Relationship between gadolinium-based MRI contrast agent consumption and anthropogenic gadolinium in the influent of a wastewater treatment plant.

Gadolinium-based contrast agents (GBCAs) used in magnetic resonance imaging (MRI) are highly resistant in the environment. They pass through wastewater treatment plants (WWTPs) unhindered escaping degradation. Although GBCAs are subjects of intensive research, we recognized that a quantitative approach to the mass balance of gadolinium, based on known input and output data, is missing. The administered amount of Gd as GBCAs, the number of out- and inpatients and the concentration of rare earth elements (REEs) in wastewater were monitored for 45 days in a medium sized city (ca. 203,000 inhabitants) with two MRI centres. An advection-dispersion type model was established to describe the transport of Gd in the wastewater system. The model calculates with patient locality, excretion kinetics of Gd and the yield of wastewater. The estimated and measured daily amount of anthropogenic gadolinium released to the WWTP were compared. GBCAs (Omniscan and Dotarem) were administered to 1008 patients representing a total of 700 ± 1 g Gd. The amount of total Gd entering the WWTP was 531 ± 2 g, of which the anthropogenic contribution (i.e. GBCAs) was 261 ± 6 g (49 ± 1 % of the total Gd) during the sampling campaign. Local residents and inpatients should fully release Gd in the city, but outpatients only partially. Overall, 37 ± 1 % of the total administered Gd was recovered in the wastewater, so the remaining 63 ± 1 % of administered Gd is expected to be dispensed outside of the sewer system. Our approach enables to better understand the dispersion of GBCAs originated Gd in an urban environment.

Regional differences in the ependyma of the optic tectal ventricle of adult zebrafish with structures referring to brain hydrodynamics.

Classical electron microscopic morphological studies provide detailed ultrastructural information, which may lend insights into cellular functions. As a follow-up to our morphological investigation of the adult zebrafish (Danio rerio) optic tectum, in this study, we have analyzed the ependymal structures lining the surfaces of the tectal ventricle: the torus, tegmental surface of the valvula cerebelli and the periventricular gray zone of the optic tectal cortex. We used toluidine blue stained plastic (semithin) sections for light microscopy and scanning electron microscopy. Our morphological findings of gated entrances and/or egresses indicate that, at least in the adult zebrafish brain, there may be a bidirectional direct flow communication between the ventricular cerebrospinal fluid and the parenchymal interstitial fluid.

Amphotericin B loaded solid lipid nanoparticles (SLNs) and nanostructured lipid carrier (NLCs): physicochemical and solid-solution state characterizations.

Amphotericin B (AmB) is one of the most effective systemic antifungal agents, but its use is circumscribed by the dose-limiting toxicity of the conventional micellar dispersion formulation, Fungizone®. Significantly lesser toxicity is obtained when AmB incorporated into the aqueous dispersion of lipid nanoparticles. The aim of this study was to develop and characterize AmB loaded solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs). NLC differed from SLN by the presence of liquid lipid, glyceryl tri(caprylate/caprate) in the lipid matrix. Various surfactants i.e. tween 20, cremophor RH40, poloxamer 407 (P407) and Myrj 52 were used to stabilize SLN and NLC. The effect of phospholipid incorporated in those lipid dispersions was also determined. Among surfactants tested, only P407 could stabilize AmB lipid dispersions. There was no chemical reaction occurred between AmB and other components that confirmed by Fourier transform infrared spectroscopy (FT-IR) spectra. The differential scanning calorimetry (DSC), hot-stage microscopy (HSM), powder X-ray diffractometry (PXRD) data showed that AmB was molecularly dispersed or in amorphous form in the lipid matrix. The proton nuclear magnetic resonance (1H-NMR) results showed that in the presence of phospholipid oil clusters within the lipid matrix are formed. These results indicate that SLN and NLC stabilized by P407 and/or phospholipid as the colloidal carrier for AmB were successfully developed.

Phytoextraction with Salix viminalis in a moderately to strongly contaminated area.

We tested the suitability of Salix viminalis for phytoextraction with the analysis of selected elements in soil, root, and leaf, and by visual tree condition assessment in an area with varying levels of contamination. Bioconcentration factor (BCF) and translocation factor (TF) were used to assess the phytoextraction potential of willows. The middle part of the study area was strongly contaminated, while the northern and southern parts were moderately contaminated. We found increasing element concentrations toward deeper layers. Mean concentrations of elements in roots were similar among the three parts, while in leaves the highest concentrations were found in the strongly contaminated part of the study area. Tree condition scores were the lowest in the strongly contaminated part of the study area, which was caused by Al, Ca, K, Mg, Ni, Sr, and Zn concentration. These elements induced leaf disease and leaf feeders. The highest BCF values were found for Cu, Fe, Mn, and Zn in root, and for Cd and Zn in leaves, indicating that S. viminalis had high accumulation potential of these elements. Furthermore, TF values were high for Cd, Mn, Sr, and Zn. Our results also demonstrated that soil element composition has major influence on the condition of S. viminalis individuals. Furthermore, visual condition assessment was found to be a useful tool to assess the phytoextraction potential of trees.

Formulations and toxicologic in vivo studies of aqueous cyclosporin A eye drops with cyclodextrin nanoparticles.

