Gold(I) ion and the phosphine ligand are necessary for the anti-Toxoplasma gondii activity of auranofin.

Auranofin, an FDA-approved drug for rheumatoid arthritis, has emerged as a promising antiparasitic medication in recent years. The gold(I) ion in auranofin is postulated to be responsible for its antiparasitic activity. Notably, aurothiomalate and aurothioglucose also contain gold(I), and, like auranofin, they were previously used to treat rheumatoid arthritis. Whether they have antiparasitic activity remains to be elucidated. Herein, we demonstrated that auranofin and similar derivatives, but not aurothiomalate and aurothioglucose, inhibited the growth of Toxoplasma gondii in vitro. We found that auranofin affected the T. gondii biological cycle (lytic cycle) by inhibiting T. gondii's invasion and triggering its egress from the host cell. However, auranofin could not prevent parasite replication once T. gondii resided within the host. Auranofin treatment induced apoptosis in T. gondii parasites, as demonstrated by its reduced size and elevated phosphatidylserine externalization (PS). Notably, the gold from auranofin enters the cytoplasm of T. gondii, as demonstrated by scanning transmission electron microscopy-energy dispersive X-ray spectroscopy (STEM-EDS) and Inductively Coupled Plasma-Mass Spectrometry (ICP-MS).IMPORTANCEToxoplasmosis, caused by Toxoplasma gondii, is a devastating disease affecting the brain and the eyes, frequently affecting immunocompromised individuals. Approximately 60 million people in the United States are already infected with T. gondii, representing a population at-risk of developing toxoplasmosis. Recent advances in treating cancer, autoimmune diseases, and organ transplants have contributed to this at-risk population's exponential growth. Paradoxically, treatments for toxoplasmosis have remained the same for more than 60 years, relying on medications well-known for their bone marrow toxicity and allergic reactions. Discovering new therapies is a priority, and repurposing FDA-approved drugs is an alternative approach to speed up drug discovery. Herein, we report the effect of auranofin, an FDA-approved drug, on the biological cycle of T. gondii and how both the phosphine ligand and the gold molecule determine the anti-parasitic activity of auranofin and other gold compounds. Our studies would contribute to the pipeline of candidate anti-T. gondii agents.

Symptoms of depression in a large healthy population cohort are related to subjective memory complaints and memory performance in negative contexts.

BACKGROUND: Decades of research have investigated the impact of clinical depression on memory, which has revealed biases and in some cases impairments. However, little is understood about the effects of subclinical symptoms of depression on memory performance in the general population. METHODS: Here we report the effects of symptoms of depression on memory problems in a large population-derived cohort (N = 2544), 87% of whom reported at least one symptom of depression. Specifically, we investigate the impact of depressive symptoms on subjective memory complaints, objective memory performance on a standard neuropsychological task and, in a subsample (n = 288), objective memory in affective contexts. RESULTS: There was a dissociation between subjective and objective memory performance, with depressive symptoms showing a robust relationship with self-reports of memory complaints, even after adjusting for age, sex, general cognitive ability and symptoms of anxiety, but not with performance on the standardised measure of verbal memory. Contrary to our expectations, hippocampal volume (assessed in a subsample, n = 592) did not account for significant variance in subjective memory, objective memory or depressive symptoms. Nonetheless, depressive symptoms were related to poorer memory for pictures presented in negative contexts, even after adjusting for memory for pictures in neutral contexts. CONCLUSIONS: Thus the symptoms of depression, associated with subjective memory complaints, appear better assessed by memory performance in affective contexts, rather than standardised memory measures. We discuss the implications of these findings for understanding the impact of depressive symptoms on memory functioning in the general population.

Turning unreactive copper acetylides into remarkably powerful and mild alkyne transfer reagents by oxidative umpolung.

