[Oxidative stress in psychosis: a new target for intervention?] / Oxidatieve stress bij psychotische stoornissen: een nieuw target voor interventie?

BACKGROUND: Oxidative stress is a state of imbalance between reactive oxidants and anti-oxidants. Oxidative stress and a disrupted redox regulation in the brain might contribute to the pathophysiology of psychotic disorders and could serve as interesting new targets for clinical intervention. Advanced glycation end products (AGEs) in the skin can be measured non-invasively and indicate cumulative oxidative stress. AIM: To investigate cross-sectional and longitudinal differences in AGE-levels in patients with recent onset psychosis (patients) and healthy controls (controls). To investigate association of AGE-levels and brain volume in psychosis. METHOD: An autofluorescence measurement of AGEs in the skin was performed in patients and controls. AGEs were compared in patients and controls. Furthermore, the association between AGEs and volumes of the amygdala, hippocampus and total cortical gray matter was investigated in patients. RESULTS: AGEs in the skin were elevated by 15% (or 0.66 standard deviations) in patients (n = 86) compared to controls (n = 135) (p < 0.001). An indication of a higher AGE-accumulation rate (p = 0.07) was found in patients (n = 66) compared to controls (n = 160). We found a negative association between AGEs in the skin and hippocampus volume (standardized beta= 0.27; p = 0.03) in patients (n = 46). CONCLUSION: Findings of a high level of AGEs in the skin indicate excessive oxidative stress in patients with recent onset psychosis.

Reversible N-Heterocyclic Carbene-Induced α-H Abstraction in Tungsten(VI) Imido Dialkyl Dialkoxide Complexes.

The first reversible N-heterocyclic carbene (NHC) induced α-H abstraction in tungsten(VI) imido-dialkyl dialkoxide complexes is reported. Treatment of W(NAr)(CH2 Ph)2 (OtBu)2 (Ar=2,6-dichlorophenyl, 2,6-dimethylphenyl, 2,6-diisopropylphenyl) with different NHCs leads to the formation of complexes of the type W(NAr)(CHPh)(NHC)(CH2 Ph)(OtBu) in excellent isolated yields of up to 96 %. The highly unusual release of the tert-butoxide ligand as tBuOH in the course of the reaction was observed. The formed alkylidene complexes and tBuOH are in an equilibrium with the NHC and the dialkyl complexes. Reaction kinetics were monitored by 1 H NMR spectroscopy. A correlation between the steric and electronic properties of the NHC and the reaction rates was observed. Kinetics of a deuterium-labeled complex in comparison to its non-deuterated counterpart revealed the presence of a strong primary kinetic isotope effect (KIE) of 4.2, indicating that α-H abstraction is the rate-determining step (RDS) of the reaction.

A Spirocyclic Parabanic Acid Masked N-Heterocyclic Carbene as Thermally Latent Pre-Catalyst for Polyamide 6 Synthesis and Epoxide Curing.

1,3-Dicyclcohexyl-6,9-dimethyl-1,3,6,9-tetraazaspiro[4.4]non-7-ene-2,4-dione, a spirocyclic parabanic acid derivative of N,N-dimethylimidazole, is used as thermally latent, protected N-heterocyclic carbene (NHC) in polymerizing anhydride-cured epoxide resins, and azepan-2-one, respectively. The protected carbene is synthesized from 1,3-dimethylimidazolium-2-carboxylate in the presence of two equivalents of cyclohexyl isocyanate. In the synthesis of epoxide resin thermosets, this class of latent NHC allows the production of fast and fully cured materials with high crosslinking content. Fast and complete conversion is found in the anionic ring opening polymerization (AROP) of azepan-2-one (ε-caprolactam, CLA) with and without additional activators.

Volumetric laser endomicroscopy and its application to Barrett's esophagus: results from a 1,000 patient registry.

Volumetric laser endomicroscopy (VLE) uses optical coherence tomography (OCT) for real-time, microscopic cross-sectional imaging. A US-based multi-center registry was constructed to prospectively collect data on patients undergoing upper endoscopy during which a VLE scan was performed. The objective of this registry was to determine usage patterns of VLE in clinical practice and to estimate quantitative and qualitative performance metrics as they are applied to Barrett's esophagus (BE) management. All procedures utilized the NvisionVLE Imaging System (NinePoint Medical, Bedford, MA) which was used by investigators to identify the tissue types present, along with focal areas of concern. Following the VLE procedure, investigators were asked to answer six key questions regarding how VLE impacted each case. Statistical analyses including neoplasia diagnostic yield improvement using VLE was performed. One thousand patients were enrolled across 18 US trial sites from August 2014 through April 2016. In patients with previously diagnosed or suspected BE (894/1000), investigators used VLE and identified areas of concern not seen on white light endoscopy (WLE) in 59% of the procedures. VLE imaging also guided tissue acquisition and treatment in 71% and 54% of procedures, respectively. VLE as an adjunct modality improved the neoplasia diagnostic yield by 55% beyond the standard of care practice. In patients with no prior history of therapy, and without visual findings from other technologies, VLE-guided tissue acquisition increased neoplasia detection over random biopsies by 700%. Registry investigators reported that VLE improved the BE management process when used as an adjunct tissue acquisition and treatment guidance tool. The ability of VLE to image large segments of the esophagus with microscopic cross-sectional detail may provide additional benefits including higher yield biopsies and more efficient tissue acquisition. Clinicaltrials.gov NCT02215291.

Latent and Air-Stable Pre-Catalysts for the Polymerization of Dicyclopentadiene: From Penta- to Hexacoordination in Molybdenum Imido Alkylidene N-Heterocyclic Carbene Complexes.

