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Decompression illness (DCI) is a complex clinical syndrome caused by supersaturation of respiratory gases in blood and tissues after abrupt reduction in ambient pressure. The resulting formation of gas bubbles combined with pulmonary barotrauma leads to venous and arterial gas embolism. Severity of DCI depends on the degree of direct tissue damage caused by growing bubbles or indirect cell injury by impaired oxygen transport, coagulopathy, endothelial dysfunction, and subsequent inflammatory processes. The standard therapy of DCI requires expensive and not ubiquitously accessible hyperbaric chambers, so there is an ongoing search for alternatives. In theory, perfluorocarbons (PFC) are ideal non-recompressive therapeutics, characterized by high solubility of gases. A dual mechanism allows capturing of excess nitrogen and delivery of additional oxygen. Since the 1980s, numerous animal studies have proven significant benefits concerning survival and reduction in DCI symptoms by intravenous application of emulsion-based PFC preparations. However, limited shelf-life, extended organ retention and severe side effects have prevented approval for human usage by regulatory authorities. These negative characteristics are mainly due to emulsifiers, which provide compatibility of PFC to the aqueous medium blood. The encapsulation of PFC with amphiphilic biopolymers, such as albumin, offers a new option to achieve the required biocompatibility avoiding toxic emulsifiers. Recent studies with PFC nanocapsules, which can also be used as artificial oxygen carriers, show promising results. This review summarizes the current state of research concerning DCI pathology and the therapeutic use of PFC including the new generation of non-emulsified formulations based on nanocapsules.

Purpose: Perfluorinated chemicals are widespread pollutants persistent in the environment with links to some major health issues. The two main compounds, perfluoro-octanoic acid (PFOA) and perfluoro-alkyl sulphonate (PFOS), were recently classified as carcinogenetic and thus their use has been restricted. Short-chain PFCs were recently developed as an alternative, but no data regarding the possible endocrine toxicities of these compounds are available. Aim of this study was to investigate whether short-chain PFCs could jeopardize thyroid cell viability and/or interfere with the functional effect TSH., Methods: Fisher rat thyroid line-5 (FRTL-5) was treated with increasing concentrations of PFOA, PFOS, perfluorobutanesulfonic acid (PFBS), perfluorobutanoic acid (PFBA), pentafluoropropionic anhydride (PFPA), perfluoropentanoic acid (PFPeA) to evaluate modifications in cell viability and TSH-stimulated cAMP production., Results: Neither long nor short-chain PFCs affected cell viability (apart from PFOS 100 µM), or interfered with cAMP production., Conclusions: The results of the present study demonstrate for the first time that short-chain PFCs have no acute cytotoxic effect on thyroid cells in vitro and that cAMP production is not modulated by any of the tested PFCs.

Purpose: The purpose of the present paper is to describe a surgical technique aimed at creating multiple layers of Internal Limiting Membrane (ILM) using Perfluorocarbon Liquid (PFCL) in order to favour the closure of large, chronic and myopic Macular Holes (MH)., Methods: Thirty patients belonging to 3 subgroups: large (> 500 μm), chronic (> 12 months) and myopic (> - 9 diopters), MHs, underwent surgery and completed 6 months follow-up. The ILM was engaged and peeled 360° around the MH, hinged to the rim and folded over the hole. A PFCL bubble spanning the vascular arcades was then injected and the ILM is grasped repeatedly to fold the distal edge towards the MH centre, creating multiple ILM layers over the MH., Results: MH closed in 26/30 cases (86.6%) with no significant difference among subgroups. Vision improved 2.57 ± 1.56 Snellen lines from LogMAR 1.50 ± 1.19 to 1.19 ± 1.32 (p < 0.01). Ellipsoid Zone (EZ) interruption width reduced from 1129 ± 439 μm to 258 ± 507 μm (p < 0.001) and correlated to pattern of MH closure, post-BCVA and line improvement (p < 0.001 in all cases)., Discussion: The use PFCL allows multiple ILM layers and resulted in a high closure rate. Pattern of MH closure differs from those previously described leaving a plug of ILM tissue that interrupts retinal architecture often only in the inner layers. PFCL gravity and hydrophobicity displace aqueous while the intensely polar opposite faces of the ILM attract each other. The folded ILM plugs MH and bridges the gap and may help glial cell proliferation and migration.

The purpose of this work is to investigate whether imaging sequences of flash-replenishment contrast enhanced ultrasound (CEUS) of the kidney result in chronic or acute bioeffects. Kidneys of female Fischer 344 rats were imaged using the flash-replenishment technique. Animals were separated into four groups (N = 31). Imaging was conducted with a 4C1 probe, driven by an Acuson Sequoia system with Definity microbubbles as the ultrasound contrast agent. During the flash phase of the imaging sequence, one kidney in each animal was exposed to either a mechanical index (MI) of 1.0 or 1.9. For each MI, half of the animals were sacrificed shortly after imaging (4 h) or after 2 weeks. A blinded veterinary nephropathologist reviewed the histopathology of both the imaged and control (non-imaged) kidney. Blood urea nitrogen (BUN) was measured for each animal prior to imaging and at the time of necropsy. Histopathology assessments in both the 1.0 and 1.9 MI groups revealed no signs of hemorrhage at either the 4-h or 2-week time point. BUN showed minor but statistically significant elevations in both the 1.0 and 1.9 MI groups, but no significant difference was present at the 2-week time point in the 1.0 MI group. All BUN levels (at both time points) remained in the normal range. In conclusion, CEUS with flash-replenishment imaging sequences did not result in kidney bioeffects observable with histology at early or late time points. Increases in BUN levels were observed after imaging, but were minimized when using a moderate MI (1.0)., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Methylmercury (MeHg) and perfluorooctanesulfonate (PFOS) are major contaminants of human blood that are both common in dietary fish, thereby raising questions about their combined impact on human development. Here, pregnant Sprague-Dawley rats ingested a daily dose, from gestational day 1 through to weaning, of either 1 mg/kg bw PFOS (PFOS-only), 1 mg/kg MeHg (MeHg-only), a mixture of 0.1 mg/kg PFOS and 1 mg/kg MeHg (Low-Mix), or of 1 mg/kg of PFOS and 1 mg/kg MeHg (High-Mix). Newborns were monitored for physical milestones and reflexive developmental responses, and in juveniles the spontaneous activity, anxiety, memory, and cognition were assessed. Targeted metabolomics of 199 analytes was applied to sectioned brain regions of juvenile offspring. Newborns in the High-Mix group had decreased weight gain as well as delayed reflexes and innate behavioral responses compared to controls and individual chemical groups indicating a toxicological interaction on early development. In juveniles, cumulative mixture effects increased in a dose-dependent manner in tests of anxiety-like behavior. However, other developmental test results suggested antagonism, as PFOS-only and MeHg-only juveniles had increased hyperactivity and thigmotaxic behavior, respectively, but fewer effects in Low-Mix and High-Mix groups. Consistent with these behavioral observations, a pattern of antagonism was also observed in neurochemicals measured in rat cortex, as PFOS-only and MeHg-only juveniles had altered concentrations of metabolites (e.g., lipids, amino acids, and biogenic amines), while no changes were evident in the combined exposures. The cortical metabolites altered in PFOS-only and MeHg-only exposed groups are involved in inhibitory and excitatory neurotransmission. These proof-of-principle findings at relatively high doses indicate the potential for toxicological interaction between PFOS and MeHg, with developmental-stage specific effects. Future mixture studies at lower doses are warranted, and prospective human birth cohorts should consider possible confounding effects from PFOS and mercury exposure on neurodevelopment.

The mechanism of environmental pollution promoting gastric cancer incidence and difficulty of treatment is not fully understood. In the present article, perfluorodecanoic acid (PFDA), a common persistent environmental pollutant, was used to treat the gastric cell lines and mice to test its genotoxicity. The γ-H2AX immunoblot and plasmid fragment PCR results showed that PFDA had a promotion effect on the DNA double-strand breaks (DSBs) in human and mouse cells. Subsequent results showed that PFDA significantly altered the sensitivity of cells to chemotherapy. Microarray data showed that the expressions of some important DNA repair genes were changed. Further investigation discovered that PFDA inhibition of DNA repair was mediated by X-ray repair cross complementing 4 (XRCC4). The cells deficient in XRCC4 generally exhibited reduced proliferation and premature aging in culture; however, our results indicated that PFDA induced p53 inhibition rescued cells from the apoptosis that was triggered by nonhomologous end-joining (NHEJ) inactivation, and overexpression of p53 expression in PFDA-treated cells enhanced their apoptosis. Finally, T-cell specific factor 4 was suggested by the results as an upstream regulator of XRCC4. This article revealed for the first time that perfluorinated chemicals affect chemotherapeutic sensitivity and the NHEJ pathway, and p53 reduction rescues cells from death., (© 2019 Wiley Periodicals, Inc.)

