[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.

Functional genomics approaches in parasitic helminths.

As research on parasitic helminths is moving into the post-genomic era, an enormous effort is directed towards deciphering gene function and to achieve gene annotation. The sequences that are available in public databases undoubtedly hold information that can be utilized for new interventions and control but the exploitation of these resources has until recently remained difficult. Only now, with the emergence of methods to genetically manipulate and transform parasitic worms will it be possible to gain a comprehensive understanding of the molecular mechanisms involved in nutrition, metabolism, developmental switches/maturation and interaction with the host immune system. This review focuses on functional genomics approaches in parasitic helminths that are currently used, to highlight potential applications of these technologies in the areas of cell biology, systems biology and immunobiology of parasitic helminths.

Familial Kleefstra syndrome due to maternal somatic mosaicism for interstitial 9q34.3 microdeletions.

The Kleefstra syndrome (Online Mendelian Inheritance in Man 607001) is caused by a submicroscopic 9q34.3 deletion or by intragenic euchromatin histone methyl transferase 1 (EHMT1) mutations. So far only de novo occurrence of mutations has been reported, whereas 9q34.3 deletions can be either de novo or caused by complex chromosomal rearrangements or translocations. Here we give the first descriptions of affected parent-to-child transmission of Kleefstra syndrome caused by small interstitial deletions, approximately 200 kb, involving part of the EHMT1 gene. Additional genome-wide array studies in the parents showed the presence of similar deletions in both mothers who only had mild learning difficulties and minor facial characteristics suggesting either variable clinical expression or somatic mosaicism for these deletions. Further studies showed only one of the maternal deletions resulted in significantly quantitative differences in signal intensity on the array between the mother and her child. But by investigating different tissues with additional fluorescent in situ hybridization (FISH) and multiplex ligation-dependent probe amplification (MLPA) analyses, we confirmed somatic mosaicism in both mothers. Careful clinical and cytogenetic assessments of parents of an affected proband with an (interstitial) 9q34.3 microdeletion are merited for accurate estimation of recurrence risk.

Circular stapled pyloroplasty: a fast and effective technique for pyloric disruption during esophagectomy with gastric pull-up.

The necessity of pyloroplasty after esophagectomy and gastric pull-up is debated. Disadvantages of a standard pyloroplasty include the potential for leak, shortening of the length of the graft, and complexity when done during a minimally invasive procedure. The aim of this study is to report our experience with a novel internal pyloroplasty technique using a circular stapler (CS pyloroplasty), which is applicable for both laparoscopic and open esophagectomy. The records of all patients who underwent an esophagectomy with gastric pull-up and pyloroplasty between 2002 and 2007 were reviewed. The CS pyloroplasty was performed through a lesser curve gastrotomy with a 21-mm CS, while the standard pyloroplasty entailed a longitudinal full thickness incision through the pylorus with mucosal closure in the same direction and a Graham patch. A CS pyloroplasty was performed in 144 and a standard pyloroplasty in 133 patients. The median patient age was 66years, and the median follow-up was 17months, and was similar for both types of pyloroplasty. Routine postoperative videoesophagram was significantly more likely to show a delay in contrast transit through the pylorus after standard pyloroplasty (16% standard vs. 8% CS pyloroplasty, P= 0.03). Significantly more patients had postoperative endoscopy after standard pyloroplasty (40% standard vs. 24% CS pyloroplasty, P= 0.004), but the frequency of pyloric dilatation was similar. There were no leaks with either technique. A circular stapled pyloroplasty is as efficacious as a standard pyloroplasty after esophagectomy with gastric pull-up. Potential advantages include the ease and simplicity of the procedure along with virtually no risk of a leak and no graft shortening. The technique is amenable to both open and minimally invasive procedures.

The gene expression profile of cardia intestinal metaplasia is similar to that of Barrett's esophagus, not gastric intestinal metaplasia.

