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The subduction of seamounts and basement ridges affects the structure, morphology, and physical state of a convergent margin. To evaluate their impact on the seismo-tectonic setting of the subduction zone and the tectonic development of the lower subducting and upper overriding plate, it is essential to know the precise location of subducted topographic features under the marine forearc. Offshore Northern Chile, the Iquique Ridge represents a broad zone of complex and heterogeneous structure of variable width on the oceanic Nazca Plate, which complicates attempts to project it beneath the forearc of the Chilean subduction zone. Here we use a state-of-the-art seismic reflection data processing approach to map structures related to ridge subduction under the marine forearc with unprecedented accuracy and resolution and evaluate their impact on the deformation of both the plate boundary and the upper plate. We show that significant ridge-related topography is currently subducting south of 20.5 °S and that the combined effect of horst and graben subduction with subduction of Iquique ridge-related thickened and elevated crust causes an upward bulging of the entire upper plate from the plate interface up to the seafloor as well as the presence of kilometer-scale anticlinal structures observed in multibeam bathymetric data that are approximately aligned with horsts seaward of the trench. In the area affected by the subducting ridge, a frontal prism is absent, which may relate to frontal subduction erosion caused by the excess lower plate topography. In contrast farther towards the north, where only isolated seamounts subduct, a small frontal prism and a slope/apron sediment cover down to 3000 m water depth are found.

The genetic architecture of atrial fibrillation (AF) encompasses low impact, common genetic variants and high impact, rare variants. Here, we characterize a high impact AF-susceptibility allele, KCNQ1 R231H, and describe its transcontinental geographic distribution and history. Induced pluripotent stem cell-derived cardiomyocytes procured from risk allele carriers exhibit abbreviated action potential duration, consistent with a gain-of-function effect. Using identity-by-descent (IBD) networks, we estimate the broad- and fine-scale population ancestry of risk allele carriers and their relatives. Analysis of ancestral migration routes reveals ancestors who inhabited Denmark in the 1700s, migrated to the Northeastern United States in the early 1800s, and traveled across the Midwest to arrive in Utah in the late 1800s. IBD/coalescent-based allele dating analysis reveals a relatively recent origin of the AF risk allele (~5000 years). Thus, our approach broadens the scope of study for disease susceptibility alleles to the context of human migration and ancestral origins., Many rare high-impact variants have been associated with disease, but the origins and functional impact are not always explored. Here, the authors trace the ancestry of a rare high impact atrial fibrillation allele in KCNQ1, and use iPSC-derived cardiomyocytes to characterize the effect of the allele.

Sediment geotechnical properties are an important component of geohazard analyses and studies on submarine slope failures on continental margins. The northern Cascadia margin is a region of repeated subduction earthquakes and related geohazards including devastating tsunamis. Despite several drilling campaigns at this margin mostly for gas hydrate studies, sediment geotechnical properties are lacking to date. We therefore investigated a set of 20 half-round samples from four drill sites of Integrated Ocean Drilling Program (IODP) Expedition 311 along a margin-perpendicular transect. Samples were analysed for Atterberg properties (liquid limit, plasticity limit, plasticity index) and consolidation state (pre-consolidation stress, over-consolidation ratio, initial void ratio and compression index). Results of these parameters are in good agreement with similar studies at the southern Cascadia margin from Ocean Drilling Program (ODP) Leg 204 and are regarded robust, despite the long time-span between sample recovery in 2005 and our analyses. Individual results are interpreted at each of the drill sites and reflect the overall tectonic state of the location within the accretionary prism. An interplay of site-specific tectonic forcing, including thrust faulting, uplift, folding, and erosion appears to govern the depth-dependent consolidation state of the sediments.

We resolve a previously unrecognized shallow subducting seamount from a re-processed multichannel seismic depth image crossing the 1994 M7.8 Java tsunami earthquake slip area. Seamount subduction is related to the uplift of the overriding plate by lateral shortening and vertical thickening, causing pronounced back-thrusting at the landward slope of the forearc high and the formation of splay faults branching off the landward flank of the subducting seamount. The location of the seamount in relation to the 1994 earthquake hypocentre and its co-seismic slip model suggests that the seamount acted as a seismic barrier to the up-dip co-seismic rupture propagation of this moderate size earthquake. The wrapping of the co-seismic slip contours around the seamount indicates that it diverted rupture propagation, documenting the control of forearc structures on seismic rupture.

