Impact of Surface Chemistry of Ultrasmall Superparamagnetic Iron Oxide Nanoparticles on Protein Corona Formation and Endothelial Cell Uptake, Toxicity, and Barrier Function.

Ultrasmall superparamagnetic iron oxide nanoparticles (USPIONs) have been investigated for biomedical applications, including novel contrast agents, magnetic tracers for tumor imaging, targeted drug delivery vehicles, and magneto-mechanical actuators for hyperthermia and thrombolysis. Despite significant progress, recent clinical reports have raised concerns regarding USPION safety related to endothelial cell dysfunction; however, there is limited information on factors contributing to these clinical responses. The influence of USPION surface chemistry on nanoparticle interactions with proteins may impact endothelial cell function leading to adverse responses. Therefore, the goal of this study was to assess the effects of carboxyl-functionalized USPION (CU) or amine-functionalized USPION (AU) (approximately 30 nm diameter) on biological responses in human coronary artery endothelial cells. Increased protein adsorption was observed for AU compared with CU after exposure to serum proteins. Exposure to CU, but not AU, resulted in a concentration-dependent decrease in cell viability and perinuclear accumulation inside cytoplasmic vesicles. Internalization of CU was correlated with endothelial cell functional changes under non-cytotoxic conditions, as evidenced by a marked decreased expression of endothelial-specific adhesion proteins (eg, vascular endothelial-cadherin and platelet endothelial cell adhesion molecule-1) and increased endothelial permeability. Evaluation of downstream signaling indicated endothelial permeability is associated with actin cytoskeleton remodeling, possibly elicited by intracellular events involving reactive oxygen species, calcium ions, and the nanoparticle cellular uptake pathway. This study demonstrated that USPION surface chemistry significantly impacts protein adsorption and endothelial cell uptake, viability, and barrier function. This information will advance the current toxicological profile of USPION and improve development, safety assessment, and clinical outcomes of USPION-enabled medical products.

Specific cannabinoids revive adaptive immunity by reversing immune evasion mechanisms in metastatic tumours.

Emerging cancers are sculpted by neo-Darwinian selection for superior growth and survival but minimal immunogenicity; consequently, metastatic cancers often evolve common genetic and epigenetic signatures to elude immune surveillance. Immune subversion by metastatic tumours can be achieved through several mechanisms; one of the most frequently observed involves the loss of expression or mutation of genes composing the MHC-I antigen presentation machinery (APM) that yields tumours invisible to Cytotoxic T lymphocytes, the key component of the adaptive cellular immune response. Fascinating ethnographic and experimental findings indicate that cannabinoids inhibit the growth and progression of several categories of cancer; however, the mechanisms underlying these observations remain clouded in uncertainty. Here, we screened a library of cannabinoid compounds and found molecular selectivity amongst specific cannabinoids, where related molecules such as Δ9-tetrahydrocannabinol, cannabidiol, and cannabigerol can reverse the metastatic immune escape phenotype in vitro by inducing MHC-I cell surface expression in a wide variety of metastatic tumours that subsequently sensitizing tumours to T lymphocyte recognition. Remarkably, H3K27Ac ChIPseq analysis established that cannabigerol and gamma interferon induce overlapping epigenetic signatures and key gene pathways in metastatic tumours related to cellular senescence, as well as APM genes involved in revealing metastatic tumours to the adaptive immune response. Overall, the data suggest that specific cannabinoids may have utility in cancer immunotherapy regimens by overcoming immune escape and augmenting cancer immune surveillance in metastatic disease. Finally, the fundamental discovery of the ability of cannabinoids to alter epigenetic programs may help elucidate many of the pleiotropic medicinal effects of cannabinoids on human physiology.

Fontan procedure: Early outcomes of 87 consecutive patients in a tertiary care center.

Al Absi and colleagues report their early results of the Fontan procedure in 87 consecutive patients between August 2008 and July 2017 in a tertiary care hospital. The use of the intra/extracardiac fenestration is a promising modification because it is unlikely to be occluded by surrounding tissue and may be associated with decreased pleural effusions, length of hospital stay, and incidence of postoperative arrhythmias.

Crossover between anti- and pro-oxidant activities of different manganese oxide nanoparticles and their biological implications.