Cyclosporin A (CyA) is an immunosuppressive drug used topically to treat ocular inflammatory disorder such as dry eye disease (DES). It is a lipophilic cyclic peptide with molecular weight of 1202.6Da. The aim of this study was to develop surfactant free aqueous 0.2% (w/v) CyA eye drops where the drug is present in an aqueous vehicle containing CyA/cyclodextrin (CyA/CD) nanoparticles and then do three-month toxicological testing in rabbits. Five formulations of different CD concentrations were studied, all of them contained 12.5% (w/v) of α-cyclodextrin (αCD) and various amounts of γ-cyclodextrin (γCD) (ranging from 0 to 12.5% w/v). αCD was used to solubilize the drug and γCD to promote formation of complex aggregates. CyA/CD complex aggregates were formed in all the formulations tested. However, the formulation containing 12.5% (w/v) αCD and 12.5% (w/v) γCD created more CyA/CD nanoparticles of suitable size and was therefore tested in vivo. The eye drops did not cause ocular irritation or toxic side effects upon topical administration to rabbits once or twice a day for three months.

Sulfobutylether-ß-cyclodextrin/chitosan nano- and microparticles and their physicochemical characteristics.

Metastable polymer/cyclodextrin nano- and microparticles (NPs) were prepared from low molecular weight chitosan (CS), Mw about 10 kDa, and sulfobutylether ß-cyclodextrin (SBEßCD). CS is a cationic polysaccharide containing numerous protonated amino groups (pKa about 6.5). SBEßCD is a ß-cyclodextrin derivative with six to seven negatively charged sulfobutyl ether groups per cyclodextrin molecule. Ionotropic gelation technique was used to prepare the NPs. The NP matrix was composed of low molecular weight cationic CS polysaccharide cross-linked with polyvalent anions (SBEßCD). The diameter of the NPs ranged from 200 to almost 1,000 nm and was controlled by the CS:SBEßCD molar ratio during NP preparation. Hydrocortisone (HC) is a lipophilic drug with limited aqueous solubility (0.3mg/ml). HC displayed AL-type phase-solubility diagrams in aqueous solutions containing either SBEßCD or CS, although CS had negligible solubilizing effect. The ability of the NPs to encapsulate HC decreased with increasing CS concentration during preparation of the NPs even though the SBEßCD content of the NPs increased with increasing CS concentration. This decrease in HC encapsulation was related to the concentration; the ionic crosslinking provides better encapsulation at low initial SBEßCD and CS concentrations.

Dextran-based cyclodextrin polymers: their solubilizing effect and self-association.

Cyclodextrins and their water-soluble derivatives are excellent solubilizers and stabilizers and widely used as enabling pharmaceutical excipients. However, still new cyclodextrin derivatives are being designed and synthesized in an effort to improve their physicochemical properties. In this study physicochemical and self-associating characteristics of dextran-based cyclodextrin polymers, with ether or ester linkage between the ß-cyclodextrin and the dextran backbone, were investigated. Methods applied include phase-solubility studies, permeation studies and dynamic light scattering. Results with a model drug, hydrocortisone, showed that the solubilization and binding efficiency slowly declined with increasing molecular weight. The degree of substitution had significant effect on the properties, making the polymers with ether linkage more favorable. Self-association of the drug-polymer complexes was observed, although the instability can hamper their utilization.

A permeation method for detection of self-aggregation of doxorubicin in aqueous environment.

For pharmaceutical scientists, it is important to know if dissolved drug molecules are present only as monomers or in the form of aggregates in a test solution or formulation. Amphiphilic or hydrophobic drugs frequently self-associate to form dimers, trimers or higher order aggregates. Doxorubicin aggregation was examined by a previously developed permeation technique to detect oligosaccharide aggregation in aqueous solutions. At very low doxorubicin concentrations dimers and trimers have been observed, but in aqueous 0.5mg/ml doxorubicin solutions aggregates containing about 40 molecules were observed. The permeation studies were supported by TEM studies. The results indicate that neutral doxorubicin molecules aggregate more readily than the protonated ones. Doxorubicin aggregation is a stepwise process resulting in formation of aggregates of variable sizes are enhanced aggregation with increasing doxorubicin concentration.

Use of different morphological techniques to analyze the cellular composition of the adult zebrafish optic tectum.

Cellular composition of the adult zebrafish (Danio rerio) optic tectal cortex was examined in this study. Morphological techniques such as 1 µm thick serial plastic sections stained with osmium tetroxide and toluidine blue, modified rapid Golgi silver impregnation, GFAP immunohistochemistry, confocal microscopy, as well as scanning and transmission electron microscopy were used. Neuronal and glial components are described and the layers of the cortex are revisited. Specific neuronal arrangements as well as unique glial/ependymal cells are described. A three dimensional rendering of the astrocytic fiber arrangement in the marginal zone is presented and a composite drawing summarizes the cellular composition of the optic tectum.

The blueprint for stress can be found in invertebrates.

Through an extremely complicated equilibrium called homeostasis, all living organisms maintain their survival in the face of both externally and internally generated "stimuli". This apparent harmony is constantly challenged. Survival through successful adaptation is maintained as close to steady state as possible by adaptive responses, which may also be called perturbation responses since they have a constitutively defined dynamic capacity, i.e., an immediate limit, in a series of balancing and feedback activities reflecting an astounding array of biological, psychological and sociological behaviors. The broad spectrum of stimuli capable of engaging this protective response is remarkable. We define stress as a type of stimulation that is stronger and lasts for a longer duration, upsetting a typical perturbation response given its dynamic parameters. The stress response, which evolves out of the perturbation response, involves inducible signal molecules, i.e., cytokines. We surmise that the ability to exist in an ever-changing environment was a requirement for all life forms, including invertebrates and single celled organisms. It would be expected that these organisms exhibit both perturbation and stress responses. In this regard, we demonstrate that these organisms have mammalian-like signal molecule systems, i.e., opioid, and corresponding behaviors that are similar to those found in mammals with regard to both perturbation and stress responses. Thus, it would appear that these responses evolved first in simpler organisms and were then maintained and enhanced during evolution.