Mega‐scale glacial lineations formed by the raking of ice shelves across the seafloor have been reported from multiple polar regions. Here, we present the first evidence of continental slope situated buried lineations in the southern Canadian Beaufort Sea in present‐day water depths of 220 to 800 m. Three separate surfaces with lineations are defined at sub‐seafloor depths of 40 m to 390 m. All lineations are mostly parallel to the general trend of slope contours. The uppermost surface is recognized over a distance of 56 km. In water depths > 500 m the lineations are parallel to each other at a consistent direction (43°–44°). The second lineated surface is a regionally occurring erosional unconformity. This event has two sub‐sets of lineations: mid‐slope situated lineations oriented at 42°–48°, and lineations closer to the continental shelf break at 55°–59°. The third lineated surface is an unconformable horizon buried up to 390 m below seafloor with lineaments oriented between 30° and 55°. All three sets of lineations are interpreted to have been produced by ice‐ploughing on the paleo‐seafloor through the grounding of an ice shelf. Our observations are similar to those documented along the slope off northern Alaska, Chukchi Rise, and Lomonosov Ridge. Collectively, these observations support the concept of an extensive ice shelf across the Arctic Ocean that grounded locally along its margins during multiple glaciations, including during the penultimate (or an earlier) glaciation. The youngest set of lineations indicates ice movement to the southwest with a suggested source in Amundsen Gulf and/or M'Clure Strait. Tentative age considerations for these youngest lineations indicate the first evidence for an analogous extensive ice shelf configuration for the Last Glacial Maximum., We present the first evidence of continental slope situated buried lineations in the southern Canadian Beaufort Sea in present‐day water depths of 220 to 800 m. Three stratigraphically separate surfaces with lineations have been defined from three‐dimensional seismic data. All three sets of lineations are interpreted to have originated from interactions of an ice‐shelf that locally grounded with soft sediments at the paleo‐seafloor., Ministry of Oceans and Fisheries, Korea http://dx.doi.org/10.13039/501100003566, Geological Survey of Canada‐Pacific, British Petroleum Canada, Imperial Oil Resources Canada Ltd

Seafloor heat flow measurements are utilized to determine the geothermal regime of the Danube deep-sea fan in the western Black Sea and are presented in the larger context of regional gas hydrate occurrences. Heat flow data were collected across paleo-channels in water depths of 550–1460 m. Heat flow across levees ranges from 25 to 30 mW m−2 but is up to 65 mW m−2 on channel floors. Gravity coring reveals sediment layers typical of the western Black Sea, consisting of three late Pleistocene to Holocene units, notably red clay within the lowermost unit cored. Heat flow derived from the bottom-simulating reflector (BSR), assumed to represent the base of the gas hydrate stability zone (GHSZ), deviates from seafloor measurements. These discrepancies are linked either to fast sedimentation or slumping and associated variations in sediment physical properties. Topographic effects account of up to 50% of heat flow deviations from average values. Combined with climate-induced variations in seafloor temperature and sea-level since the last glacial maximum large uncertainties in the prediction of the base of the GHSZ remain. A regional representative heat flow value is ~30 mW m−2 for the study region but deviations from this value may be up to 100%.

Highlights • In-situ temperature measurements were conducted at the Danube deep sea fan. • Operations were performed with the MARUM-MeBo200 seafloor drill rig. • The BSR is located ∼20 m below the current gas hydrate stability zone. • Seismic data suggest presence of shallower BSR-like events. Abstract Coring, geophysical logging, and in-situ temperature measurements were performed with the MARUM-MeBo200 seafloor rig to characterize gas hydrate occurrences in sediments of the Danube deep sea fan, off Romania, Black Sea. The new drilling data showed no evidence for significant gas hydrate saturations within the sediments but the presence of free gas at the depth of the bottom-simulating reflector (BSR). In-situ temperature and core-derived geochemical data suggest that the current base of the gas hydrate stability zone (BGHSZ) is ∼20 m shallower than the BSR. Investigation of the seismic data around the drill sites shows several locations where free gas previously trapped at a former BGHSZ migrated upwards forming a new reflection above the BSR. This shows that the gas hydrate system in the Danube deep sea fan is still responding to climate changes initiated at the end of the last glacial maximum.