Manganese oxide nanoparticles (MnOx NPs) have been suggested to possess several enzyme-like activities. However, studies often used either color change or fluorescence to determine the catalytic activity. Despite the simplicity and sensitivity of these probes, these methods may give distracting artifacts or not reflect the catalytic activities in biological systems. To address this issue, herein, we used electron spin resonance (ESR) spectroscopy, a technique proven effective in identifying and quantifying the free radicals produced/scavenged in nanomaterial-catalyzed reactions, to systematically evaluate the catalytic activities of three MnOx NPs (MnO2, Mn2O3, and Mn3O4 NPs) towards biologically relevant antioxidants (ascorbate and glutathione (GSH)) and reactive oxygen species (ROS) (hydrogen peroxide (H2O2), superoxide anion, and hydroxyl radical). We found that all three MnOx NPs possess both pro- and anti-oxidant activities, including oxidase-, catalase-, and superoxide dismutase (SOD)-like activities but without peroxidase-like or hydroxyl radical scavenging activity. In addition, there are differences among these MnOx NPs in their catalytic activities towards different reactions. Mn2O3 shows the strongest ascorbate oxidation activity, followed by MnO2 and Mn3O4, while Mn3O4 shows the strongest oxidation efficiency towards GSH compared to Mn2O3 and MnO2. In the catalyzed decomposition of H2O2, MnO2 NPs show higher efficiency in the generation of molecular oxygen than Mn2O3 or Mn3O4. Cellular studies indicate that all three MnOx NPs induced concentration-dependent decreases in the cell viability, with Mn3O4 > Mn3O2 > MnO2. At lower concentrations (<100 µM), consistent with the enzyme-like activities detected in solution, all three NPs significantly decreased H2O2-induced cytotoxicity in Caco-2 cells. Our study determined the multi-enzymatic activities of MnOx NPs and exhibited differences among MnOx NPs of different valences in their enzyme-like activities and their biological implications; these results provide valuable information for safe and efficient applications of MnOx NPs as ROS-scavenging biomedical nanomaterials.

Influences of simulated gastrointestinal environment on physicochemical properties of gold nanoparticles and their implications on intestinal epithelial permeability.

Gold nanoparticles (Au NPs) hold great promise in food, industrial and biomedical applications due to their unique physicochemical properties. However, influences of the gastrointestinal tract (GIT), a likely route for Au NPs administration, on the physicochemical properties of Au NPs has been rarely evaluated. Here, we investigated the influence of GIT fluids on the physicochemical properties of Au NPs (5, 50, and 100 nm) and their implications on intestinal epithelial permeability in vitro. Au NPs aggregated in fasted gastric fluids and generated hydroxyl radicals in the presence of H2O2. Cell studies showed that GIT fluids incubation of Au NPs affected the cellular uptake of Au NPs but did not induce cytotoxicity or disturb the intestinal epithelial permeability.

Preoperative Clinical and Echocardiographic Factors Associated with Surgical Timing and Outcomes in Primary Repair of Common Atrioventricular Canal Defect.

In complete atrioventricular canal defect (CAVC), there are limited data on preoperative clinical and echocardiographic predictors of operative timing and postoperative outcomes. A retrospective, single-center analysis of all patients who underwent primary biventricular repair of CAVC between 2006 and 2015 was performed. Associated cardiac anomalies (tetralogy of Fallot, double outlet right ventricle) and arch operation were excluded. Echocardiographic findings on first postnatal echocardiogram were correlated with surgical timing and postoperative outcomes using bivariate descriptive statistics and multivariable logistic regression. 153 subjects (40% male, 84% Down syndrome) underwent primary CAVC repair at a median age of 3.3 (IQR 2.5-4.2) months. Median postoperative length of stay (LOS) was 7 (IQR 5-15) days. Eight patients (5%) died postoperatively and 24 (16%) required reoperation within 1 year. On multivariable analysis, small aortic isthmus (z score < - 2) was associated with early primary repair at < 3 months (OR 2.75, 95% CI 1.283-5.91) and need for early reoperation (OR 3.79, 95% CI 1.27-11.34). Preoperative ventricular dysfunction was associated with higher postoperative mortality (OR 7.71, 95% CI 1.76-33.69). Other factors associated with mortality and longer postoperative LOS were prematurity (OR 5.30, 95% CI 1.24-22.47 and OR 5.50, 95% CI 2.07-14.59, respectively) and lower weight at surgery (OR 0.17, 95% CI 0.04-0.75 and OR 0.55, 95% CI 0.35-0.85, respectively). Notably, preoperative atrioventricular valve regurgitation and Down syndrome were not associated with surgical timing, postoperative outcomes or reoperation, and there were no echocardiographic characteristics associated with late reoperation beyond 1 year after repair. Key preoperative echocardiographic parameters helped predict operative timing and postoperative outcomes in infants undergoing primary CAVC repair. Aortic isthmus z score < - 2  was associated with early surgical repair and need for reoperation, while preoperative ventricular dysfunction was associated with increased mortality. These echocardiographic findings may help risk-stratified patients undergoing CAVC repair and improve preoperative counseling and surgical planning.