The etiology and significance of cardia intestinal metaplasia (CIM) is disputed. CIM may represent a form of Barrett's esophagus due to reflux or could reflect generalized gastric intestinal metaplasia due to Helicobacter pylori. The aim of this study was to utilize gene expression data to compare CIM to Barrett's and gastric intestinal metaplasia. Endoscopic biopsies were classified by endoscopic and histologic criteria as CIM (n= 33), Barrett's (n= 25), or gastric intestinal metaplasia of the antrum or body (n= 18). The squamocolumnar and gastroesophageal junctions were aligned in CIM patients and patients with diffuse gastric intestinal metaplasia were excluded. H. pylori was tested for in the biopsies of all patients. After laser-capture microdissection, quantitative reverse transcription-polymerase chain reaction (RT-PCR) was used to measure the mRNA expression of a panel of nine genes that has been shown to differentiate Barrett's from other foregut mucosa. Cluster analysis with linear discriminant analysis of the expression data was used to classify each sample into groups based solely on similarity of gene expression. Cluster analysis was performed for three groups (CIM vs. Barrett's vs. gastric intestinal metaplasia) and two groups (CIM + Barrett's vs. gastric intestinal metaplasia). There was no difference in H. pylori infection among groups (P= 0.66). Clustering into three groups resulted in frequent misclassification between CIM and Barrett's while misclassification of gastric intestinal metaplasia was uncommon. The CIM and Barrett's groups were then combined for two group clustering and linear discriminant analysis correctly predicted 95% of CIM and Barrett's samples and 83% of gastric intestinal metaplasia samples based on gene expression alone. In conclusion, the gene expression profiles of CIM and Barrett's esophagus were similar in 95% of biopsies and differed significantly from that of gastric intestinal metaplasia. The indistinguishable gene expression profile of CIM and BE suggests that they may share a common etiology in the majority of patients with a similar biology, and calls into question the perception that CIM is an innocuous process.

Genetic screening for nevoid basal cell carcinoma syndrome in patients with a solitary keratocystic odontogenic tumour is not useful.

AIM: The aim of this study was to investigate the need for routine genetic counselling for identification of features of nevoid basal cell carcinoma syndrome (NBCCS) in patients presenting with a solitairy keratocystic odontogenic tumour (KCOT) of the jaws. METHODS: Sixty-nine patients treated for a solitary KCOT have been followed for the possible development of second KCOTs or other signs indicative of NBCCS. In addition, 11 randomly selected patients of this group were referred for genetic counselling, including identification of germ-line mutations in the Patched gene (PTCH gene). RESULTS: In none of the 69 patients clinical and radiographic manifestations of second KCOTs and/or other features associated with NBCCS were found during a follow-up period of 49.8 months. In the 11 patients referred for genetic counselling, there were no features indicative of the presence of NBCCS. No mutations in the PTCH gene could be identified. CONCLUSION: This study does not support the need for routine genetic counselling in patients presenting with a solitairy keratocystic odontogenic tumour of the jaws.

Esophagectomy for cancer in octogenarians.

Because of changes in life expectancy, there is an increasing number of elderly patients with esophageal cancer. The aim of this study was to assess the outcome of esophagectomy for cancer in patients 80 years or older. A retrospective review was performed of the records of all patients who underwent esophagectomy for cancer from 1992 to 2007. A cardiac and pulmonary evaluation was obtained on an individual basis in the younger patients and in all octogenarians. Among 560 patients with esophagectomy for cancer, 47 patients (8%) were octogenarians. The median age of the younger group (n= 513) was 63 years (interquartile range 56-71). Octogenarians had significantly more stage III disease (49% vs 31%, P= 0.02) but received less neoadjuvant therapy than younger patients (2% vs 21%, P= 0.0004). In octogenarians, the transhiatal resection was more common than in the younger group (79% vs 36%, P < 0.0001). Weight loss prior to surgery was similar in both groups, but body mass index was significantly lower in octogenarians (25 vs 28 kg/m(2) , P= 0.0002). Major complications occurred in 26% in octogenarians and 31% in the younger group (P= 0.51). Hospital mortality was similar (9% for octogenarians vs 4% in the younger group, P= 0.13). The median postoperative hospital stay was similar at 16 days (P= 0.69). There was no difference in cancer-related survival (median survival 48.9 vs 59.3 months, P= 0.31 log-rank test). Esophagectomy can be performed safely in carefully selected octogenarians with good cardiac and pulmonary function. Patients should not be denied an esophagectomy based only on their age.

Low elevation of Svalbard glaciers drives high mass loss variability.