This is not breaking news: copper acetylides, readily available polymeric rock-stable solids, have been known for more than a century to be unreactive species and piteous nucleophiles. This lack of reactivity actually makes them ideal alkyne transfer reagents that can be easily activated under mild oxidizing conditions. When treated with molecular oxygen in the presence of simple chelating nitrogen ligands such as TMEDA, phenanthroline or imidazole derivatives, they are smoothly oxidized to highly electrophilic species that formally behave like acetylenic carbocations and can therefore be used for the mild and practical alkynylation of a wide range of nitrogen, phosphorus and carbon nucleophiles.

Mössbauer spectroscopy of europium-containing glasses: Optical activator study for x-ray image plates.

A fluorozirconate glass (ZBLAN) containing BaCl2 nanocrystals doped with divalent Eu is a promising material for x-ray image plates for medical diagnosis. Since it is known that Eu2+ readily oxidizes to Eu3+, which reduces fluorescence efficiency of the image plates, 151Eu Mössbauer spectroscopy was used in this work to monitor the Eu oxidation state of the samples during degradation over time in the presence of ambient humidity. In addition, Mössbauer spectroscopic experiments show that the oxidation state has already changed during the glass melt: The sample made from 5 mol% EuCl2 contained 78% EuCl2 + 22% EuCl3 deduced from the relative areas of the absorption lines. The sample made from 2.5 mol% EuCl2 + 2.5 mol% EuCl2 contained 37% EuCl2 + 63% EuCl3, i.e. 26% of the original EuCl2 was oxidized to EuCl3.

Multiphonon relaxation in rare-earth doped fluorozirconate-based glasses containing BaCl2 nanocrystals.

Nd3+-doped fluorozirconate-based glasses which contain hexagonal BaCl2 nanocrystals are analyzed for their photoluminescence and multiphonon relaxation (MPR) properties. The MPR rates of various Nd3+ levels are obtained from time-resolved spectroscopy using selective laser pulse excitation. The nonradiative decay rates are estimated from the difference between measured and calculated radiative decay rates as well as from the analysis of luminescence rise times. The MPR rates display an exponential dependence on the energy gap. Temperature-dependent studies of the decay indicate that phonons of the BaCl2 nanocrystals are involved in the MPR processes leading to extremely low MPR rates which are orders of magnitude lower than in conventional oxide and halide glasses. Photoluminescence emissions,which are usually quenched by MPR, and enhanced radiative quantum efficiencies are found.

Crystallization studies on rare-earth co-doped fluorozirconate-based glasses.

This work focuses on the structural changes of barium chloride (BaCl2) nanoparticles in fluorochlorozirconate-based glass ceramics when doped with two different luminescent activators, in this case rare-earth (RE) ions, and thermally processed using a differential scanning calorimeter. In a first step, only europium in its divalent and trivalent oxidation states, Eu2+ and Eu3+, is investigated, which shows no significant influence on the crystallization of hexagonal phase BaCl2. However, higher amounts of Eu2+ increase the activation energy of the phase transition to an orthorhombic crystal structure. In a second step, nucleation and nanocrystal growth are influenced by changing the structural environment of the glasses by co-doping with Eu2+ and trivalent Gd3+, Nd3+, Yb3+, or Tb3+, due to the different atomic radii and electro-negativity of the co-dopants.

Mössbauer spectroscopy of europium-doped fluorochlorozirconate glasses and glass ceramics: optimization of storage phosphors in computed radiography.

Eu(2+)-doped fluorochlorozirconate (FCZ) glasses and glass ceramics, which are being developed for medical and photovoltaic applications, have been analysed by Mössbauer spectroscopy. The oxidation state and chemical environment of the europium ions, which are important for the performance of these materials, were investigated. Routes for maximizing the divalent europium content were also investigated. By using EuCl2 instead of EuF2 in the starting material a fraction of about 90% of the europium was maintained in the Eu(2+) state as opposed to about 70% when using EuF2. The glass ceramics produced by subsequent thermal processing contain BaCl2 nanocrystals in which Eu(2+) is incorporated, as shown by the narrower linewidth in the Mössbauer spectrum. Debye temperatures of 147 K and 186 K for Eu(2+) and Eu(3+), respectively, were determined from temperature dependent Mössbauer measurements. The f-factors were used to obtain the Eu(2+)/Eu(3+) ratio from the area ratio of the corresponding absorption lines.

