tumor cure and corresponded to a DLI of 3 h. At this DLI, tumors showed apoptosis of endothelial cells in residual vessels. Concentrations of mTHPC observed in plasma and tumor for the fractionated injection were not statistically different and were less than the total drug dose in each compartment.Conclusions: The present work suggests that clinical PDT protocols with mTHPC could be greatly improved by fractionation of the drug administration. Time points should be chosen based on the intratumoral spatiotemporal drug distribution. [ABSTRACT FROM AUTHOR]