The pentacoordinated, 16-valence electron (VE) Mo imido alkylidene N-heterocyclic carbene (NHC) complexes I1-I5 and the hexacoordinated 18-VE Mo imido alkylidene NHC complexes 1-4, 8, 10 and 12 containing a chelating ligand have been prepared and used as thermally latent catalysts in the ring-opening metathesis polymerization (ROMP) of dicyclopentadiene (DCPD). Both 10 and 12 are the first Mo imido alkylidene complexes with a chelating alkylidene featuring a carboxylate group. Complexes I1-I3 and I5 as well as 1-4 proved to be fully thermally latent in the presence of DCPD. With the changes in both the electronic and steric situation at the imido ligand provided by these pre-catalysts, different temperatures of the onset of polymerization (Tonset =65-140 °C) and for the exothermic maximum of the curing curve (Texo,max =98-183 °C) of DCPD were achieved. Also, the degree of crosslinking was successfully varied as indicated by swelling experiments in toluene, which revealed degrees of swelling between 0 and 50 %. While the introduction of a chelating alkylidene increases Tonset , the introduction of more electron-donating anionic ligands (tert-butoxide, phenoxide) resulted in a drastic reduction in Tonset , underlining the high flexibility of these systems. The hexacoordinated high-oxidation state molybdenum imido alkylidene NHC complexes 2, 3 and 4 were stable under air for at least twelve hours in the solid state.

Grubbs-Hoveyda type catalysts bearing a dicationic N-heterocyclic carbene for biphasic olefin metathesis reactions in ionic liquids.

The novel dicationic metathesis catalyst [(RuCl2(H2ITapMe2)(=CH-2-(2-PrO)-C6H4))(2+) (OTf(-))2] (Ru-2, H2ITapMe2 = 1,3-bis(2',6'-dimethyl-4'-trimethylammoniumphenyl)-4,5-dihydroimidazol-2-ylidene, OTf(-) = CF3SO3 (-)) based on a dicationic N-heterocyclic carbene (NHC) ligand was prepared. The reactivity was tested in ring opening metathesis polymerization (ROMP) under biphasic conditions using a nonpolar organic solvent (toluene) and the ionic liquid (IL) 1-butyl-2,3-dimethylimidazolium tetrafluoroborate [BDMIM(+)][BF4 (-)]. The structure of Ru-2 was confirmed by single crystal X-ray analysis.

Leukodystrophies underlying cryptic spastic paraparesis: frequency and phenotype in 76 patients.

BACKGROUND AND PURPOSE: In chronic progressive spasticity of the legs many rare causes have to be considered, including leukodystrophies due to neurometabolic disorders. To determine the frequency of leukodystrophies and the phenotypic spectrum patients with cryptic spasticity of the legs were screened for underlying neurometabolic abnormalities. METHODS: Seventy-six index patients presenting with adult-onset lower limb spasticity of unknown cause consistent with autosomal recessive inheritance were included in this study. Screening included serum levels of very long chain fatty acids for X-linked adrenoleukodystrophy/adrenomyeloneuropathy and lysosomal enzyme activities in leukocytes for metachromatic leukodystrophy, GM1-gangliosidosis, Tay-Sachs, Sandhoff and Krabbe disease. If clinical evidence was indicative of other types of leukodystrophies, additional genetic testing was conducted. Clinical characterization included neurological and psychiatric features and magnetic resonance imaging. RESULTS: Basic screening detected one index patient with metachromatic leukodystrophy, two patients with Krabbe disease and four patients with adrenoleukodystrophy/adrenomyeloneuropathy. Additional genetic testing revealed one patient with vanishing white matter disease. These patients accounted for an overall share of 11% of leukodystrophies. One patient with Krabbe disease and three patients with adrenoleukodystrophy/adrenomyeloneuropathy presented with pure spasticity of the lower limbs, whilst one patient each with Krabbe disease, metachromatic leukodystrophy and adrenoleukodystrophy/adrenomyeloneuropathy showed additional complicating symptoms. CONCLUSIONS: Adult patients presenting with cryptic spasticity of the legs should be screened for underlying X-linked adrenoleukodystrophy/adrenomyeloneuropathy and lysosomal disorders, irrespective of the presence of additional complicating symptoms. Leukodystrophies may manifest as late as the sixth decade and hyperintensity of cerebral white matter on magnetic resonance FLAIR images is not obligatory.

Predicting performance in attention by measuring key metabolites in the PCC with 7T MRS.

The posterior cingulate cortex (PCC) is a key hub of the default mode network and is known to play an important role in attention. Using ultra-high field 7 Tesla magnetic resonance spectroscopy (MRS) to quantify neurometabolite concentrations, this exploratory study investigated the effect of the concentrations of myo-inositol (Myo-Ins), glutamate (Glu), glutamine (Gln), aspartate or aspartic acid (Asp) and gamma-amino-butyric acid (GABA) in the PCC on attention in forty-six healthy participants. Each participant underwent an MRS scan and cognitive testing, consisting of a trail-making test (TMT A/B) and a test of attentional performance. After a multiple regression analysis and bootstrapping for correction, the findings show that Myo-Ins and Asp significantly influence (p < 0.05) attentional tasks. On one hand, Myo-Ins shows it can improve the completion times of both TMT A and TMT B. On the other hand, an increase in aspartate leads to more mistakes in Go/No-go tasks and shows a trend towards enhancing reaction time in Go/No-go tasks and stability of alertness without signal. No significant (p > 0.05) influence of Glu, Gln and GABA was observed.