Purpose: The aim of this study was to investigate whether intraoperative 360° prophylactic endolaser photocoagulation is necessary for the treatment of uncomplicated retinal detachment., Methods: This prospective, randomized, comparative and interventional study includes 50 consecutive patients with primary rhegmatogenous retinal detachment (RRD) who were treated by pars plana vitrectomy. The patients were divided into two groups: in Group A endolaser applied to all existing breaks as well as a 360° laser retinopexy, while Group B received endolaser only to the retinal breaks. Primary anatomical success rate, a final best-corrected visual acuity (BCVA) and postoperative complications were analyzed and compared between the groups at 1 and 3 months., Results: After the primary procedure, the retina was reattached in 96% (24 of 25) of patients in Group A and in 88% (22 of 25) of patients in Group B at 1 and 3 months. The mean final BCVA (logarithm of the minimum angle of resolution) improved from 1.26 to 0.52 in Group A with 17 cases (68%) macula-off and 1.19 to 0.77 in Group B with 18 cases (72%) macula-off at preoperative and final follow-up visit. Epiretinal membranes were seen in four cases in Group A and four cases in Group B at 3 months. No statistically significant difference in the anatomical, functional and complication outcomes between the two groups was recorded., Conclusions: Pars plana vitrectomy without the 360° peripheral endolaser can provide successful anatomic outcomes and functional improvement in uncomplicated primary RRDs.

Purpose : To evaluate the effects of perfluorobutylpentane (F4H5) on corneal endothelial cell density (ECD) and morphology using a porcine corneal endothelial organ culture model. Materials and methods : "Split corneal buttons" were cultivated for 15 days (d) after incubation in F4H5 (15, 30, 60, and 120 min) or BSS (controls). ECD was assessed manually on d1, d8, and d15. After histological staining (trypan blue, alizarin red S) on d15 morphological changes (reformation figures, rosette formations, and alizarin red cells) were evaluated. Results : ECD was significantly reduced after incubation in F4H5 for 120 min (median ± 25%/75%-quartile; 3281 ± 43/222 cells/mm 2 ; p = 0.046) on d15 compared to controls (3658 ± 129/296 cells/mm 2 ), but not after shorter incubation times (15, 30, and 60 min). Morphological assessment supports these findings as reformation figures (F4H5 120 min: 10.5 ± 9.3/13.9/mm 2 vs. controls: 5.2 ± 2.8/7.2/mm 2 ; p = 0.010), rosette formations (F4H5 120 min 25.566 ± 17.044/36.219/mm 2 vs. controls: 8.333 ± 0.000/15.667/mm 2 ; p = 0.002), and alizarin red cells (F4H5 120 min: 38.350 ± 29.827/51.333/mm 2 vs. controls: 20.833 ± 10.417/25.000/mm 2 ; p = 0.049) were significantly more prevalent after incubation in F4H5 for 120 min compared to controls. Also, F4H5 60 min showed significantly more rosette formations (25.452 ± 16.968/36.057/mm 2 ; p = 0.006) and alizarin red cells (46.662 ± 42.420/50.903/mm 2 ; p = 0.007), but not reformation figures (7.0 ± 2.2/1.6 %; p = 0.953). Conclusion : Short exposure (≤30 min) of porcine corneal endothelial cells to F4H5 does not have significant effects on ECD or morphological characteristics. Longer exposure times (≥60-120 min) may cause ECD decline and/or induce morphological changes.

Background: Emulsions on the basis of Perfluorohexyloctane (F6H8), a semifluorinated alkane (SFA), have shown to dissolve and transport highly lipophilic compounds. It is unknown how F6H8-containing emulsions (F6H8-cEM) interact with compartment blood, the reticuloendothelial system (RES), or influence injured organs in vivo. The current study was conducted to investigate the in vitro biocompatibility of F6H8-cEM and their drug delivery properties. Afterward, an in vivo study was performed as a proof-of-concept study in a rat model of acute kidney injury (AKI), which focused on the potential influence of F6H8-cEM on inflammation in an injured organ., Methods: Two different F6H8-cEM were stabilized by the emulsifying agents Poloxamer 188 (Pluronic ® F68) or lecithin (S75). The two resulting emulsions F6H8-Pluronic or F6H8-lecithin were tested in vitro for the potential modulation of acute inflammation via whole blood assay, FACS, and ELISA. Antioxidant capacity and drug delivery properties were measured with an oxidation assay. Secondly, AKI was induced in the rats, which were treated with the F6H8-lecithin emulsion. Renal function and inflammation were assessed., Results: Both F6H8-cEM were phagocytized by monocytes and both dose-dependently affected apoptosis (Annexin V binding) in monocytes. TNF-α expression increased dose-dependency for F6H8-Pluronic emulsion but not for F6H8-lecithin in a whole blood assay. Both F6H8-cEM were able to carry α-tocopherol as a model drug. Animals with AKI treated with the F6H8-lecithin emulsion showed a significantly better renal function and less infiltration of inflammatory cells in renal tissue compared to the control, while inflammatory markers in renal tissue, except HO-1, were not affected by F6H8-lecithin., Conclusions: Pluronic ® F68 does not seem suitable as a biocompatible surfactant for F6H8-cEM. The injured kidney was not negatively influenced by the F6H8-lecithin emulsion. Lecithin-stabilized F6H8-cEM could be tested for preclinical studies as a carrier system for lipophilic agents., Competing Interests: Dr Tsagogiorgas and Dr Hoeger report grants and nonfinancial support from Novaliq GmbH, during the conduct of the study. The authors report no other conflicts of interest in this work.

Perfluorocarbon nanoparticles have been reported to deliver oxygen to tumors and reduce hypoxia-induced radioresistance, however few studies have been carried out to study its role in reducing hypoxia-induced chemoresistance. The oxygenation effect also varies dramatically between different perfluorocarbon formulations and protocols, and there have been no efficient tools to monitor dynamic changes of tumor oxygenation non-invasively. Our goal was to promote tumor oxygenation using perfluorooctyl bromide (PFOB) nanoemulsion and to assess its role in sensitizing tumors to cisplatin treatment. A novel optical imaging protocol was also created to monitor the dynamic changes of tumor oxygenation in real-time. Methods: PFOB nanoemulsion with high oxygen-carrying capacity was prepared and administered to tumor-bearing mice intravenously. Tumor oxygenation was monitored using optical imaging with a hypoxia probe injected intratumorally, thus the oxygenation dynamics and best oxygenation protocol were determined. Various treatment groups were studied, and the tumor growth was monitored to evaluate the role of oxygenation in sensitizing tumors to cisplatin treatment. Results: PFOB nanoemulsion with and without pre-oxygenation along with carbogen breathing resulted in much better tumor oxygenation compared to carbogen breathing alone, while PFOB with air breathing did not show significant increase in tumor oxygenation. Pre-oxygenated PFOB with carbogen breathing produced the most effective oxygenation as early as 5 min post administration. In vitro and in vivo data showed preoxygenated PFOB nanoemulsion with carbogen breathing could increase cisplatin-mediated apoptosis of cancer cells and inhibited tumor growth at a low dose of cisplatin (1 mg/kg) treatment. Furthermore, the treatment did not induce nephrotoxicity. Conclusions: Preoxygenated PFOB nanoemulsion with carbogen breathing can effectively increase tumor oxygenation, which has a great potential to prevent/overcome hypoxia-induced chemotherapy resistance. In addition, optical imaging with intratumoral injection of the hypoxia probe was an efficient tool to monitor tumor oxygenation dynamics during PFOB administration, providing better understanding on oxygenation effects under different protocols., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Artificial environmental endocrine disrupting chemicals (EDCs) exert public health concerns. Exposure to EDCs may induce various disorders in the cardiometabolic system. However, the underlying mechanisms remain largely unknown. Over the past decade, an abundance of evidence has emerged demonstrating a close link between cardiometabolic disorders and inflammation. The aim of the present study was to evaluate the immunological effects on macrophages from six EDCs via sirtuin (SIRT) regulation using the murine macrophage RAW 264.7 cell. We studied first the effects of these EDCs, including a series of doses of benzyl butyl phthalate (BBP), bisphenol A (BPA), diethylhexyl phthalate (DEHP), mono-(2-ethylhexyl)phthalate (MEHP), perfluorooctanoate (PFOA), or perfluorooctanesulfonate (PFOS), on SIRT1-7 transcriptional level. Among these EDCs, MEHP significantly decreased all sirtuin genes' expression in a dose-dependent manner. Under MEHP treatment, SIRT activity and protein expression were significantly decreased, while the protein expression of acetylated NF-κB was significantly increased along with significant increases in IL-1β transcription. These results indicate that MEHP may induce the inflammatory response via SIRT-mediated acetylation of NF-κB. Additionally, the enhanced IL-1β secretion in the presence of 50 μM MEHP ( P < 0.01) also supports inflammasome activation (significant ASC and NLRP3 protein augmentation). Both events may be regulated by MEHP induced reactive oxygen species ( P < 0.01). In conclusion, our study suggests for the first time that EDCs differentially modulate sirtuins' gene expression levels in macrophages and that a specific phthalate MEHP can lead to an increased inflammatory response by impairing vital epigenetic regulators and inflammasome activation.