Highlights • Physical properties obtained from core and log data at the Danube deep sea fan are reported. • Core-log-seismic integration defines stratigraphic framework at the S2 channel. • All data suggest no gas hydrate is present at drill sites within uncertainties of methods employed. Abstract Drilling, coring, and geophysical logging were performed with the MARUM-MeBo200 seafloor drilling rig to investigate gas hydrate occurrences of the Danube deep sea fan, off Romania, Black Sea. Three sites within a channel-levee complex were investigated. Geophysical log data of P-wave velocity, electrical resistivity, and spectral gamma ray are combined with core-derived physical properties of porosity, magnetic susceptibility, and bulk density. Core- and log physical property data are used to define a time-depth conversion by synthetic seismogram modeling, which is then used to interpret the seismic data. Individual polarity reversed reflectors within the stratigraphic column drilled are linked to reduction in P-wave velocity and bulk density. Those reflectors (and associated reflection packages) are accompanied by distinct and systematic changes in sediment porosity, magnetic susceptibility, and electrical resistivity. Overall, the sediments at drill site GeoB22605 (MeBo-17) represent the younger (upper) levee sequence of the channel, that has been eroded at drill site GeoB22603 (MeBo-16). Splicing seismic data across the channel from the East (MeBo-16) to the West (MeBo-17) demonstrates the continuation of reflectors underneath the channel. The upper ∼50 m below seafloor (mbsf) at site MeBo-16 do not stratigraphically belong to the same sequence of the (deeper) levee-deposits. Above the marked erosional unconformity, sediments at Site MeBo-16 are likely derived by a mixture of repeated slump-events (identified as seismically transparent units) interbedded with hemi-pelagic sedimentation. Similarly, sediments within the upper ∼20 mbsf at Site MeBo-17 are not stratigraphically the same levee-deposits, but are derived by a mixture of slump-events (also seen in the marked seafloor amphitheatre architecture of a large failure complex extending further upslope) and hemi-pelagic sedimentation. All observations combined show that the seismically observed stratigraphic pattern represents a reflectivity sequence mostly driven by variations in density (porosity) and correspondingly by changes in P-wave velocity and electrical resistivity. All observations from the geophysical log- and core, as well as geochemical data do show no evidence for the presence of any significant gas hydrates within the drilled/cored sequences.

Highlights • A modified cementation theory is developed by introducing generalized pressure-dependent normalized contact-cemented radii. • A generalized effective medium model is proposed to merge the effective medium theory and cementation theory. • Modeling and inversion schemes are proposed to quantify hydrate saturation and morphology from laboratory and well-log data. • Hydrates mainly grow as matrix-supporting form (~54%) in sands and as pore-filling form (~59%) in clay-rich marine sediments. Abstract Numerous models have been developed for prediction of gas hydrate saturation based on the microstructural relationship between gas hydrates and sediment grains. However, quantification of hydrate saturation and morphology from elastic properties has been hindered by failing to account for complex hydrate distributions. Here, we develop a generalized effective medium model by applying the modified Hashin-Shtrikman bounds to a newly developed cementation theory. This model is validated by experimental data for synthetic methane and tetrahydrofuran hydrates. Good comparison of model predictions with experimental measurements not only reveals its ability to merge the results of contact cementation theory and effective medium theory, but also indicates its feasibility for characterizing complex morphologies. Moreover, the results of inverting acoustic measurements quantitatively confirm that for synthetic samples in “excess-gas” condition gas hydrates mainly occur as a hybrid-cementing morphology with a low percentage of pore-filling morphology, whereas for pressure-core hydrate-bearing sediments in natural environments they exist as matrix-supporting and pore-filling morphologies with a very low percentage of hybrid-cementing morphology. The hydrate saturations estimated from sonic and density logs in several regions including northern Cascadia margin (Integrated Ocean Drilling Program Expedition 311, Hole U1326D and Hole U1327E), Alaska North Slope (Mount Elbert test well) and Mackenzie Delta (Mallik 5L-38), are comparable to the referenced hydrate saturations derived from core data and resistivity, and/or nuclear magnetic resonance log data, confirming validity and applicability of our model. Furthermore, our results indicate that ~8% hybrid-cementing, ~33% matrix-supporting and ~59% pore-filling hydrates may coexist in the fine-grained and clay-rich marine sediments on the northern Cascadia margin, whereas ~10% hybrid-cementing, ~54% matrix-supporting and ~36% pore-filling hydrates may coexist in the coarse-grained and sand-dominated terrestrial sediments of the Alaska North Slope and Mackenzie Delta.

