Distortion-sensitive insight into the pretransitional behavior of 4- n -octyloxy-4′-cyanobiphenyl (8OCB)

Results of studies of the static and dynamic dielectric properties in rod-like 4-n-octyloxy-4'-cyanobiphenyl (8OCB) with isotropic (I)–nematic (N)–smectic A (SmA)–crystal (Cr) mesomorphism, combined with measurements of the low-frequency nonlinear dielectric effect and heat capacity are presented. The analysis is supported by the derivative-based and distortion-sensitive transformation of experimental data. Evidence for the I–N and N–SmA pretransitional anomalies, indicating the influence of tricritical behavior, is shown. It has also been found that neither the N phase nor the SmA phase are uniform and hallmarks of fluid–fluid crossovers can be detected. The dynamics, tested via the evolution of the primary relaxation time, is clearly non-Arrhenius and described via τ(T) = τc(T−TC)−phgr. In the immediate vicinity of the I–N transition a novel anomaly has been found: Δτ ∝ 1/(T − T*), where T* is the temperature of the virtual continuous transition and Δτ is the excess over the 'background behavior'. Experimental results are confronted with the comprehensive Landau–de Gennes theory based modeling.

First intercomparison study on the analysis of oxygenated polycyclic aromatic hydrocarbons (oxy-PAHs) and nitrogen heterocyclic polycyclic aromatic compounds (N-PACs) in contaminated soil

Oxygenated polycyclic aromatic hydrocarbons (oxy-PAHs) and nitrogen heterocyclic polycyclic aromatic compounds (N-PACs) are toxic, highly leachable and often abundant at sites that are also contaminated with PAHs. However, due to lack of regulations and standardized methods for their analysis, they are seldom included in monitoring and risk-assessment programs. This intercomparison study constitutes an important step in the harmonization of the analytical methods currently used, and may also be considered a first step towards the certification of reference materials for these compounds. The results showed that the participants were able to determine oxy-PAHs with accuracy similar to PAHs, with average determined mass fractions agreeing well with the known levels in a spiked soil and acceptable inter- and intra-laboratory precisions for all soils analyzed. For the N-PACs, the results were less satisfactory, and have to be improved by using analytical methods more specifically optimized for these compounds.

Cytotoxic steroidal saponins from the rhizomes of Tacca integrifolia

Three new steroid saponins (3beta,25R)-spirost-5-en-3-yl 6-deoxy-alpha-L-mannopyranosyl-(1-->2)-[beta-D-glucopyranosyl-(1-->4)-6-deoxy-alpha-L-mannopyranosyl-(1-->3)]-beta-D-glucopyranoside (1), (3beta,22R,25R)-26-(beta-D-glucopyranosyloxy)-22-hydroxyfurost-5-en-3-yl 6-deoxy-alpha-L-mannopyranosyl-(1-->2)-[6-deoxy-alpha-L-mannopyranosyl-(1-->3)]-beta-D-glucopyranoside (3), and (3beta,22R,25R)-26-(beta-D-glucopyranosyloxy)-22-hydroxyfurost-5-en-3-yl 6-deoxy-alpha-L-mannopyranosyl-(1-->2)-[beta-D-glucopyranosyl-(1-->4)-6-deoxy-alpha-L-mannopyranosyl-(1-->3)]-beta-D-glucopyranoside (5), as well as the new pregnane glycoside (3beta,16beta)-3-{[6-deoxy-alpha-L-mannopyranosyl-(1-->2)-[6-deoxy-alpha-L-mannopyranosyl-(1-->3)]-beta-D-glucopyranosyl]oxy}-20-oxopregn-5-en-16-yl (4R)-5-(beta-D-glucopyranosyloxy)-4-methylpentanoate (6), were isolated from the rhizomes of Tacca integrifolia together with two known (25R) configurated steroid saponins (3beta,25R)-spirost-5-en-3-yl 6-deoxy-alpha-L-mannopyranosyl-(1-->2)-[6-deoxy-alpha-L-mannopyranosyl-(1-->3)]-beta-D-glucopyranoside (2) and (3beta,22R,25R)-26-(beta-D-glucopyranosyloxy)-22-methoxyfurost-5-en-3-yl 6-deoxy-alpha-L-mannopyranosyl-(1-->2)-[6-deoxy-alpha-L-mannopyranosyl-(1-->3)]-beta-D-glucopyranoside (4). The cytotoxic activity of the isolated compounds was evaluated in HeLa cells and showed the highest cytotoxicity value for compound 2 with an IC(50) of 1.2+/-0.4 muM. Intriguingly, while compounds 1-5 exhibited similar cytotoxic properties between 1.2+/-0.4 (2) and 4.0+/-0.6 muM (5), only compound 2 showed a significant microtubule-stabilizing activity in vitro.