Background and Objective: To assess the efficacy of perfluorodecalin (PFD) or Densiron 68 heavy silicone oil (HSO) in the management of inferior complex retinal detachment recurrence., Patients and Methods: A retrospective, comparative consecutive case series study. Twenty-four eyes of 24 patients affected by inferior complex retinal detachment recurrence underwent pars plana vitrectomy with PFD or HSO as endotamponade. All patients recruited were affected by complicated inferior retinal detachments and had already undergone at least one vitreoretinal procedure. The primary endpoint was anatomical success with primary and secondary surgery. The secondary endpoints were functional outcome and inflammatory complications., Results: Out of 24 cases of inferior retinal detachment recurrence, 12 were tamponed with PFD (PFD group) and 12 with HSO (D68 group). Retinal reattachment rate at first surgery was 50% for the D68 group and 66.6% for the PFD group. Final reattachment rate after two or more surgical operations was 91.6% for the PFD group and 83.3% for the D68 group. Best-corrected visual acuity improved in both groups from a mean of 1.00 logMAR (20/200; standard deviation [SD]: 1) to 0.60 logMAR (20/80; SD: 0.3), and from a mean of 1.81 logMAR (20/2000; SD: 1.1) to a mean of 2.00 logMAR (20/2,000; SD:1) for the PFD and D68 groups, respectively., Conclusion: Both the endotamponades used showed good results in solving inferior retinal detachment recurrence with a slightly better rate in the PFD group, but it was not statistically significant (P > .05). [Ophthalmic Surg Lasers Imaging Retina. 2019;50:274-280.]., (Copyright 2019, SLACK Incorporated.)

Background/aim: Perfluorooctanoic acid (PFOA) is one of the most common perfluorinated compounds widely used in several applications. Due to its persistence in the environment, PFOA has been associated with various diseases, including cancer. This study explored the effects of PFOA on follicular thyroid carcinoma cells (FTC133)., Materials and Methods: Cell invasion, migration, adhesion and activity of matrix metalloproteinase-2 (MMP-2) were investigated using Transwell assays, adhesion assay and gelatin zymography, respectively. The underlying mechanism involved in the effects observed was evaluated by immunoblot analyses., Results: Treatment with PFOA did not affect cell migration, but enhanced cell invasion, adhesion and activity of MMP-2 in FTC133 cells. PFOA selectively enhanced the phosphorylation of nuclear factor kappa B (NF-κB) p65, as well as induced NF-κB nuclear translocation. Treatment with a NF-κB inhibitor (BAY 11-7085) was able to reverse PFOA-induced cell invasiveness., Conclusion: PFOA promotes invasiveness of FTC133 cells mediated through the activation of NF-κB signaling., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

A theranostic nanoplatform (DTX/PFH@PPy-FA) for multi-modal imaging-guided photothermal-chemotherapy has been constructed. Lipid-perfluorohexane (PFH) nanodroplet loaded with docetaxel (DTX) was coated with a polypyrrole (PPy) shell. Then the folic acid (FA) molecule with active tumor-targeting function was modified on the surface of PPy shell. Due to the good photothermal conversion performance, PPy shell can raise the temperature under the near infrared laser irradiation, which not only produces photothermal effect to kill tumor cells, but also promotes liquid-gas phase change of PFH, and produces ultrasound imaging effect. The results of photothermal experiment and imaging experiment confirmed that the obtained DTX/PFH@PPy-FA possessed good photothermal, photoacoustic imaging and ultrasound imaging effects in vitro and in vivo. The results of in vitro cell experiments showed that DTX/PFH@PPy-FA had a active targeting ability to tumor cells, and its photothermal-chemotherapy synergistically inhibited the proliferation of tumor cells. In vivo study on 4T1-bearing BALB/c mice indicated that the photothermal-chemotherapy of DTX/PFH@PPy-FA not only effectively inhibited the growth of 4T1 breast cancer, but also inhibited lung metastasis. This multifunctional nanoparticle is expected to become a new nanoplatform for the visualized photothermal-chemotherapy of cancer. STATEMENT OF SIGNIFICANCE: In this work, we presented a multi-modal imaging-guided photothermal-chemotherapy theranostic nanoplatform (DTX/PFH@PPy-FA) for visualized treatment of breast cancer. The docetaxel (DTX) loaded perfluorohexane (PFH) nanodroplets (DTX/PFH@SPC) were firstly prepared and then coated with polypyrrole shell (PPy). Then, PEGylated folic acid was covalently modified to obtain the folate-targeted multifunctional nanoparticle (DTX/PFH@PPy-FA). Due to the good photothermal conversion performance, PPy shell can raise the temperature under the near infrared laser irradiation, which not only produces photothermal effect to kill tumor cells, but also promotes liquid-gas phase change of PFH, and produces good ultrasound imaging effect. The PPy shell also imparts photoacoustic imaging characteristics to the nanoparticles. Experimental results show that our prepared DTX/PFH@PPy-FA possesses folic acid-mediated tumor targeting ability, ultrasound and photoacoustic imaging, and photothermal-chemotherapy synergistic effect. This multi-functional nanoparticle is expected to become a new platform for the visualized photothermal-chemotherapy of breast cancer., (Copyright © 2019 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Hypoxia-based agents (HBAs), such as anaerobic bacteria and bioreductive prodrugs, require both a permeable and hypoxic intratumoural environment to be fully effective. To solve this problem, herein, we report that perfluorocarbon nanoparticles (PNPs) can be used to create a long-lasting, penetrable and hypoxic tumour microenvironment for ensuring both the delivery and activation of subsequently administered HBAs. In addition to the increased permeability and enhanced hypoxia caused by the PNPs, the PNPs can be retained to further achieve the long-term inhibition of intratumoural O 2 reperfusion while enhancing HBA accumulation for over 24 h. Therefore, perfluorocarbon materials may have great potential for reigniting clinical research on hypoxia-based drugs.

The treatment of lengthy peripheral nerve defect is challenging in the field of nerve regeneration. Our previous studies have shown that low-intensity pulsed ultrasound (LIPUS) could promote the proliferation, cell viability, and neural differentiation of induced pluripotent stem cells-derived neural crest stem cells (iPSCs-NCSCs) and improve the regeneration of damaged peripheral nerve. In this study, the mechanical signal transduction pathway of LIPUS promoting iPSCs-NCSCs proliferation and differentiation was further explored, and the effects of LIPUS combined with iPSCs-NCSCs, perfluorotributylamine (PFTBA), and growth differentiation factor 5 (GDF5) on the repair of peripheral nerve injury were evaluated. Results showed LIPUS may regulate the proliferation and differentiation of iPSCs-NCSCs through FAK-ERK1/2 signal pathway. PFTBA could supply sufficient oxygen to promote the viability of iPSCs-NCSCs under 5% hypoxia culture condition and provide a favourable microenvironment for nerve regeneration. The addition of GDF5 could promote the neural differentiation of iPSCs-NCSCs in vitro. LIPUS treatment of allogeneic decellularized nerve conduit containing iPSCs-NCSCs, PFTBA, and GDF5 has very good effect on the repair of sciatic nerve injury. Taken together, these results provide functional evidence that LIPUS might be a useful tool to explore alternative approaches in the field of nerve regeneration., (© 2019 John Wiley & Sons, Ltd.)

The ubiquitous environmental obesogens tributyltin (TBT) and perfluorooctane sulfonate (PFOS) may accumulate in parent and be transferred to their offspring, resulting in trans-generational adverse effects. In this study, we investigated the combined toxic and obesogenic effects of TBT and PFOS on the early life stages of Japanese medaka (Oryzias latipes). In ovo nanoinjection was used to simulate the maternal transfer process. Doses were controlled at 0, 0.05, 0.5, and 2.5 ng/egg (TBT) and at 0, 0.05, 0.5, and 5.0 ng/egg (PFOS), with a full factorial design for mixture formulations. Relatively high doses of agents in mixtures were needed to induce significant mortality (TBT ≥ 0.5 ng/egg) or delayed hatching (PFOS = 5.0 ng/egg) of embryos. The interaction between TBT and PFOS in mixtures had significant effects on the observed hatching delay, but not on acute mortality. Compared with controls, separate exposure to TBT (or PFOS) notably elevated adipose areas at the doses of 0.05 and 0.5 ng/egg, but not at the highest doses. Combined exposure significantly promoted the fat accumulation in newly hatched larvae, even when the doses of TBT and PFOS were both at the levels that did not show obesogenic effect. The interactive effect of TBT and PFOS could aggravate the total obesogenic effect of their mixtures, indicating a synergistic interaction. These results highlight the importance of paying close attention to interaction effects when addressing the impacts of mixtures of environmental obesogens., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Liquid perfluorocarbon (PFC) instillation has been studied experimentally as an adjuvant therapy in the preservation of lung grafts during cold ischemia. The objective of this study was to evaluate whether vaporized PFC is also protective of lung grafts at different cold ischemia times. We performed histological analysis of and measured oxidative stress in the lungs of animals that received only preservation solution with low-potassium dextran (LPD) or vaporized PFC together with LPD. We conclude that vaporized PFC reduces the production of free radicals and the number of pulmonary structural changes resulting from cold ischemia.