We report on the geochemistry of hydrocarbons and pore waters down to 62.5 mbsf, collected by drilling with the MARUM‐MeBo70 and by gravity coring at the Lunde pockmark in the Vestnesa Ridge. Our data document the origin and transformations of volatiles feeding gas emissions previously documented in this region. Gas hydrates are present where a fracture network beneath the pockmark focusses migration of thermogenic hydrocarbons characterized by their C1/C2+ and stable isotopic compositions (δ2H‐CH4, δ13C‐CH4). Measured geothermal gradients (~80°C km‐1) and known formation temperatures (>70°C) suggest that those hydrocarbons are formed at depths >800 mbsf. A combined analytical/modeling approach, including concentration and isotopic mass balances, reveals that pockmark sediments experience diffuse migration of thermogenic hydrocarbons. However, at sites without channeled flow this appears to be limited to depths > ~50 mbsf. At all sites we document a contribution of microbial methanogenesis to the overall carbon cycle that includes a component of secondary carbonate reduction (CR) – i.e. reduction of dissolved inorganic carbon (DIC) generated by anaerobic oxidation of methane (AOM) in the uppermost methanogenic zone. AOM and CR rates are spatially variable within the pockmark and are highest at high‐flux sites. These reactions are revealed by 13C‐DIC depletions at the sulfate‐methane interface at all sites. However, 13C‐CH4 depletions are only observed at the low methane flux sites because changes in the isotopic composition of the overall methane pool are masked at high‐flux sites. 13C‐depletions of TOC suggest that at seeps sites, methane‐derived carbon is incorporated into de novo synthesized biomass.

Despite being recommended for use in clinical trials, the consensus remission criteria were found to leave patients with persisting symptoms, relevant areas of functional impairment and a decreased sense of wellbeing. Therefore, to evaluate the appropriateness of the schizophrenia consensus criteria, a definition of remission based on the Clinical Global Impression Scale (CGI) was developed and remitter subgroups were compared.239 patients with a schizophrenia spectrum disorder were evaluated regarding their remission status after inpatient treatment. Remission in schizophrenia was defined according to the symptom-severity component of the consensus criteria by Andreasen et al. and a CGI based definition was calculated using sensitivity and specificity using receiver operating curves (asymptomatic remitter). Both remitter groups (schizophrenia consensus versus asymptomatic remitters) were compared regarding different clinical variables at discharge as well as the likelihood to relapse within a 1-year follow-up period. Both schizophrenia remitter subgroups were compared to remitters in major depression as a reference value.Following the consensus criteria, 63% of the schizophrenia patients were in remission compared to only 18% following the asymptomatic criterion. The schizophrenia consensus remitters were less likely to be concurrent treatment responders (p 0.0001), had a significantly greater illness severity (p 0.0001) and less functioning (p = 0.0358) as well as a significantly greater risk to relapse (p = 0.0174) compared to the schizophrenia asymptomatic remitters as well as the depressed remitters.It should be critically re-evaluated if the currently proposed consensus criteria are adequate to measure what is traditionally understood to be remission.

The Nootka fault zone is a ridge‐trench‐trench transform fault that was initiated ~4 Ma when the Explorer ridge became independent of the Juan de Fuca ridge. Multibeam data around the fault zone and a compilation of several seismic reflection surveys provide insight into initiation of strike‐slip faults. Previous interpretations assumed that the two faults seen cutting the seafloor are subparallel to shear between the Explorer and Juan de Fuca plates and formed instantaneously at 4 Ma. Increased data density shows that these faults are subparallel to seafloor magnetic anomalies and appear to have utilized extensional faults formed at the ridge. They are surrounded by numerous buried steeply dipping, small‐offset growth faults; at least some of which are likely still active. Our observations corroborate analogue models of strike‐slip fault initiation that predict formation of Riedel‐like shears within a zone of faulting and that displacement localizes over time. The existence of several long subparallel faults and a very wide zone of faulting has been predicted by models of distributed shear at depth. Along the Nootka fault zone basement has risen by several hundred meters and bright reversed‐polarity reflectors some of which are interpreted to be methane hydrate reflectors are common. Hydration, likely as serpentinization, of the upper mantle could explain both sets of observations: Serpentinization can result in a 30–50% volume expansion and methane is observed in vents driven by this process. Biogenic sources of methane are likely to be present and concentrated by currently active fluid flow in the faulted sediments.