The metastatic potential of canine mammary tumours can be assessed by mRNA expression analysis of connective tissue modulators.

Metastases are the crucial factor for the prognosis of canine mammary tumours (CMTs). In women, the peptide hormone relaxin is linked with metastatic breast cancer. Therefore, the impact of relaxin and its receptors on matrix metalloproteinase (MMP) expression, metastatic disease and survival was analysed using qRT-PCR and immunohistochemistry of CMT samples from 59 bitches. The expression of relaxin and its receptor RXFP1 (relaxin family peptide receptor 1) was discovered on gene and protein levels. Intratumoural relaxin mRNA expression and relaxin plasma levels had no prognostic value. High mRNA levels RXFP1 were an independent marker of metastatic potential, with a more than 15-fold risk increase, and a predictor for shorter survival. Also, MMP-2 expression was associated with early death because of CMT. The mRNA expressions of relaxin, RXFP1 and MMP-2 were positively correlated indicating a common pathogenetic linkage. Thus, RXFP1 is proposed as a new early marker of metastatic potential in CMT and a possible therapeutic target.

The oxidation state of europium in halide glasses.

The luminescent properties of divalent europium ions can be exploited to produce storage phosphors for x-ray imaging applications. The relatively high cost and limited availability of divalent europium halides makes it desirable to synthesize them from the readily available trivalent salts. In this work, samples of pure EuCl(3) and fluoride glass melts doped with EuCl(3) were processed at 700-800 °C in an inert atmosphere furnace. The Eu oxidation state in the resulting materials was determined using fluorescence and Mössbauer spectroscopy. Heat treatment of pure EuCl(3) for 10 min at 710 °C resulted in a material comprising approximately equal amounts of Eu(2+) and Eu(3+). Glasses made using mixtures of EuCl(2) and EuCl(3) in the starting material contained both oxidation states. This paper describes the sample preparation and analysis and discusses the results in the context of chemical equilibria in the melts.

Crystallization behavior of rare-earth doped fluorochlorozirconate glasses.

A series of fluorochlorozirconate (FCZ) glasses, each doped with a different rare-earth, was prepared and examined to determine thermal stability and activation energy, Ea , of the dopant dependent BaCl2 crystallization. Non-isothermal differential scanning calorimetry (DSC) measurements were done to investigate the endothermic and exothermic reactions upon heat treatment of the glass samples. In comparison to the rare-earth free FCZ glass, significant changes in the Hruby constant, Hr , and Ea were found due to the addition of a rare-earth and also between the individual dopants.

Structural properties of fluorozirconate-based glass ceramics doped with multivalent europium.

The structure/property relationships of fluorochlorozirconate glass ceramics as a function of divalent and trivalent europium (Eu) co-doping and thermal processing have been investigated; the influence of doping ratio on the formation of barium chloride (BaCl(2)) nanocrystals therein was elucidated. X-ray absorption near-edge structure spectroscopy shows that the post-thermal annealing changes the Eu valence of the as-poured glass slightly, but during the melting process Eu(3+) is more strongly reduced to Eu(2+), in particular, when doped as a chloride instead of fluoride compound. The Eu(2+)-to-Eu(3+) doping ratio also plays a significant role in chemical equilibrium in the melt. X-ray diffraction measurements indicate that a higher Eu(2+) fraction leads to a BaCl(2) phase transition from hexagonal to orthorhombic structure at a lower temperature.

In-vivo assessment of tissue metabolite levels using 1H MRS and the Electric REference To access In vivo Concentrations (ERETIC) method.

Quantitative values of metabolite concentrations in (1)H magnetic resonance spectroscopy have been obtained using the Electric REference To access In vivo Concentrations (ERETIC) method, whereby a synthetic reference signal is injected during the acquisition of spectra. The method has been improved to enable quantification of metabolite concentrations in vivo. Optical signal transmission was used to eliminate random fluctuations in ERETIC signal coupling to the receiver coil due to changes in position of cables and highly dielectric human tissue. Stability and reliability of the signal were tested in vitro, achieving stability with a mean error of 2.83%. Scaling of the signal in variable loading conditions was demonstrated and in-vivo measurements of brain were acquired on a 3T Philips system using a transmit/receive coil. The quantitative brain water and metabolite concentration values are in good agreement with those in the literature.