Inductively Coupled Plasma Collision Cell Quadrupole Mass Spectrometric Determination of Extractible Arsenic, Cadmium, Chromium, Lead, Mercury, and Other Elements in Food Using Microwave-Assisted Digestion: Results from an FDA Interlaboratory Study.

Background: An interlaboratory study was conducted to test U.S. Food and Drug Administration (FDA) Elemental Analysis Manual (EAM) Method 4.7, "Inductively Coupled Plasma-Mass Spectrometric Determination of Arsenic, Cadmium, Chromium, Lead, Mercury, and Other Elements in Food Using Microwave Assisted Digestion." Objective: The goal of the study was to demonstrate the performance of FDA EAM Method 4.7. Methods: Fourteen laboratories participated in the collaborative study, including nine Food Emergency Response Network state laboratories and five federal FDA laboratories. Laboratories tested 8 labeled standard reference materials and 12 blinded foods: mayonnaise, dark chocolate, sunflower seeds, hamburger with cheese, brown rice flour (blinded reference material included as a test food), infant formula, canned smoked oysters, sardines in tomato paste, swordfish, mineral water, cinnamon, and a multivitamin. The blinded test foods represented every sector of the AOAC food triangle. Participants measured the mass fraction of each element in each sample in triplicate. Results: Horwitz Ratio (HorRat) values were better than 1.5 for all As, Cd, Cu, Hg, Mo, Ni, Pb, and Se measurements when at least eight laboratories reported results greater than LOQ. The HorRat values were better than 1.5 for all Mn and Zn measurements except for the multivitamin and for all Cr measurements except for sunflower seeds, in which the nonhomogeneity was identified. The average HorRat value of the blinded test foods was 0.66 for results greater than LOQ (n = 4206). Conclusions: The study showed that the method performed satisfactorily as a standard method for extractible elemental analysis of food. Highlights: The method met or exceeded the performance expected.

Cadmium and lead in cocoa powder and chocolate products in the US Market.

Cocoa powder and chocolate products are known to sometimes contain cadmium (Cd) and lead (Pb) from environmental origins. A convenience sample of cocoa powder, dark chocolate, milk chocolate, and cocoa nib products was purchased at retail in the US and analysed using inductively coupled plasma mass spectrometry to assess Cd and Pb concentrations. Cd and Pb were evaluated in relation to the percent cocoa solids and to the reported origin of the cocoa powder and chocolate products. Cd ranged from 0.004 to 3.15 mg/kg and Pb ranged from

Fish oil supplementation reduces markers of oxidative stress but not muscle soreness after eccentric exercise.

Due to the potential anti-inflammatory properties of fish-derived long chain n-3 fatty acids, it has been suggested that athletes should regularly consume fish oils-although evidence in support of this recommendation is not clear. While fish oils can positively modulate immune function, it remains possible that, due to their high number of double bonds, there may be concurrent increases in lipid peroxidation. The current study aims to investigate the effect of fish oil supplementation on exercise-induced markers of oxidative stress and muscle damage. Twenty males underwent a 6-week double-blind randomized placebo-controlled supplementation trial involving two groups (fish oil or placebo). After supplementation, participants undertook 200 repetitions of eccentric knee contractions. Blood samples were taken presupplementation, postsupplementation, immediately, 24, 48, and 72 hr postexercise and muscle soreness/maximal voluntary contraction (MVC) assessed. There were no differences in creatine kinase, protein carbonyls, endogenous DNA damage, muscle soreness or MVC between groups. Plasma thiobarbituric acid reactive substances (TBARS) were lower (p < .05) at 48 and 72 hr post exercise and H2O2 stimulated DNA damage was lower (p < .05) immediately postexercise in the fish oil, compared with the control group. The current study demonstrates that fish oil supplementation reduces selected markers of oxidative stress after a single bout of eccentric exercise.