Supplemental Digital Content is available in the text., Rationale: Telomerase is a nuclear regulator of telomere elongation with recent reports suggesting a role in regulation of mitochondrial reactive oxygen species. Flow-mediated dilation in patients with cardiovascular disease is dependent on the formation of reactive oxygen species. Objective: We examined the hypothesis that telomerase activity modulates microvascular flow-mediated dilation, and loss of telomerase activity contributes to the change of mediator from nitric oxide to mitochondrial hydrogen peroxide in patients with coronary artery disease (CAD). Methods and Results: Human coronary and adipose arterioles were isolated for videomicroscopy. Flow-mediated dilation was measured in vessels pretreated with the telomerase inhibitor BIBR-1532 or vehicle. Statistical differences between groups were determined using a 2-way analysis of variance repeated measure (n≥4; P

Long‐term warming of the continental shelf of the Canadian Beaufort Sea caused by the transgression associated with the last deglaciation may be causing decomposition of relict offshore subsea permafrost and gas hydrates. To evaluate this possibility, pore waters from 118 sediment cores up to 7.3‐m long were taken on the shelf and slope and analyzed for chloride concentrations and δ180 and δD composition. We observed downcore decreases in pore waters Cl− concentration in sediments from all sites from the inner shelf (

An edited version of this paper was published by AGU. Copyright 2018 American Geophysical Union. Source at https://doi.org/10.1002/2017GC007288. During expedition MARIA S. MERIAN MSM57/2 to the Svalbard margin offshore Prins Karls Forland, the seafloor drill rig MARUM‐MeBo70 was used to assess the landward termination of the gas hydrate system in water depths between 340 and 446 m. The study region shows abundant seafloor gas vents, clustered at a water depth of ∼400 m. The sedimentary environment within the upper 100 m below seafloor (mbsf) is dominated by ice‐berg scours and glacial unconformities. Sediments cored included glacial diamictons and sheet‐sands interbedded with mud. Seismic data show a bottom simulating reflector terminating ∼30 km seaward in ∼760 m water depth before it reaches the theoretical limit of the gas hydrate stability zone (GHSZ) at the drilling transect. We present results of the first in situ temperature measurements conducted with MeBo70 down to 28 mbsf. The data yield temperature gradients between ∼38°C km−1 at the deepest site (446 m) and ∼41°C km−1 at a shallower drill site (390 m). These data constrain combined with in situ pore‐fluid data, sediment porosities, and thermal conductivities the dynamic evolution of the GHSZ during the past 70 years for which bottom water temperature records exist. Gas hydrate is not stable in the sediments at sites shallower than 390 m water depth at the time of acquisition (August 2016). Only at the drill site in 446 m water depth, favorable gas hydrate stability conditions are met (maximum vertical extent of ∼60 mbsf); however, coring did not encounter any gas hydrates.

Introduction The aim of this double-blind randomized study was to evaluate the response to antipsychotic treatment in schizophrenia patients with predicted high/low risk of nonresponse identified by applying a set of well-established scales and predictors of outcome and to compare efficacy between ziprasidone and haloperidol. Methods One hundred twelve schizophrenia patients (ziprasidone: n=54; haloperidol: n=58) were rated weekly on the Positive and Negative Syndrome Scale for Schizophrenia (PANSS), the Global Assessment of Functioning Scale (GAF), the Social and Occupational Functioning Scale (SOFAS), the Simpson-Angus Scale (SAS), and Hillside Akathisia Scale (HAS). Results Ninety-two patients (82%) were predicted to have a high risk of nonresponse. No significant difference regarding PANSS improvement in this subsample was found comparing ziprasidone and haloperidol (p=0.563). Also, for the total patient sample, no significant difference was found regarding the course of the PANSS total score, GAF (p=0.921), and SOFAS (p=0.658) between ziprasidone and haloperidol. Haloperidol resulted in higher scores on the SAS (p=0.001) and HAS (p=0.011). Discussion An alarmingly high number of patients were at high risk of nonresponse to antipsychotic treatment.

How long clinicians should wait before considering an antipsychotic ineffective and changing treatment in schizophrenia is an unresolved clinical question. Guidelines differ substantially in this regard. The authors conducted a diagnostic test meta-analysis using mostly individual patient data to assess whether lack of improvement at week 2 predicts later nonresponse. The search included EMBASE, MEDLINE, BIOSIS, PsycINFO, Cochrane Library, CINAHL, and reference lists of relevant articles, supplemented by requests to authors of all relevant studies. The main outcome was prediction of nonresponse, defined as

Subtyping depression is important in order to further delineate biological causes of depressive syndromes. The aim of this study was to evaluate clinical and outcome characteristics of distinct subtypes of depression and to assess proportion and features of patients fulfilling criteria for more than one subtype. Melancholic, atypical and anxious subtypes of depression were assessed in a naturalistic sample of 833 inpatients using DSM-IV specifiers based on operationalized criteria. Baseline characteristics and outcome criteria at discharge were compared between distinct subtypes and their overlap. A substantial proportion of patients (16%) were classified with more than one subtype of depression, 28% were of the distinct anxious, 7% of the distinct atypical and 5% of the distinct melancholic subtype. Distinct melancholic patients had shortest duration of episode, highest baseline depression severity, but were more often early improvers; distinct anxious patients had higher NEO-Five Factor Inventory (NEO-FFI) neuroticism scores compared with patients with unspecific subtype. Melancholic patients with overlap of anxious features had worse treatment outcome compared to distinct melancholic and distinct anxious subtype. Distinct subtypes differed in only few variables and patients with overlap of depression subtypes may have independent clinical and outcome characteristics. Studies investigating biological causes of subtypes of depression should take influence of features of other subtypes into account.