Here we report a vertically integrated in vitro - in silico study that aims to elucidate the molecular initiating events involved in the induction of oxidative stress (OS) by seven diverse chemicals (cumene hydroperoxide, t-butyl hydroperoxide, hydroquinone, t-butyl hydroquinone, bisphenol A, Dinoseb, and perfluorooctanoic acid). To that end, we probe the relationship between chemical properties, cell viability, glutathione (GSH) depletion, and antioxidant gene expression. Concentration-dependent effects on cell viability were assessed by MTT assay in two Hepa-1 derived mouse liver cell lines: a control plasmid vector transfected cell line (Hepa-V), and a cell line with increased glutamate-cysteine ligase (GCL) activity and GSH content (CR17). Changes to intracellular GSH content and mRNA expression levels for the Nrf2-driven antioxidant genes Gclc, Gclm, heme oxygenase-1 ( Hmox1), and NADPH quinone oxidoreductase-1 ( Nqo1) were monitored after sublethal exposure to the chemicals. In silico models of covalent and redox reactivity were used to rationalize differences in activity of quinones and peroxides. Our findings show CR17 cells were generally more resistant to chemical toxicity and showed markedly attenuated induction of OS biomarkers; however, differences in viability effects between the two cell lines were not the same for all chemicals. The results highlight the vital role of GSH in protecting against oxidative stress-inducing chemicals as well as the importance of probing molecular initiating events in order to identify chemicals with lower potential to cause oxidative stress.

Nanoscale perfluorocarbon (PFC) droplets have enormous potential as clinical theranostic agents. They are biocompatible and are currently used in vivo as contrast agents for a variety of medical imaging modalities, including ultrasound, computed tomography, photoacoustic and 19 F-magnetic resonance imaging. PFC nanodroplets can also carry molecular and nanoparticulate drugs and be activated in situ by ultrasound or light for targeted therapy. Recently, there has been renewed interest in using PFC nanodroplets for hypoxic tumor reoxygenation towards radiosensitization based on the high oxygen solubility of PFCs. Previous studies showed that tumor oxygenation using PFC agents only occurs in combination with enhanced oxygen breathing. However, recent studies suggest that PFC agents that accumulate in solid tumors can contribute to radiosensitization, presumably due to tumor reoxygenation without enhanced oxygen breathing. In this study, we quantify the impact of oxygenation due to PFC nanodroplet accumulation in tumors alone in comparison with other reoxygenation methodologies, in particular, carbogen breathing. Methods: Lipid-stabilized, PFC (i.e., perfluorooctyl bromide, CF 3 (CF 2 ) 7 Br, PFOB) nanoscale droplets were synthesized and evaluated in xenograft prostate (DU145) tumors in male mice. Biodistribution assessment of the nanodroplets was achieved using a fluorescent lipophilic indocarbocyanine dye label (i.e., DiI dye) on the lipid shell in combination with fluorescence imaging in mice (n≥3 per group). Hypoxia reduction in tumors was measured using PET imaging and a known hypoxia radiotracer, [ 18 F]FAZA (n≥ 3 per group). Results: Lipid-stabilized nanoscale PFOB emulsions (mean diameter of ~250 nm), accumulated in the xenograft prostate tumors in mice 24 hours post-injection. In vivo PET imaging with [ 18 F]FAZA showed that the accumulation of the PFOB nanodroplets in the tumor tissues alone significantly reduced tumor hypoxia, without enhanced oxygen (i.e., carbogen) breathing. This reoxygenation effect was found to be comparable with carbogen breathing alone. Conclusion: Accumulation of nanoscale PFOB agents in solid tumors alone successfully reoxygenated hypoxic tumors to levels comparable with carbogen breathing alone, an established tumor oxygenation method. This study confirms that PFC agents can be used to reoxygenate hypoxic tumors in addition to their current applications as multifunctional theranostic agents., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Introduction: The objective of this study was to investigate the cardioprotective effects of a dodecafluoropentane (DDFP)-based perfluorocarbon emulsion (DDFPe) as an artificial carrier for oxygen delivery to ischemic myocardium, using 99m Tc-duramycin SPECT imaging., Methods: Rat hearts with Ischemia-reperfusion (I/R) was prepared by coronary ligation for 45-min followed by reperfusion. The feasibility of 99m Tc-duramycin in detecting myocardial I/R injury and its kinetic profile were first verified in the ischemic hearts with 2-h reperfusion (n = 6). DDFPe (0.6 mL/kg) was intravenously administered at 10 min after coronary ligation in fifteen rats and saline was given in thirteen rats as controls. 99m Tc-duramycin SPECT images were acquired in the DDFPe-treated hearts and saline controls at 2-h (DDFPe-2 h, n = 7 and Saline-2 h, n = 6) or 24-h (DDFPe-24 h, n = 8 and Saline-24 h, n = 7) of reperfusion., Results: SPECT images, showing "hot-spot" 99m Tc-duramycin uptake in the ischemic myocardium, exhibited significantly lower radioactive retention and smaller hot-spot size in the DDFPe-2 h and DDFPe-24 h hearts compared to controls. The infarcts in the Saline-24 h hearts extended significantly relative to measurements in the Saline-2 h. The extension of infarct size did not reach a statistical difference between the DDFPe-2 h and DDFPe-24 h hearts. Ex vivo measurement of 99m Tc-duramycin activity (%ID/g) was lower in the ischemic area of DDFPe-2 h and DDFPe-24 h than that of the Saline-2 h and Saline-24 h hearts (P < 0.05). The area of injured myocardium, delineated by the uptake of 99m Tc-duramycin, extended more substantially outside the infarct zone in the controls., Conclusions: Significant reduction in myocardial I/R injury, as assessed by 99m Tc-duramycin cell death imaging and histopathological analysis, was induced by DDFPe treatment after acute myocardial ischemia. 99m Tc-duramycin imaging can reveal myocardial cell death in ischemic hearts and may provide a tool for the non-invasive assessment of cardioprotective interventions., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Donation after circulatory death (DCD) liver grafts are known to be predisposed to primary nonfunction and ischemic cholangiopathy. Many DCD grafts are discarded because of older donor age or long warm ischemia times. Thus, it is critical to improve the quality of DCD liver grafts. Here, we have tested whether an enriched oxygen carrier added to the preservation solution can prolong graft survival and reduce biliary damage., Methods: We assessed the adenosine triphosphate (ATP) content decay of mouse liver grafts after cold ischemia, warm ischemia, and combined warm+cold ischemia. In addition, we used a rat model of liver transplantation to compare survival of DCD grafts preserved in high-oxygen solution (preoxygenated perfluorocarbon [PFC] + University of Wisconsin [UW] solution) versus lower oxygen solution (preoxygenated UW solution)., Results: Adenosine triphosphate levels under UW preservation fall to less than 10% after 30 minutes of warm ischemia. Preoxygenated UW solution with PFC reached a significantly higher PaO2. After 45 minutes of warm ischemia in oxygenated UW + PFC solution, grafts showed 63% higher levels of ATP (P = 0.011). In addition, this was associated with better preservation of morphology when compared to grafts stored in standard UW solution. Animals that received DCD grafts preserved in higher oxygenation solution showed improved survival: 4 out of 6 animals survived long-term whereas all control group animals died within 24 hours., Conclusions: The additional oxygen provided by PFC during static cold preservation of DCD livers can better sustain ATP levels, and thereby reduce the severity of ischemic tissue damage. PFC-based preservation solution extends the tolerance to warm ischemia, and may reduce the rate of ischemic cholangiopathy.

Phase-change contrast agents are rapidly developing as an alternative to microbubbles for ultrasound imaging and therapy. These agents are synthesized and delivered as liquid droplets and vaporized locally to produce image contrast. They can be used like conventional microbubbles but with the added benefit of reduced size and improved stability. Droplet-based agents can be synthesized with diameters on the order of 100 nm, making them an ideal candidate for extravascular imaging or therapy. However, their synthesis requires low boiling point perfluorocarbons (PFCs) to achieve activation (i.e., vaporization) thresholds within FDA approved limits. Minimizing spontaneous vaporization while producing liquid droplets using conventional methods with low boiling point PFCs can be challenging. In this study, a new method to produce PFC nanodroplets using spontaneous nucleation is demonstrated using PFCs with boiling points ranging from -37 to 56 °C. Sometimes referred to as the ouzo method, the process relies on saturating a cosolvent with the PFC before adding a poor solvent to reduce solvent quality, forcing droplets to spontaneously nucleate. This approach can produce droplets ranging from under 100 nm to over 1 μm in diameter. Ternary plots showing solvent and PFC concentrations leading to droplet nucleation are presented. Additionally, acoustic activation thresholds and size distributions with varying PFC and solvent conditions are measured and discussed. Finally, ultrasound contrast imaging is demonstrated using ouzo droplets in an animal model.