Differential scanning calorimetry investigations on Eu-doped fluorozirconate-based glass ceramics.

The properties of Eu-doped fluorochlorozirconate (FCZ) glass ceramics upon thermal processing and the influence of Eu-doping on the formation of BaCl(2) nanocrystals therein have been investigated. Differential scanning calorimetry indicates that higher Eu-doping shifts the crystallization peak of the nanocrystals in the glass to lower temperatures, while the glass transition temperature remains constant. The activation energy and the thermal stability parameters for the BaCl(2) crystallization are determined.

Saturation effects in the upconversion efficiency of Er-doped fluorozirconate glasses.

A series of transparent erbium-doped fluorozirconate glasses has been investigated using differential scanning calorimetry, optical absorption, and upconverted fluorescence spectroscopy. The upconverted fluorescence intensity versus excitation power dependence shows that the ratio of the two-photon upconverted emission in the near infrared at 980 nm to the three-photon upconverted emissions in the visible at 530, 550, and 660 nm decreases with increasing excitation power. The integrated upconverted fluorescence intensity to excitation power ratio shows 'saturation' with increasing excitation power, while the point of saturation shifts to lower excitation power with increasing erbium concentration. The experimental lifetime of the upconverted fluorescence decreases with increasing erbium concentration.

Scanning translucent glass-ceramic x-ray storage phosphors.

A simple benchtop apparatus has been built, to measure the x-ray imaging properties of fluorozirconate-based glass-ceramic x-ray storage phosphor materials. The MTF degradation due to stimulating light spreading in the plate is lower in comparison to optically turbid screens resulting in higher image MTF. In addition, the degree of transparency, or the amount of light scattering at the wavelength of the stimulating (laser) light is adjustable by means of the glass preparation process. The amount of stimulating exposure required for plate readout is generally higher than in previous systems, but well within the range of commercially available laser systems, for practical readout times. The effects of flare or unwanted readout due to back-reflection from the imaging plate is also less than in previous systems.A novel telecentric scanning system has been developed that is able to rapidly read out the latent image stored in the translucent imaging plates. This system features a reflective primary scan mirror to achieve telecentricity, optical correction for scan line bow, and the design should enable the construction of a relatively inexpensive scanner system for the translucent x-ray storage plates.

Multi-functionality of fluorescent nanocrystals in glass ceramics.

Thermal processing of as-made fluorozirconate glasses, which were additionally doped with rare-earth and chlorine ions, results in the formation of fluorescent nanocrystals therein. For medical applications, the glasses were doped with divalent europium ions as the fluorescent rare-earth ion, while trivalent neodymium was used to develop up-conversion systems. The samples were annealed up to 290 °C to initiate the growth of hexagonal or orthorhombic phase BaCl2 nanocrystals therein. Upon annealing some of the rare-earth ions were incorporated into the BaCl2 nanocrystals leading to enhanced fluorescence properties. The particle diameters were in the range of a few nanometers to several tens of nanometers.

Crystallization in heat-treated fluorochlorozirconate glasses.

Crystallization phenomena of fluorochlorozirconate glasses were investigated by means of differential scanning calorimetry and inelastic neutron scattering. The precipitation of barium chloride nanoparticles from the glass matrix upon heat treatment was found to be suppressed when re-melting the glass with a reducing agent but not if the agent was present in the initial synthesis. Addition of small amounts of oxide to the predominantly fluoride melt was found to maintain the presence of nanoparticles but not to induce the predicted phase transition of the barium chloride nanoparticles from hexagonal to orthorhombic structure. Inelastic neutron scattering performed on an 'as-made' glass and a heat-treated glass showed an increase in 'hardness', consistent with a more ordered structure.