The aim of this study was to evaluate residual symptoms in patients achieving remission according to the consensus criteria and to analyze their potential influence on the patient’s outcome one year after discharge. In total, 399 patients suffering from a schizophrenia spectrum disorder were evaluated within a naturalistic study. Remission status was examined using the consensus criteria. Residual symptoms were defined as any symptom present at the time-point of remission following analogous analyses performed in depressed patients. Therefore, a PANSS item with a symptom severity of >1 (= at least borderline mentally ill) was defined to be a residual symptom. Remitters with and without residual symptoms were compared regarding psychopathology, functioning and side effects. In total, 236 patients (59 %) were remitters at discharge with 94 % of them suffering from at least one residual symptom. The most common residual symptoms were blunted affect (49 %), conceptual disorganization (42 %) and social withdrawal (40 %). A significant association was found between the presence of residual symptoms and the severity of side effects (p < 0.0001) and functioning (p = 0.0003) at discharge as well as between residual symptoms and the risk of relapse and chance of remission one year after discharge. Residual symptoms were highly prevalent in remitted schizophrenia inpatients following the suggested definition. Most residual symptoms were persistent baseline symptoms suggesting an ongoing illness severity. Also, the necessity to re-evaluate the consensus criteria questioning the status of remission in these patients is also pointed out.

Human induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM)-based assays are emerging as a promising tool for the in vitro preclinical screening of QT interval-prolonging side effects of drugs in development. A major impediment to the widespread use of human iPSC-CM assays is the low throughput of the currently available electrophysiological tools. To test the precision and applicability of the near-infrared fluorescent voltage-sensitive dye 1-(4-sulfanatobutyl)-4-{β[2-(di- n-butylamino)-6-naphthyl]butadienyl}quinolinium betaine (di-4-ANBDQBS) for moderate-throughput electrophysiological analyses, we compared simultaneous transmembrane voltage and optical action potential (AP) recordings in human iPSC-CM loaded with di-4-ANBDQBS. Optical AP recordings tracked transmembrane voltage with high precision, generating nearly identical values for AP duration (AP durations at 10%, 50%, and 90% repolarization). Human iPSC-CMs tolerated repeated laser exposure, with stable optical AP parameters recorded over a 30-min study period. Optical AP recordings appropriately tracked changes in repolarization induced by pharmacological manipulation. Finally, di-4-ANBDQBS allowed for moderate-throughput analyses, increasing throughput >10-fold over the traditional patch-clamp technique. We conclude that the voltage-sensitive dye di-4-ANBDQBS allows for high-precision optical AP measurements that markedly increase the throughput for electrophysiological characterization of human iPSC-CMs.

The role of the brain-derived neurotrophic factor (BDNF) in the pathophysiology of major depressive disorder (MDD) remains to be elucidated. Recent post hoc analyses indicated a potential association of three polymorphisms in the BDNF gene with worse treatment outcome in patients with the subtype of melancholic depression. We aimed at replicating these findings in a German naturalistic multicenter follow-up. Three polymorphisms in the BDNF gene (rs7103411, rs6265 (Val66Met) and rs7124442) were genotyped in 324 patients with MDD and 470 healthy controls. We applied univariate tests and logistic regression models stratifying for depression subtype and gender. The three polymorphisms were not associated with MDD as diagnosis. Further, no associations were found in univariate tests. With logistic regression, we only found a tendency towards an association of the rs6265 (Val66Met) polymorphism with overall response to treatment (response rates: GG (val/val) < GA (val/met) < AA (met/met); p = 0.0129) and some gender differences for the rs6265 (Val66Met) and rs7103411 polymorphisms. Treatment outcome stratified for subtypes of depression did not differ significantly between the investigated polymorphisms or using haplotype analyses. However, results showed a tendency towards significance. At this stage, we cannot support an influence of these three polymorphisms. Further studies in larger patient samples to increase sample sizes of subgroups are warranted.