Perfluorocarboxylic acid compounds (PFCAs) and copper have been regarded as ubiquitous environmental contaminants in aquatic ecosystems worldwide. However, data on their possible joint toxic effects on microorganisms are still lacking. To study the combined effects of four PFCAs with different carbon chain lengths and copper, a series of experiments were conducted to explore the acute toxicity of these PFCAs in the absence and presence of copper on a metal-resistant Arthrobacter strain GQ-9 by microcalorimetry. The thermokinetic parameters, including growth rate constant ( k ), inhibitory ratio ( I ), and half inhibitory concentration ( IC 50 ), were calculated and compared using the data obtained from the power-time curves. Our work revealed that GQ-9 is more resistant to perfluorooctanoic acid (PFOA) than Escherichia coli . The single and joint toxicity of PFCAs with copper are dose- and carbon chain length-dependent. The longer the carbon chain length of PFCAs, the higher the toxicity. In addition, PFCAs interacted synergistically with copper. This work could provide useful information for the risk assessment of co-exposure to perfluorinated compounds and heavy metals in natural environments.

Perfluorooctanoic acid (PFOA) is a member of the perfluoroalkyl acid family of compounds. Due to the presence of strong carbon-fluorine bonds, it is practically nonbiodegradable and highly persistent in the environment. PFOA has been detected in the follicular fluid of women, and positively associated with reduced fecundability and infertility. However, there are no reports concerning the experimental evaluation of PFOA on oocyte toxicity in mammals. The aim of the present study was to determine if PFOA is able to induce oxidative stress in fetal ovaries and cause apoptosis in oocytes in vitro. In addition, since inhibition of the gap junction intercellular communication (GJIC) by PFOA has been demonstrated in liver cells in vivo and in vitro, the effect of PFOA on the GJIC between the oocyte and its supportive cumulus cells was studied. Results show that PFOA induced oocyte apoptosis and necrosis in vitro (medium lethal concentration, LC 50 = 112.8 μM), as evaluated with Annexin-V-Alexa 508 in combination with BOBO-1 staining. Reactive oxygen species (ROS) levels, as assessed by DCFH-DA, increased significantly in fetal ovaries exposed to ¼ LC 50 (28.2 μM, a noncytotoxic and relevant occupational exposure concentration) and LC 50 PFOA ex vivo. This perfluorinated compound also caused the blockage of GJIC in cumulus cells-oocyte complexes (COCs) obtained from female mice exposed in vivo, as evaluated by calcein transfer from cumulus cells to the oocyte. The ability of PFOA of disrupting the GJIC in COCs, generating ROS in the fetal ovary and causing apoptosis and necrosis in mammal's oocytes, might account for the reported association between increasing maternal plasma concentrations of PFOA with reduced fertility in women., (© 2018 Wiley Periodicals, Inc.)

Purpose: To report the surgical results and technique of perfluorocarbon-assisted neurosensory retinal flap transplantation into macular hole for concomitant macular hole and complicated retinal detachment., Method: This is a retrospective, consecutive case series of 7 cases with concomitant macular hole and complicated retinal detachment with proliferative vitreoretinopathy. All eyes had previous vitrectomy and internal limiting membrane peeling, or very large (>1,000 μm) macular holes. Perfluorocarbon liquid-assisted free neurosensory retinal flap transplantation into the macular hole, and subretinal fluid drainage through iatrogenic retinectomy/retinotomy were performed, followed by air-fluid exchange with gas or silicone oil tamponade., Results: All eyes had retina reattached. Macular hole was closed in all eyes, with the graft visualized by optical coherence tomography. The best corrected visual acuity in logarithm of minimal angle of resolution improved from 2.80 ± 0.45 preoperatively to 1.40 ± 0.51 postoperatively (p < 0.01)., Conclusions: Neurosensory retinal flap may be a good option in closing macular holes in eyes with concomitant macular hole and complicated retinal detachment. Because of its specific properties, the flap is easy to handle during the operation. Retinectomy or retinotomy serves to release traction, drain subretinal fluid, and provide retinal flap tissue., (© 2019 S. Karger AG, Basel.)

Background: Formally belonging to the non-steroidal anti-inflammatory drug class pyrazolones have long been used in medical practices., Objective: Our goal is to synthesize N-methylated 1-aryl-3-polyfluoroalkylpyrazolones as fluorinated analogs of antipyrine, their isomeric O-methylated derivatives resembling celecoxib structure and evaluate biological activities of obtained compounds., Methods: In vitro (permeability) and in vivo (anti-inflammatory and analgesic activities, acute toxicity, hyperalgesia, antipyretic activity, "open field" test) experiments. To suggest the mechanism of biological activity, molecular docking of the synthesized compounds was carried out into the tyrosine site of COX-1/2., Results: We developed the convenient methods for regioselective methylation of 1-aryl-3- polyfluoroalkylpyrazol-5-ols leading to the synthesis N-methylpyrazolones and O-methylpyrazoles as antipyrine and celecoxib analogs respectively. For the first time, the biological properties of new derivatives were investigated in vitro and in vivo., Conclusion: The trifluoromethyl antipyrine represents a valuable starting point in design of the lead series for discovery new antipyretic analgesics with anti-inflammatory properties., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

6:2 chlorinated polyfluorinated ether sulfonate (F-53B) has been widely applied as a mist suppressant to replace perfluorooctane sulfonate (PFOS) in the metal plating industry in China for decades. Recently, F-53B has been frequently identified in the aquatic environment and wild-caught fish. However, studies on the uptake and elimination kinetics, and the toxicological effects of F-53B were very scarce. In this study, zebrafish larvae (72 h post fertilization, hpf) were exposed to F-53B (10, 100 μg/L) for 48 h, followed by a 24 h of depuration to examine both the dynamics of accumulation and elimination of F-53B and responses of antoxidant defense system in fish. The results showed that F-53B rapidly accumulated in zebrafish larvae in a concentration and time-dependent manner with BCF values of 3612-3615, but was eliminated slowly (half-life ranged from 241.5 to 258.6 h). F-53B exposure induced oxidative stress in zebrafish larvae, as reflected by the reduction in the GSH and MDA contents, CAT, SOD, CuZn-SOD, and GSH-ST activities, and the increase in GSH-Px activity as well as CAT and SOD protein levels. However, these oxidative stress markers were restored to control levels except for a decrease in protein level of SOD after depuration. Collectively, the results of this work indicate that F-53B behaves like PFOS and is bioaccumulative and persistent in zebrafish larvae, and further induced oxidative stress responses., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Aims: To report new information related to acute retinal toxicity of Bio Octane Plus, a mixture of 90% perfluorooctane (PFO) and 10% perfluorohexyloctane., Methods: This retrospective, descriptive case series reports the occurrence of acute retinal toxicity after vitreoretinal surgery in which Bio Octane Plus (batch number 1605148) was used as an endotamponade. Cytotoxicity biocompatibility tests and chemical analyses by Fourier-transformed infrared (FTIR) spectroscopy and gas chromatography-mass spectrometry (GC-MS) of the presumed toxic product were performed., Results: Four patients presented with acute severe visual loss after uneventful ocular surgery assisted by Bio Octane Plus (batch number 1605148) as endotamponade. Patients experienced extensive retinal vascular occlusion leading to retinal and optic nerve atrophy. The viability of ARPE-19 cells directly exposed to the suspect batch for 30 min was 0%. The agarose overlay method used by the manufacturer according to European Union regulations and International Organization for Standardization (ISO) International Standards failed to detect toxicity. FTIR spectroscopy showed small differences between the non-toxic and toxic batches. GC-MS analysis showed the presence of bromotributyl stannane (whose toxicity was demonstrated in the dose-response curve) only in the toxic batch of Bio Octane Plus., Conclusion: This is the third report of retinotoxicity due to PFO in 4 years. The clinical profiles may be missed as they resemble other postsurgical complications; therefore, more cases worldwide could have gone unreported. Protocols to determine cytotoxicity of intraocular medical devices and approved by the ISO International Standards based on indirect methods have failed and should be revised to ensure safety., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2019. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Artificial blood is an innovative concept of transfusion medicine where specifically designed compounds perform the task of transport and delivery of oxygen in the body to replace this function of allogenic human blood transfusion. Several molecules have been developed in the past few decades to achieve this objective and continous refinements are being continuously made in the quest of the ideal blood substitute. Currently, available technology manufactures artificial blood from haemoglobin obtained from outdated human/bovine blood (Haemoglobin Based Oxygen Carriers) or utilizing Perfluorocarbons. These synthetic blood substitutes are advantageous in that they do not require compatibility testing, are free from blood borne infections, have prolonged shelf life and do not require refrigeration. Artificial blood is projected to have a significant impact on the development of medical care in the future. It can complement the current blood products for transfusion and create a stable supply of safe and effective products. It is likely to reduce the requirements of blood transfusions drastically especially in settings of trauma and surgery thereby reducing the reliance on banked donated blood., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Fluorinert (perfluorocarbon) represents an inexpensive option for minimizing susceptibility artifacts in ex vivo brain MRI scanning, and provides an alternative to Fomblin. However, its impact on fixed tissue and histological analysis has not been rigorously and quantitatively validated. In this study, we excised tissue blocks from 2 brain regions (frontal pole and cerebellum) of 5 formalin-fixed specimens (2 progressive supranuclear palsy cases, 3 controls). We excised 2 blocks per region per case (20 blocks in total), one of which was subsequently immersed in Fluorinert for a week and then returned to a container with formalin. The other block from each region was kept in formalin for use as control. The tissue blocks were then sectioned and histological analysis was performed on each, including routine stains and immunohistochemistry. Visual inspection of the stained histological sections by an experienced neuropathologist through the microscope did not reveal any discernible differences between any of the samples. Moreover, quantitative analysis based on automated image patch classification showed that the samples were almost indistinguishable for a state-of-the-art classifier based on a deep convolutional neural network. The results showed that Fluorinert has no effect on subsequent histological analysis of the tissue even after a long (1 week) period of immersion, which is sufficient for even the lengthiest scanning protocols.