Retention force of plastic clips on implant bars: a randomized controlled trial

Retention of overdentures is important for patients' satisfaction. The study tested whether the clinical performance of retentive clips made of poly-ether-ether-ketone (PEEK) is superior to those made of poly-oxy-methylene (POM).

Protein and lipid binding parameters in rainbow trout (Oncorhynchus mykiss) blood and liver fractions to extrapolate from an in vitro metabolic degradation assay to in vivo bioaccumulation potential of hydrophobic organic chemicals

Binding of hydrophobic chemicals to colloids such as proteins or lipids is difficult to measure using classical microdialysis methods due to low aqueous concentrations, adsorption to dialysis membranes and test vessels, and slow kinetics of equilibration. Here, we employed a three-phase partitioning system where silicone (polydimethylsiloxane, PDMS) serves as a third phase to determine partitioning between water and colloids and acts at the same time as a dosing device for hydrophobic chemicals. The applicability of this method was demonstrated with bovine serum albumin (BSA). Measured binding constants (K(BSAw)) for chlorpyrifos, methoxychlor, nonylphenol, and pyrene were in good agreement with an established quantitative structure-activity relationship (QSAR). A fifth compound, fluoxypyr-methyl-heptyl ester, was excluded from the analysis because of apparent abiotic degradation. The PDMS depletion method was then used to determine partition coefficients for test chemicals in rainbow trout (Oncorhynchus mykiss) liver S9 fractions (K(S9w)) and blood plasma (K(bloodw)). Measured K(S9w) and K(bloodw) values were consistent with predictions obtained using a mass-balance model that employs the octanol-water partition coefficient (K(ow)) as a surrogate for lipid partitioning and K(BSAw) to represent protein binding. For each compound, K(bloodw) was substantially greater than K(S9w), primarily because blood contains more lipid than liver S9 fractions (1.84% of wet weight vs 0.051%). Measured liver S9 and blood plasma binding parameters were subsequently implemented in an in vitro to in vivo extrapolation model to link the in vitro liver S9 metabolic degradation assay to in vivo metabolism in fish. Apparent volumes of distribution (V(d)) calculated from the experimental data were similar to literature estimates. However, the calculated binding ratios (f(u)) used to relate in vitro metabolic clearance to clearance by the intact liver were 10 to 100 times lower than values used in previous modeling efforts. Bioconcentration factors (BCF) predicted using the experimental binding data were substantially higher than the predicted values obtained in earlier studies and correlated poorly with measured BCF values in fish. One possible explanation for this finding is that chemicals bound to proteins can desorb rapidly and thus contribute to metabolic turnover of the chemicals. This hypothesis remains to be investigated in future studies, ideally with chemicals of higher hydrophobicity.