Factors contributing to treatment-emergent suicidal ideation (TESI) using antidepressants have been in the focus of recent research strategies. We investigated previously established clinical predictors of TESI and combined these with several polymorphisms of candidate genes in patients with major depressive disorder. Common polymorphisms involved in the tryptophan hydroxylase 1 (TPH1) and 2 (TPH2), serotonin transporter, monoamine oxidase A (MAOA) and brain-derived neurotrophic factor (BDNF) were investigated in a naturalistic inpatient study of the German research network on depression. We compared patients showing TESI with non-TESI suicidal patients and with non-suicidal patients using univariate tests to detect relevant factors, which were further tested in logistic regression and CART (Classification and Regression Trees) analyses. Of the 269 patients, TESI occurred in 22 patients (17 female), 117 patients were defined as non-TESI suicidal patients, and 130 patients were classified as non-suicidal. When comparing cases with both control groups we found the TPH2 rs1386494 (C/T) polymorphism to be moderately associated with TESI (Univariate tests: TESI vs. non-suicidality: p=0.005; adjusted: p=0.09; TESI vs. non-TESI suicidal patients: p=0.0024; adjusted: p=0.086). This polymorphism remained the only significant genetic factor in addition to clinical predictors in logistic regression and CART analyses. CART analyses suggested interactions with several clinical predictors. Haplotype analyses further supported a contribution of this polymorphism in TESI. The TPH2 rs1386494 (C/T) polymorphism might contribute to the genetic background of TESI. This polymorphism has been previously associated with committed suicide and major depressive disorder. The small number of cases warrants replication in larger patient samples. Lack of a placebo control group hampers definite conclusions on an association with antidepressive treatment.

This paper investigates the structure of psychopathological symptoms. Based on AMDP symptom profiles, a symptom space was calculated by robust nonmetric multidimensional scaling (NMDS) and the symptom structures of a sample dating from 1980 and a sample from 2002/2003 were compared. The method of NMDS presented in this study allows results from other studies to be confirmed and complemented. The symptom factors identified in the past by factor-analytic studies were replicated as clusters in two-dimensional symptom maps. Additionally, some theoretically assumed clusters of symptoms were detected that were not found in previous factor analysis approaches. From the results, which are depicted in a continuous space, new insights can be gained, especially with regard to questions of categorical and dimensional classifications. The comparison of the structural aspects of the symptomatology across more than two decades resulted in only small divergences and allows conclusions to be drawn about the stability of these structures and consequently of the symptom clusters and dimensions.

We introduce a diagnostic map that was calculated by robust non-metric multidimensional scaling based on AMDP symptom profiles of patients with schizophrenic and affective disorders to demonstrate a possibility to combine the categorical and the dimensional perspective at the same time. In the diagnostic map, a manic, a depressive, and a non-affective cluster clearly emerged. At the same time, the mania dimension (r = 0.82), the depression dimension (r = 0.68), and the apathy dimension (r = 0.74) showed high multiple regression values in the map. We found substantial overlaps of the diagnostic groups with regard to the affective spectrum but irrespective of the ICD-10 classification. Within this sample, we found the association and quality of mood symptoms to be a structuring principle in a diagnostic map. We demonstrate that this approach represents a promising way of combining the categorical and the dimensional perspective. As a practical implementation of these findings, a multidimensional diagnostic map could serve as an automated diagnostic tool based on psychopathological symptom profiles.

Background: The aim of this paper is to apply the proposed consensus remission criteria to an acutely ill inpatient sample at admission and evaluate their adaptability in this patient population and pharmaceutical trials. Methods: The Remission in Schizophrenia Working Group's consensus criteria were applied to 272 acutely ill schizophrenia patients. Patients were examined using the PANSS, HAMD, UKU and SWN-K total scales at admission as well as the GAF, SOFAS and the Strauss-Carpenter Prognostic Scale. Sociodemographic and clinical baseline variables were assessed using a standardized documentation system. Results: 33 patients ( 12 %) fulfilled the symptom severity component of the proposed remission criteria already at baseline. Almost no significant differences were found when comparing patients with achieved and failed symptom severity component that would explain the hospitalization of the patients with achieved criteria despite their apparently mild psychopathological symptoms. The only explainable difference was that patients with an achieved symptom severity component had received significantly more antipsychotics and had suffered from significantly more life events before admission. Conclusion: The present results raise the question whether the symptom severity threshold is adequate to identify patients in remission when applied in clinical trials.