Fish oil supplementation augments post-exercise immune function in young males.

PURPOSE: Fish oils and related fatty acid components have anti-inflammatory properties, with beneficial effects against various disorders such as cardiovascular disease. A single bout of exercise can alter immune function. However, the effects of fish oil on immune function after a single bout of exercise are currently unknown. This study investigated the effect of supplementation with fish oil on the immune response to an acute bout of endurance exercise. METHODS: Sixteen male subjects underwent a six week double blind randomised placebo controlled supplementation trial involving two groups (fish oil or placebo oil, 3g/day). They attended for two visits, the first involving a maximal exercise test and the second involving a 1-h bout of endurance exercise on a cycle ergometer at 70% (V)O(2peak). Blood samples were taken pre-supplementation, pre-exercise (post-supplementation), immediately, 1 and 3h post-exercise. Samples were analysed for plasma IL-6, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and cortisol; peripheral blood mononuclear cell (PBMC) IL-2, IL-4 and IFN-γ production; neutrophil phagocytosis/oxidative burst; and natural killer (NK) cell cytotoxic activity. RESULTS: Post-supplementation EPA concentration was increased (P=0.0127) in the fish oil group. At 3h post-exercise PBMC IL-2 (P=0.0067) and NK cell activity (P=0.0163) was greater in the fish oil compared with the control group. However, PBMC IL-4 and IFN-γ productions, plasma IL-6 and cortisol concentrations, as well as neutrophil activity were unaffected by fish oil supplementation. CONCLUSION: The current study demonstrates that fish oil supplementation reduces increases PBMC IL-2 production and NK cell cytotoxic activity in the recovery period after exercise.

The long-term management of nuclear emergencies: the principles.

The long-term impact of the Chernobyl accident on the most affected populations in Belarus, Ukraine and the Russian Federation is still evident in terms of a continuing elevated level of thyroid cancer, prominent psychosocial effects, a depressed economy and a low level of well being. Some of these impacts are directly and primarily attributable to exposure to ionising radiation, while others have more complex origins and have evolved over the period since the accident. It is argued that although these latter impacts were largely unpredictable at the time of the accident, they could have been minimised had an appropriate management plan been in force. The principles underlying such a management plan for use in future accidents are enumerated. An essential component in further developing such a plan would be a thorough review of the experience of the Chernobyl accident in order to 'learn the lessons' that accident holds.

IFN-gamma-inducible expression of thymus and activation-regulated chemokine/CCL17 and macrophage-derived chemokine/CCL22 in epidermal keratinocytes and their roles in atopic dermatitis.

Thymus and activation-regulated chemokine (TARC)/CCL17 and macrophage-derived chemokine (MDC)/CCL22 are a pair of CC chemokines known to selectively attract T(h)2 type memory T cells via CCR4. Here we examined circulating levels of TARC and MDC in patients with atopic dermatitis (AD) and control subjects by using plasma samples, which reflect blood contents of chemokines more accurately than serum samples. The plasma levels of TARC and MDC were significantly elevated in AD patients. These values also strongly correlated with disease severity and serum lactate dehydrogenase levels, and weakly correlated with serum total IgE levels and blood eosinophilia. Previous studies demonstrated TARC immunoreactivity in the epidermal layer of AD lesional skin and production of TARC by a human keratinocytic cell line HaCaT upon stimulation with IFN-gamma. Here we demonstrated MDC immunoreactivity in the epidermal layer of AD skin at levels stronger than that of TARC. Furthermore, primary epidermal keratinocytes expressed both TARC and MDC mRNA upon stimulation with IFN-gamma, but efficiently secreted only MDC. These results suggest a post-transcriptional regulation in TARC production. IFN-gamma also induced TARC and MDC mRNA in mouse skin. Collectively, both TARC and MDC play important roles in the local accumulation of T(h)2 cells in AD lesional skin. Production of T(h)2-attracting chemokines by epidermal keratinocytes upon treatment with IFN-gamma, which is also the potent inducer of T(h)1-attracting chemokines, may underline the pivotal role of IFN-gamma in the chronic phase of AD where both T(h)1 and T(h)2 responses are mixed.