Physiological effects of mechanical pain stimulation at the lower back measured by functional near-infrared spectroscopy and capnography

The aim was to investigate the effect of mechanical pain stimulation at the lower back on hemodynamic and oxygenation changes in the prefrontal cortex (PFC) assessed by functional near-infrared spectroscopy (fNIRS) and on the partial pressure of end-tidal carbon dioxide ( PetCO 2) measured by capnography. 13 healthy subjects underwent three measurements (M) during pain stimulation using pressure pain threshold (PPT) at three locations, i.e., the processus spinosus at the level of L4 (M1) and the lumbar paravertebral muscles at the level of L1 on the left (M2) and the right (M3) side. Results showed that only in the M2 condition the pain stimulation elicited characteristic patterns consisting of (1) a fNIRS-derived decrease in oxy- and total hemoglobin concentration and tissue oxygen saturation, an increase in deoxy-hemoglobin concentration, (2) a decrease in the PetCO 2 response and (3) a decrease in coherence between fNIRS parameters and PetCO 2 responses in the respiratory frequency band (0.2-0.5 Hz). We discuss the comparison between M2 vs. M1 and M3, suggesting that the non-significant findings in the two latter measurements were most likely subject to effects of the different stimulated tissues, the stimulated locations and the stimulation order. We highlight that PetCO 2 is a crucial parameter for proper interpretation of fNIRS data in experimental protocols involving pain stimulation. Together, our data suggest that the combined fNIRS-capnography approach has potential for further development as pain monitoring method, such as for evaluating clinical pain treatment.

A review on continuous wave functional near-infrared spectroscopy and imaging instrumentation and methodology

This year marks the 20th anniversary of functional near-infrared spectroscopy and imaging (fNIRS/fNIRI). As the vast majority of commercial instruments developed until now are based on continuous wave technology, the aim of this publication is to review the current state of instrumentation and methodology of continuous wave fNIRI. For this purpose we provide an overview of the commercially available instruments and address instrumental aspects such as light sources, detectors and sensor arrangements. Methodological aspects, algorithms to calculate the concentrations of oxy- and deoxyhemoglobin and approaches for data analysis are also reviewed. From the single-location measurements of the early years, instrumentation has progressed to imaging initially in two dimensions (topography) and then three (tomography). The methods of analysis have also changed tremendously, from the simple modified Beer-Lambert law to sophisticated image reconstruction and data analysis methods used today. Due to these advances, fNIRI has become a modality that is widely used in neuroscience research and several manufacturers provide commercial instrumentation. It seems likely that fNIRI will become a clinical tool in the foreseeable future, which will enable diagnosis in single subjects.

The value of susceptibility-weighted imaging (SWI) in patients with non-neonatal hypoxic-ischemic encephalopathy

OBJECTIVE In susceptibility-weighted imaging (SWI) in the normal brain, cortical veins appear hypointense due to paramagnetic properties of deoxy-hemoglobin. Global cerebral anoxia decreases cerebral oxygen metabolism, thereby increasing oxy-hemoglobin levels in cerebral veins. We hypothesized that a lower cerebral oxygen extraction fraction in comatose patients with non-neonatal hypoxic ischemic encephalopathy (IHE) produce a pattern of global rarefied or pseudo-diminished cortical veins due to higher oxy-hemoglobin. PURPOSE 1. To investigate the topographic relationship between susceptibility effects in cortical veins and related diffusion restrictions on diffusion-weighted imaging (DWI) in patients with IHE. 2. To relate imaging findings to patterns of altered resting activity on surface EEG. METHODS Twenty-three IHE patients underwent MRI. EEG patterns were used to classify the depth of coma. Regional vs. global susceptibility changes on SWI and patterns of DWI restrictions were compared with the depth of coma. RESULTS All patients exhibited areas of restricted cortical diffusion and SWI abnormalities. The dominant DWI restrictions encompassed widespread areas along the precuneus, frontal and parietal association cortices and basal ganglia. For SWI, nineteen patients had generalized bi-hemispherical patterns, the EEG patterns correlated with coma grades III to V. Four patients had focal decreases of deoxy-hemoglobin following DWI restrictions; associated with normal EEGs. CONCLUSION Focal patterns of diamagnetic effects on SWI according to relative decreases in deoxy-hemoglobin due to reduced metabolic demand are associated with normal EEG in IHE patients. Global patterns indicated increased depth of coma and widespread cortical damage. CLINICAL RELEVANCE The results indicate a potential diagnostic value of SWI in patients with IHE.