Background and Objective: To determine whether subretinal fluid drainage (SRF) using perfluorocarbon (PFC) during rhegmatogenous retinal detachment (RRD) repair reduces postoperative metamorphopsia., Patients and Methods: Consecutive patients after RRD were evaluated for best-corrected visual acuity (BCVA), funduscopy, and metamorphopsia using M-CHARTS. Fundus autofluorescence and optical coherence tomography were performed. Clinical and operative data were collected., Results: The cohort included 30 patients, of whom 11 (36.7%) underwent intraoperative PFC injection. Rates of macula-off RRD were similar in the two groups (54.5% and 47.4%, P = .705). No association was found between PFC injection and metamorphopsia score. Preoperative macula-off RRD was associated with significantly higher vertical and horizontal metamorphopsia scores than preoperative macula-on. BCVA was significantly worse in the patients with metamorphopsia (logMAR 0.15 vs. logMAR 0.04; P = .042) CONCLUSION: Intraoperative SRF drainage with PFC appears to have no beneficial effect on postoperative metamorphopsia. Metamorphopsia is associated with macular status. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:e263-e270.]., (Copyright 2018, SLACK Incorporated.)

Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are synthetic chemicals that have been used in industry and consumer products. Because the presence of PFAS has been identified in humans and the environment in the last decade, human exposure to PFAS is a current public health concern. It has been shown that some PFAS lead to adverse health effects in the male reproductive system. However, there is no information about probable genotoxic effects of these chemicals on sperm cells. This study aimed to investigate the possible genotoxic damage on human sperm cells exposed to certain major PFAS compounds that were selected considering their extensive usage, high persistence in the environment, and high bioaccumulation in humans. These PFAS are perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), and perfluorohexanoic acid (PFHxA). The alkaline comet assay was used to detect the DNA damage to sperm. Sperm cells were treated with 0.1-1 mM of each PFAS at 32°C for 1 h to obtain optimal survival. As a result of the experiments, it was discovered that the exposure to PFOS, PFOA, PFNA, and PFHxA did not cause significant levels of cytotoxicity and did not cause damage to sperm DNA under these conditions. The results suggest that the exposure to these PFAS did not interfere with sperm DNA. Indirect toxicity mechanisms should be taken into account to assess the association between the PFAS exposure and male reproductive toxicity.

Application of per- and polyfluoroalkyl substances (PFASs) is shifting to short-chain analogs (C ≤ 6) that raises concerns for their potential ecotoxicological risks. In the present study, pot experiments were carried out to study the effects of perfluoroalkyl acids (PFAAs), including perfluoroalkyl carboxylic acids (PFCAs) and perfluoroalkyl sulfonic acids (PFSAs), with different carbon chain lengths (C4, C6, and C8) on the growth of wheat seedlings and their plant uptake and transfer at two spiking levels (200 and 2000 μg/kg soil). Exposure to C4 PFAAs slightly inhibited chlorophyll activity, whereas exposure to C8 PFAAs showed enhancement. The bioaccumulation factors (BAFs) for C4 PFAAs in wheat were over 10, while BAFs for C8 PFAAs were all below 1. Rhizospheric and root to shoot transfer factors for PFAAs were both negatively correlated with their log K ow (p < 0.05). PFCAs exhibited both higher rhizospheric mobility and accumulation potentials than PFSAs of the same chain lengths. Hence, perfluoroalkyl chain governs the mobility of PFAAs in a soil-plant system besides interactions of their head groups, and the substitution with shorter chain PFASs raises concerns for their higher plant accumulation potential that brings higher ecotoxicological and human exposure risks via food chains.

Objective: To evaluate efficacy of using 2D and 3D contrast enhanced ultrasound (CEUS) for surveillance of RCC recurrence in patients post-ablation and identify imaging hallmarks of recurrence., Methods: 53 patients >8 months post ablation of RCC provided informed consent for this IRB approved study. Patients received 2D and 3D CEUS examinations with Optison (GE Healthcare). Three radiologists of varying CEUS experience described enhancement characteristics, made a diagnosis of recurrence/no-recurrence, and quantified their diagnostic confidence levels., Results: Cases of RCC recurrence showed full ablation cavity enhancement with equal arrival times and intensity compared to the renal cortex. Lack of recurrence was characterized as a complete lack of enhancement within the cavity, or delayed enhancement stemming from the periphery of the ablation cavity. Sensitivity for detecting RCC recurrence was 100% for all readers and specificity was 90%-94%. Reader agreement ranged from 88% to 96%. No significant improvements were achieved with the addition of 3D CEUS, and its inclusion resulted in decreased reader confidence., Conclusion: Contrast-enhanced ultrasound successfully identified all cases of RCC recurrence in this study. Importantly, some patients with complete response to treatment developed delayed enhancement at the periphery of the ablation cavity over time, corresponding to fat necrosis, scarring or granulation tissue within the ablation cavity., (Copyright © 2018 Elsevier Inc. All rights reserved.)

2,3',4,4',5-Pentachlorobiphenyl (CB118) is one of the most abundant polychlorinated biphenyl (PCB) congeners in the environment, and perfluoroalkyl acids, including perfluorocarboxylic acids (PFCAs), are widely distributed in the environment. Although CB118 and perfluoroalkyl acids are present in all humans and biota, effects in the metabolic fate of CB118 leading to toxicity change are unclear. P450BM3, which is isolated from the soil bacterium Bacillus megaterium, metabolized CB118 to three different hydroxylated pentachlorobiphenyls (M1-M3). M2 was identified as 4'-OH-2,3',4,5,5'-pentachlorobiphenyl. These reactions were promoted by the presence of PFCAs, and perfluorooctanoic acid (PFCA-C8) was the most effective for accelerating these reactions among PFCAs with different carbon chain length. The production rate of M2 was accelerated by 25-times using PFCA-C8. Furthermore, the docking models of P450BM3 with CB118 and PFCAs revealed that the conformational changes of the substrate-binding cavity of P450BM3 after binding of PFCAs to P450BM3 were important for selective production of CB118 metabolites. This study leads to the clarification of the different metabolic fates of PCBs under complex contamination with PFCAs., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The introduction of fluorine into bioactive molecules is a matter of importance in medicinal chemistry. In this study, representatives of various chemical entities of fluoroaromatic compounds were synthesized. Depending on the reaction conditions, either tetrafluorophthalimides or ammonium tetrafluorophthalamates are accessible from tetrafluorophthalic anhydride and primary amines. Tetrafluorophthalamic acids undergo thermal decarboxylation to yield tetrafluorobenzamides. These could be successfully converted upon treatment with primary amines, in the course of an aromatic nucleophilic substitution, to 2,3,5-trifluorobenzamides with respective amino substituents at the 4-position. The five structure types were characterized by means of spectroscopic and crystallographic methods. The synthesized compounds were evaluated as inhibitors of angiogenesis by measuring microvessel outgrowth in a rat aortic ring assay. The biological activity was maintained throughout these different polyfluorinated chemotypes., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Perfluorooctane sulfonate (PFOS) is a persistent organic pollutant, which has been detected at significant concentrations in soils at sites used for fire-fighting training operations. Recent ecotoxicological research has mainly focused on earthworms to assess the toxicity of PFOS in soil. However, the inclusion of other soil taxonomic groups allow for a more holistic estimate of contaminant risk, including the derivation of more comprehensive soil quality guidelines. The present study assessed the toxicity of PFOS using the collembolan, Folsomia candida, and the oribatid mite, Oppia nitens, in two types of soil: a coarse-textured sandy loam (VSL) and fine-textured clay loam (NRS). As a standard O. nitens reproduction test is being formalized, the results of the study were also used to compare sensitivity across test species. Effects were soil dependent, with test species being 2-4 times more susceptible to PFOS in VSL, relative to NRS, likely due to differences in organic matter and clay content. Oppia nitens was significantly more sensitive to PFOS, regardless of soil type, in comparison to F. candida. The IC50s for reproduction for O. nitens were 23 mg kg -1 (95% confidence interval: 17-32 mg kg -1 ) in the VSL and 95 mg kg -1 (69-134 mg kg -1 ) in the NRS, and for F. candida were 94 mg kg -1 (72-122 mg kg -1 ) in the VSL and 233 mg kg -1 (177-306 mg kg -1 ) in the NRS. The present study demonstrates the application and inclusion of the oribatid mite, O. nitens, for the risk assessment of contaminants in soil., (Crown Copyright © 2018. Published by Elsevier Ltd. All rights reserved.)