Investigation of the local expression of the relaxin system in canine mammary tumours.

While mammary tumours are the main reasons of death in bitches, early detection of tumours and metastases is crucial for survival of affected dogs. Invasiveness and angiogenesis, which are important processes of tumour growth and spreading, require connective tissue remodelling. This process is dominantly mediated by matrix metalloproteinases (MMP), which are well known to be positively regulated by relaxin (RLX) in various tissues, including human breast cancer. So far, the presence of RLX and its receptor RXFP-1 as well as their linkage with MMP in canine mammary tumours (CMT) is completely unknown. In the first part of the present study, concentrations of RLX, oestradiol and progesterone from plasma samples of bitches with CMT were compared with clinical and survival data to investigate the predictive value of these hormones. In the second part, the expressions of RLX, RXFP-1 and MMP-2, -9 and -13 were examined by real-time reverse transcriptase polymerase chain reaction (RT-PCR) in 31 CMT samples. Finally, relationships of systemic plasma RLX or locally expressed RLX with expression of MMP in CMT were analyzed for the first time. Comparison of hormone concentrations in 93 bitches in terms of benign or malignant nature of the CMT, lung metastases, recidivation and 12-month survival discovered no significances. The expressions of RLX, RXFP-1 and MMP were independent from plasma RLX, but expressions of local RLX and RXFP-1 showed a strong correlation (p = 0.00004, r = 0.671) as well as RXFP-1 and MMP-2 (p = 0.009, r = 0.463), indicating a possible significant role of the locally produced RLX in CMT pathogenesis as an inducer of connective tissue remodelling.

Sedation with propofol for interventional endoscopy by trained nurses in high-risk octogenarians: a prospective, randomized, controlled study.

BACKGROUND AND STUDY AIMS: Sedation with the short-acting anesthetic agent propofol has shown several advantages, particularly in interventional endoscopy. So far, however, there are no valid data on the safety of nurse-administered propofol sedation (NAPS) during interventional endoscopy in elderly high-risk patients. PATIENTS AND METHODS: A total of 150 patients aged > 80 years with high comorbidity were randomized to receive midazolam plus meperidine (n = 75) or propofol alone (n = 76) for sedation during endoscopic retrograde cholangiopancreatography (ERCP), endoscopic ultrasound (EUS), or double-balloon endoscopy (DBE). Sedation was supervised by a trained nurse and a trained physician both of whom were not involved in the endoscopic procedure. Vital signs were continuously monitored as well as patient cooperation and tolerance. Mortality and morbidity at 30 days was analyzed. RESULTS: The overall cardiopulmonary complication rate was 16 % in the midazolam group and 23.7 % in the propofol group ( P > 0.05). The mean decline in oxygen saturation (initial vs. lowest O (2) saturation) and the mean decline of blood pressure (initial vs. lowest blood pressure) were significantly greater with propofol (7 % +/- 3 % vs. 4 % +/- 2 % [ P < 0.05] and 10 % +/- 2 % vs. 8 % +/- 2 %, respectively [ P < 0.05]). No procedure had to be interrupted due to serious adverse events. Patient cooperation was statistically significantly better in the propofol group (7 +/- 2 vs. 5 +/- 2 points). Patients sedated with propofol showed a significantly lower oxygen saturation rate during recovery time (8 % vs. 28 %; P < or = 0.01). CONCLUSION: NAPS during interventional endoscopy is as safe as midazolam/pethidine sedation even in high-risk patients aged > 80 years.

Upconverted fluorescence in Nd(3+)-doped barium chloride single crystals.

Upon excitation at 796 nm, Nd(3+)-doped BaCl(2) single crystals show several upconverted fluorescence bands in the visible spectral range, with the most intense bands at 530, 590 and 660 nm, in addition to the typical fluorescence bands in the infrared spectral range. The power dependence of the infrared fluorescence and the two-photon upconversion fluorescence intensities as well as the corresponding radiative lifetimes have been investigated. No 'saturation' of the fluorescence intensities was observed upon increasing the excitation power.