Novel oxazolo-oxazole derivatives of FTY720 reduce endothelial cell permeability, immune cell chemotaxis and symptoms of experimental autoimmune encephalomyelitis in mice

The immunomodulatory FTY720 (fingolimod) is presently approved for the treatment of relapsing-remitting multiple sclerosis. It is a prodrug that acts by modulating sphingosine 1-phosphate (S1P) receptor signaling. In this study, we have developed and characterized two novel oxazolo-oxazole derivatives of FTY720, ST-968 and the oxy analog ST-1071, which require no preceding activating phosphorylation, and proved to be active in intact cells and triggered S1P1 and S1P3, but not S1P2, receptor internalization as a result of receptor activation. Functionally, ST-968 and ST-1071 acted similar to FTY720 to abrogate S1P-triggered chemotaxis of mouse splenocytes, mouse T cells and human U937 cells, and reduced TNFa- and LPS-stimulated endothelial cell permeability. The compounds also reduced TNFα-induced ICAM-1 and VCAM-1 mRNA expression, but restored TNFα-mediated downregulation of PECAM-1 mRNA expression. In an in vivo setting, the application of ST-968 or ST-1071 to mice resulted in a reduction of blood lymphocytes and significantly reduced the clinical symptoms of experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice comparable to FTY720 either by prophylactic or therapeutic treatment. In parallel to the reduced clinical symptoms, infiltration of immune cells in the brain was strongly reduced, and in isolated tissues of brain and spinal cord, the mRNA and protein expressions of ICAM-1 and VCAM-1, as well as of matrix metalloproteinase-9 were reduced by all compounds, whereas PECAM-1 and tissue inhibitor of metalloproteinase TIMP-1 were upregulated. In summary, the data suggest that these novel butterfly derivatives of FTY720 could have considerable implication for future therapies of multiple sclerosis and other autoimmune diseases.

Concise Asymmetric Synthesis and Pharmacological Characterization of All Stereoisomers of Glutamate Transporter Inhibitor TFB-TBOA and Synthesis of EAAT Photoaffinity Probes

Glutamate is the major excitatory neurotransmitter in the mammalian brain. Its rapid clearance after the release into the synaptic cleft is vital in order to avoid toxic effects and is ensured by several transmembrane transport proteins, so-called excitatory amino acid transporters (EAATs). Impairment of glutamate removal has been linked to several neurodegenerative diseases and EAATs have therefore received increased attention as therapeutic targets. O-benzylated L-threo-β-hydroxyaspartate derivatives have been developed previously as highly potent inhibitors of EAATs with TFB-TBOA ((2S,3S)-2-amino-3-((3-(4-(trifluoromethyl)benzamido)benzyl)oxy)succinic acid) standing out as low-nanomolar inhibitor. We report the stereoselective synthesis of all four stereoisomers of TFB-TBOA in less than a fifth of synthetic steps than the published route. For the first time, the inhibitory activity and isoform selectivity of these TFB-TBOA enantio- and diastereomers were assessed on human glutamate transporters EAAT1-3. Furthermore, we synthesized potent photoaffinity probes based on TFB-TBOA using our novel synthetic strategy.

Liquid-Crystalline Dendrimers Designed by Click Chemistry

Liquid-crystalline dendrimers have been prepared from second-generation Percec-type poly(benzyl ether) dendrons or second-generation poly(aryl ester) dendrons carrying cyanobiphenyl mesogens. The Janus dendrimer, which combines the two types of dendromesogens, has also been synthesized. Those compounds have been prepared under copper-catalyzed azide–alkyne cycloaddition conditions. The mesomorphic properties have been studied by thermal analysis (POM, DSC) and small-angle X-ray scattering. Smectic A, nematic, and columnar phases have been observed depending on the dendritic building blocks. The click reaction has proven to be a powerful and elegant synthetic tool for the design of complex dendritic liquid-crystalline architectures.