Compared to other Arctic ice masses, Svalbard glaciers are low-elevated with flat interior accumulation areas, resulting in a marked peak in their current hypsometry (area-elevation distribution) at  ~450 m above sea level. Since summer melt consistently exceeds winter snowfall, these low-lying glaciers can only survive by refreezing a considerable fraction of surface melt and rain in the porous firn layer covering their accumulation zones. We use a high-resolution climate model to show that modest atmospheric warming in the mid-1980s forced the firn zone to retreat upward by  ~100 m to coincide with the hypsometry peak. This led to a rapid areal reduction of firn cover available for refreezing, and strongly increased runoff from dark, bare ice areas, amplifying mass loss from all elevations. As the firn line fluctuates around the hypsometry peak in the current climate, Svalbard glaciers will continue to lose mass and show high sensitivity to temperature perturbations.

Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene.

Protein tyrosine phosphatase-1B (PTP-1B) has been implicated in the negative regulation of insulin signaling. Disruption of the mouse homolog of the gene encoding PTP-1B yielded healthy mice that, in the fed state, had blood glucose concentrations that were slightly lower and concentrations of circulating insulin that were one-half those of their PTP-1B+/+ littermates. The enhanced insulin sensitivity of the PTP-1B-/- mice was also evident in glucose and insulin tolerance tests. The PTP-1B-/- mice showed increased phosphorylation of the insulin receptor in liver and muscle tissue after insulin injection in comparison to PTP-1B+/+ mice. On a high-fat diet, the PTP-1B-/- and PTP-1B+/- mice were resistant to weight gain and remained insulin sensitive, whereas the PTP-1B+/+ mice rapidly gained weight and became insulin resistant. These results demonstrate that PTP-1B has a major role in modulating both insulin sensitivity and fuel metabolism, thereby establishing it as a potential therapeutic target in the treatment of type 2 diabetes and obesity.

Recurrence of intramucosal esophageal adenocarcinoma arising in a former esophagostomy site: a unique case report.

A 75-year-old male with a long history of gastroesophageal reflux symptoms developed adenocarcinoma proximally within a long segment of Barrett's esophagus. He was taken for esophagectomy and gastric pull-up, but intraoperatively, he was found to have a marginal blood supply in the gastric tube. A temporary left-sided esophagostomy was created with the gastric tube sutured to the left sternocleidomastoid muscle in the neck. Pathology showed an intramucosal adenocarcinoma, limited to the muscularis mucosa with surrounding high-grade dysplasia and intestinal metaplasia. The proximal esophageal margin showed no tumor cells, but there was low-grade dysplasia within Barrett's esophagus. He was reconstructed after several months, and 2 years after reconstruction, the patient noticed a nodule at the former esophagostomy site. Biopsy revealed an implant metastasis of esophageal adenocarcinoma. Here, we review the literature and discuss the possible etiology.

Prevalence of depressive disorder among patients with fibromyalgia: Systematic review and meta-analysis.

BACKGROUND: It is acknowledged that fibromyalgia (FM) as a medical (rheumatological) disorder and major depressive disorder (MDD) as a mental disorder often co-occurs, but the inconsistency is prevailing at study-level and no overall estimate of the co-occurrence exist. AIMS: This systematic review and meta-analysis aimed to estimate the overall point- and life-time prevalence of MDD among FM patients based on structured clinical interviews (SCI); and to estimate the point-prevalence of MDD among FM patients based on screening symptom scales (SSS). METHOD: The electronical databases MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and PsycINFO were searched for papers that reported on prevalence of MDD among FM patients. Eligible studies were included in a random effects meta-analysis pooling the prevalence of depression. RESULTS: The literature search identified 11 eligible studies for the meta-analysis. For SCI, the overall pooled point-prevalence (PP) was 25% (95% CI 19 to 31%), and life-time prevalence (LP) was 65% (95% CI 59 to 71%). When estimating the PP with self-administered SSS the overall pooled PP was 45% (95% CI 32 to 59%), and a single clinician-administered SSS yielded a PP of 23% (95% CI 10 to 41%). There was low inconsistency for the SCI and high inconsistency for the SSS. CONCLUSION: One fourth of all FM patients had MDD, and more than half experienced MDD during their life-time according to clinician-administered instruments. Prevalence of MDD was almost twice as high when using self-administered symptom scales and may be likely to overestimate the co-occurrence.