Background and Objective: To compare the surgical outcome of 27-gauge pars plana vitrectomy (PPV) with 25-gauge PPV and evaluate the efficacy of air tamponade for the treatment of myopic foveoschisis (MF)., Patients and Methods: Sixty eyes of 60 consecutive patients were recruited to undergo vitrectomy, internal limiting membrane (ILM) peeling, and air tamponade for treatment of MF. These eyes were divided into two groups: the 27-gauge group (n = 29) and the 25-gauge group (n = 31)., Results: There were no significant differences in the mean operating time (P = .32), the mean time for vitrectomy (P = .20), and the suturing rate(P = .46) between the 27-gauge group and the 25-gauge group. At the final follow-up, anatomical resolution rate did not differ between the two groups (P = .65)., Conclusion: The 27-gauge vitrectomy system is as efficient and feasible as the 25-gauge system for the treatment of MF. Air tamponade can provide good postoperative anatomic resolution of MF. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:e135-e142.]., (Copyright 2018, SLACK Incorporated.)

Purpose: To evaluate the prevalence of foveolar lucency (FL) in surgically closed macular holes by spectral domain optical coherence tomography., Methods: One hundred forty-two eyes of 132 patients underwent pars plana vitrectomy, internal limiting membrane peeling, and gas tamponade in a 60-month time frame. Anatomical success and FL rates assessed by spectral domain optical coherence tomography, mean preoperative, and postoperative best-measured visual acuity and surgical details were retrospectively analyzed., Results: Spectral domain optical coherence tomography confirmed closed holes with FL in 33.7% (34/101) of eyes at 1 month, 7.3% (9/123) at 3 months, 4.6% (6/129) at 6 months, and 3% (4/133) at 12 months. Prevalence of FL in closed holes at Month 1 was lower in C3F8-treated eyes (9.5%, 2/21) compared with C2F6 (40.9%, 18/44, P = 0.03) and SF6-treated eyes (38.9%, 14/36, P = 0.05). No differences were observed at Month 3. No differences in best-measured visual acuity change were observed between closed holes with or without FL at Month 1 (-0.14 ± 0.19 vs. -0.11 ± 0.23, P = 0.48) or any of the other time points., Conclusion: Temporary FL is a highly prevalent feature in successfully closed macular holes. Eyes treated with C3F8 gas had lower rates of FL at Month 1 than C2F6 and SF6-treated eyes. The presence of FL in closed holes does not seem to have any effect on the visual outcomes.

The Nrf2/Keap1 interaction is a target in the development of new therapeutic agents, where inhibition of the interaction activates Nrf2 and leads to the generation of downstream anti-inflammatory effects. Peptides that mimic the β-turn in the Keap1 active site and are constrained by a disulfide bridge have high affinity for Keap1 but no intracellular activity. The introduction of a perfluoroalkyl-bridging group to constrain the peptides, coupled with a glutamic acid to proline replacement leads to a new peptide with a K i of 6.1 nM for the Nrf2/Keap1 binding interaction, although this does not translate into intracellular activity., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Purpose: To evaluate outcomes of repeat pars plana vitrectomy for proliferative vitreoretinopathy after previous failed pars plana vitrectomy., Methods: This is a retrospective case series including 51 eyes of 50 patients who underwent repeat surgery after failed previous pars plana vitrectomy for proliferative vitreoretinopathy from 2000 to 2015 at the Kresge Eye Institute, Detroit, MI. Patients were classified into successful and unsuccessful groups. Success was defined as retinal reattachment, silicone oil removed, and best-corrected visual acuity (BCVA) ≥5/200 at the final follow-up visit., Results: Forty-three eyes (84.3%) were successfully reattached at the last follow-up. Seventeen (33.3%) eyes were deemed successful and 34 (66.7%) eyes unsuccessful according to our criteria. Compared with the successful group, eyes in the unsuccessful group had more eyes with preoperative BCVA <5/200 (P < 0.001), preoperative BCVA of hand motion or worse (P = 0.002), preoperative flare ≥Grade 2+ (P = 0.03), preoperative posterior breaks (P = 0.02), previous retinectomy (P = 0.04), and final postoperative hypotony (intraocular pressure ≤ 5 mmHg) (P = 0.005). Eyes with silicone oil removed were more likely to have BCVA ≥5/200 (P < 0.001) at the final follow-up visit. Location of patients >100 miles (P = 0.04) from Detroit and preoperative BCVA of hand motion or worse (P = 0.01) were significantly associated with failure in the logistic regression analysis., Conclusion: Success after repeat surgery for proliferative vitreoretinopathy should include ambulatory vision, retinal reattachment, and silicone oil removal. We identified several preoperative and perioperative factors that were associated with success in the bivariate and logistic analyses. The decision to perform surgical reoperation in these patients should be based on multiple factors, most importantly preoperative BCVA.

Ultrasonically-stimulated microbubbles enhance the therapeutic effects of various chemotherapy drugs. However, the application of ultrasound and microbubbles (USMB) for enhancing the therapeutic effect of nucleoside analogs, which are used as front-line treatments in a range of cancers, and its underlying mechanism is not well understood. This study investigated the effect of gemcitabine, a nucleoside analog drug, in combination with USMB in increasing cell cytotoxicity relative to either treatment alone in BxPC3 pancreatic cancer cells. Cells were sonicated using low frequency (0.5 MHz) ultrasound in combination with Definity® microbubbles (1.7% v/v) in the presence of 1 µM of gemcitabine for a total of 2 h. USMB in combination with gemcitabine decreased cell viability (48 h) to 44.7 ± 5.2%, 27.7 ± 4.3%, and 12.5 ± 3.4% with increasing ultrasound peak negative pressures (220, 360, 530 kPa) from 84.7 ± 3.6%, 54.2 ± 3.8%, and 26.8 ± 3.0%, respectively, when USMB was applied in the absence of drug. We further confirmed that USMB did not enhance the internalization of 1 µM of a radiolabeled nucleoside analog (2-chloroadenosine) at each of the three chosen ultrasound PNPs, determined by radiolabeled scintillation counting. These data suggest that USMB in combination with nucleoside analog drugs leads to an additive effect on cell toxicity and that USMB does not impair transporter-mediated uptake of nucleoside analogs., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Importance: Perfluoroalkyl and polyfluoroalkyl substances (PFASs) are ubiquitous synthetic chemicals that are suspected endocrine disruptors., Objectives: To determine the extent to which PFASs are associated with increases in weight and body size and evaluate whether a lifestyle intervention modifies this association., Design, Setting, and Participants: This prospective cohort study included 957 individuals who participated in the Diabetes Prevention Program trial, conducted from July 1996 to May 2001, and the Diabetes Prevention Program Outcomes Study, conducted from September 2002 to January 2014. Statistical analysis was conducted from September 1, 2017, to May 25, 2018., Interventions and Exposures: The initial lifestyle intervention consisted of training in diet, physical activity, and behavior modification, with the major goals of achieving 7% weight loss with subsequent maintenance and a minimum of 150 minutes per week of physical activity. Participants randomized to placebo received standard information about diet and exercise. A total of 6 plasma PFASs were quantified at baseline and 2 years after randomization, means were calculated from baseline and year 2 concentrations, and means were summed to assess total PFAS burden., Main Outcomes and Measures: Weight, waist circumference, and hip girth were measured at baseline and at scheduled visits., Results: Of the 957 participants, 625 (65.3%) were women and 731 participants (76.4%) were between 40 and 64 years of age; 481 participants were randomized to the lifestyle intervention and 476 participants were randomized to the placebo arm. The PFAS concentrations were not different by treatment arm and were similar to concentrations reported for the US population in 1999-2000. The association of PFAS and weight change differed by treatment. Each doubling in total PFAS concentration was associated with an increase of 1.80 kg (95% CI, 0.43-3.17 kg; P = .01) from baseline to 9 years after randomization for the placebo group but not the lifestyle intervention group (-0.59 kg; 95% CI, -1.80 to 0.62 kg; P = .34). Similarly, each doubling in PFAS was associated with a 1.03-cm increase in hip girth in the Diabetes Prevention Program trial for the placebo group (95% CI, 0.18-1.88 cm; P = .02) but not the lifestyle intervention group (-0.09 cm; 95% CI, -0.82 to 0.63 cm; P = .80). No associations were observed for changes in mean waist circumference., Conclusions and Relevance: Among adults at high risk for diabetes, higher plasma PFAS concentration was associated with increases in weight and hip girth over time, but a lifestyle intervention attenuated these associations. Diet and exercise may mitigate the obesogenic effects of environmental chemicals., Trial Registration: ClinicalTrials.gov Identifier: NCT00004992 and NCT00038727.

Purpose: To investigate the use of 27-gauge pars plana vitrectomy (PPV) with short-term tamponade of perfluorocarbon liquid (PFCL) for repair of giant retinal tears (GRT)., Methods: Retrospective case series study. Consecutive patients with GRT were treated with 27-gauge PPV and short-term tamponade of PFCL for 7-10 days. PFCL was completely removed with a secondary surgery., Results: Twenty-three eyes of 23 patients were included. All the patients achieved primary anatomic success. Preoperative logarithm of the minimum angle of resolution (logMAR) BCVA was 1.59 ± 0.58 (Snellen 20/778). Five (21.7%), nine (39.1%), eleven (47.8%) and fifteen (65.2%) eyes experienced vision improvement at the Month-1, Month-3, Month-6 and final follow-ups, respectively. The final logMAR BCVA was 0.84 ± 0.51 (Snellen 20/138), being statistically better than the preoperative one (P < 0.001). Surgical complications included foreign body response (n = 7), transient elevated intraocular pressure (n = 5), cataract formation/deterioration (n = 11) and posterior capsule opacity (n = 16)., Conclusions: 27-Gauge PPV with short-term tamponade of PFCL is safe and effective for the repair of GRT. Side effects of the surgery mainly included foreign body response, transient elevated intraocular pressure, cataract formation/deterioration and posterior capsule opacity.

During total liquid ventilation, lung cells are exposed to perfluorocarbon (PFC) whose chemophysical properties highly differ from standard aqueous cell feeding medium (DMEM). We herein perform a systematic study of structural and mechanical properties of A549 alveolar epithelial cells in order to characterize their response to PFC exposure, using DMEM as control condition. Changes in F-actin structure, focal adhesion density and glycocalyx distribution are evaluated by confocal fluorescent microscopy. Changes in cell mechanics and adhesion are measured by multiscale magnetic twisting cytometry (MTC). Two different microrheological models (single Voigt and power law) are used to analyze the cell mechanics characterized by cytoskeleton (CSK) stiffness and characteristic relaxation times. Cell-matrix adhesion is analyzed using a stochastic multibond deadhesion model taking into account the non-reversible character of the cell response, allowing us to quantify the adhesion weakness and the number of associated bonds. The roles of F-actin structure and glycocalyx layer are evaluated by depolymerizing F-actin and degrading glycocalyx, respectively. Results show that PFC exposure consistently induces F-actin remodeling, CSK softening and adhesion weakening. These results demonstrate that PFC triggers an alveolar epithelial cell response herein evidenced by a decay in intracellular CSK tension, an adhesion weakening and a glycocalyx layer redistribution. These PFC-induced cell adjustments are consistent with the hypothesis that cells respond to a decrease in adhesion energy at cell surface. This adhesion energy can be even further reduced in the presence of surfactant adsorbed at the cell surface.

Angiogenesis is a common pathological characteristic of many solid tumors and vulnerable atherosclerotic plaques. Photothermal therapy (PTT) is a promising method to reduce neovascularization. To increase the targeting ability and efficiency of PTT, a novel polymeric nanosystem that encapsulates phthalocyanine zinc (ZnPc) and perfluorohexane (PFH) was developed to target the new blood vessels of breast tumors. After being conjugated to the anti-VEGFR-2 antibody, the polymeric nanoparticles (NPs) targeted vascular endothelial cells efficiently. The photosensitizer (PS) in the NPs could convert laser energy into heat, generating local high temperatures to kill the surrounding cells under laser irradiation. In addition, the liquid-gas phase transition of PFH was induced, and an enhanced ultrasound (US) and photoacoustic (PA) image could be obtained. US/PA imaging enables visualization of the location of NPs, and laser irradiation position can be guided to the optimal location, resulting in fewer side effects than those from traditional treatments with a high targeting ability and an efficient synergistic effect from the PTT.

Background: The renal assist device (RAD) is a blood purification system containing viable renal tubular epithelial cells (TECs) that has been proposed for the treatment of acute kidney injury (AKI) and multiple organ failure. Perfluorocarbons (PFCs) are oxygen carriers used for organ preservation in transplantation. The aim of this study was to investigate the effect of PFCs on hypoxia- and sepsis-induced TEC injury and on renal CD133+ progenitor differentiation in a microenvironment similar to the RAD., Methods: TECs were seeded in a polysulphone hollow fibre under hypoxia or cultured with plasma from 10 patients with sepsis-associated AKI in the presence or absence of PFCs and were tested for cytotoxicity (XTT assay), apoptosis (terminal deoxynucleotidyl transferase dUTP nick end labeling assay, caspases, enzyme-linked immunosorbent assay, Fas/Fas Ligand pathway activation), mitochondrial activity, cell polarity [transepithelial electrical resistance (TEER)] and adenosine triphosphate production. The effect of PFCs on proliferation and differentiation of human CD133+ progenitors was also studied., Results: In the presence of PFCs, TECs seeded into the polysulphone hollow fibre showed increased viability and expression of insulin-like growth factor 1, hepatocyte growth factor and macrophage-stimulating protein. Plasma from septic patients induced TEC apoptosis, disruption of oxidative metabolism, alteration of cell polarity and albumin uptake, down-regulation of the tight junction protein ZO-1 and the endocytic receptor megalin on the TEC surface. These detrimental effects were significantly reduced by PFCs. Moreover, PFCs induced CD133+ renal progenitor cell proliferation and differentiation towards an epithelial/tubular-like phenotype., Conclusions: PFCs improved the viability and metabolic function of TECs seeded within a polysulphone hollow fibre and subjected to plasma from septic AKI patients. Additionally, PFCs promoted differentiation towards a tubular/epithelial phenotype of CD133+ renal progenitor cells.

The perfluoroalkylated substances (PFAS) perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) are used for the fabrication of water- and dirt-repellent surfaces. The use of PFOS and PFOA was restricted due to their reprotoxic properties and their environmental persistence. Therefore, industry switches to alternative PFAS, however, in contrast to PFOA and PFOS only few toxicological data are available for their substitutes. The molecular mechanism(s) underlying reproductive toxicity of PFOA and PFOS are largely unknown. Here, the endocrine properties of PFOA, PFOS, and of six substitutes including perfluorohexanesulfonic acid (PFHxS), perfluorobutanesulfonic acid (PFBS), perfluorohexanoic acid (PFHxA), perfluorobutanoic acid (PFBA), ammonium perfluoro(2-methyl-3-oxahexanoate) (PMOH), and 3H-perfluoro-3-[(3-methoxypropoxy) propanoic acid] (PMPP) were examined in vitro by using human cell lines such as MCF-7, H295R, LNCaP and MDA-kb2. PFOA, PFOS and PMOH enhanced 17β-estradiol-stimulated estrogen receptor β activity, and PFOS, PMOH, PFHxA and PFBA enhanced dihydrotestosterone-stimulated androgen receptor activity. In the H295R steroidogenesis assay, PFOA and PFOS slightly enhanced estrone secretion, and progesterone secretion was marginally increased by PFOA. All these effects were only observed at concentrations above 10 μM, and none of the PFAS displayed any effect on any of the molecular endocrine endpoints at concentrations of 10 μM or below. Thus, as the blood serum concentrations of the different PFAS in the general Western population are in the range of 10 nM or below, the results suggest that PFAS might not exert endocrine effects in humans at exposure-relevant concentrations according to the molecular endpoints examined in this study., (Copyright © 2018 Elsevier B.V. All rights reserved.)

After ischaemic stroke, brain damage can be curtailed by rescuing the 'ischaemic penumbra' - that is, the severely hypoperfused, at-risk but not yet infarcted tissue. Current evidence-based treatments involve restoration of blood flow so as to salvage the penumbra before it evolves into irreversibly damaged tissue, termed the 'core'. Intravenous thrombolysis (IVT) can salvage the penumbra if given within 4.5 h after stroke onset; however, the early recanalization rate is only ~30%. Direct removal of the occluding clot by mechanical thrombectomy considerably improves outcomes over IVT alone, but despite early recanalization in > 80% of cases, ~50% of patients who receive this treatment do not enjoy functional independence, usually because the core is already too large at the time of recanalization. Novel therapies aiming to 'freeze' the penumbra - that is, prevent core growth until recanalization is complete - hold potential as adjuncts to mechanical thrombectomy. This Review focuses on nonpharmacological approaches that aim to restore the physiological balance between oxygen delivery to and oxygen demand of the penumbra. Particular emphasis is placed on normobaric oxygen therapy, hypothermia and sensory stimulation. Preclinical evidence and early pilot clinical trials are critically reviewed, and future directions, including clinical translation and trial design issues, are discussed.