Background Linking of the Clinical Global Impression (CGI) Scale and the Positive and Negative Syndrome Scale (PANSS) was performed within a naturalistic sample. Furthermore, these linking results were compared with those derived from randomized controlled trials to examine if the baseline severity might influence the linking results. Methods Biweekly PANSS and CGI ratings were performed from admission to discharge in 398 schizophrenia patients treated within a naturalistic study. Equipercentile linking was performed using the statistical program, R 2.8.1. To evaluate how the naturalistic study design would influence linkage results, a so-called study sample was computed with patients of the naturalistic study fulfilling common inclusion criteria of randomized controlled trials (n = 199). Patients not fulfilling these criteria (less ill sample) and those fulfilling the criteria (study sample) were compared using confidence intervals. Results We found a considerable difference between the linking of the CGI severity score and the PANSS total score comparing the less ill sample and the study sample. Being considered "mildly ill" at admission in the less ill sample corresponded to a PANSS total score of 47 points and to a PANSS total score of 67 points in the study sample. Considering the linking of the CGI improvement score and PANSS changes, similar results were found for CGI improvement ratings ranging from "very much improved" to "minimally improved". Conclusions Despite considerable differences, a 50% PANSS reduction was found to correspond to a clinical rating of much improved, which seems to be a suitable definition for response in clinical drug trials.

The initial management of patients with schizophrenia presenting to psychiatric emergency departments with an acute psychotic episode requires rapid decisions to be made by physicians concerning the treatment of individuals who are likely to be relatively uncooperative, agitated and lacking insight. The treatment decision must be adapted to the individual characteristics and needs of each patient. This article reviews the issues from the perspective of the initial management of acute psychosis as it is currently practised in Europe, and discusses the pragmatic implications for initial treatment decisions and the elaboration of a long-term treatment plan. Initially, administration of antipsychotics to control psychotic symptoms and benzodiazepines to control agitation represents the cornerstone of treatment. Oral medication is preferable to injectable forms wherever possible, and atypical antipsychotics are to be preferred over conventional agents because of their lower risk of extrapyramidal adverse effects, which are a major determinant of poor adherence to treatment. Whatever antipsychotic is chosen by the physician during the initial period, it is likely that it will need to be continued for many years, and it is thus important to take into account the long-term safety profile of the drug chosen, particularly in relation to extrapyramidal adverse effects, metabolic complications and quality of life. Building a therapeutic alliance with the patient and his/her family or carers is an important element that should be included in the initial management of psychosis. The long-term goal should be to minimize the risk of psychotic relapse through adequate treatment adherence.

Cuticular waxes were extracted from the leaves of a coconut mapping population generated by the controlled cross of an East African Tall and a Rennell Island Tall genotype for the construction of molecular linkage maps. The wax composition was analyzed by capillary gas chromatography/mass spectrometry, and for eight of the wax compounds, their absolute and relative amounts were determined. As reported previously for a different coconut ecotype (Malayan Yellow Dwarf), lupeol methyl ether, isoskimmiwallin, and skimmiwallin were identified as the major components of coconut cuticular wax. The additional compounds were characterized as 3-β-methoxy lupane (lupane methyl ether), lupeol and the acetic acid esters of lupeol, skimmiwallinol, and isoskimmiwallinol, respectively. Minor, nonidentified compounds amounted to some 5% of total wax content and included triterpenoids, sterols, primary alcohols, and fatty acids. The variation detected for parents and progeny with respect to the wax components allowed quantitative trait locus (QTL) analyses for their biosynthetic pathways. A total of 46 QTLs could be mapped onto the coconut linkage map which was extended by amplified fragment length polymorphism and single sequence repeat markers into a high density map with more than 1,000 mapped DNA markers. Several colocated QTLs for different traits were detected reflecting the observed correlations among characters.

Samples from the bottom of the sea were used in the exact determination of the crystals structures of naturally occurring hydrocarbon hydrates. The hydrates of methane, ethane, and propane had a cubic structure II with hexakaidecahedral and pentagonal dodecahedral cages occupied by the guest molecule.

OBJECTIVE: The aim was to investigate the hypothesis that patients with first episode schizophrenic disorders have a more favorable treatment response than those with multiple episodes. METHOD: A total of 400 inpatients from an ongoing multi-centre, follow-up program who fulfilled ICD-10 criteria for schizophrenic disorders (F2) were assessed at admission to and discharge from hospital using the Positive and Negative Syndrome Scale (PANSS). RESULTS: At admission, first episode patients (n = 121) showed higher levels of positive symptoms (PANSS positive subscore) and lower ones of negative symptoms (PANSS negative subscore) than multiple episode patients (n = 279), whereas the global disease severity (PANSS total score) was comparable. Analyses of covariance revealed that treatment response (adjusted symptom levels at discharge) was more favorable in first-episode patients, with respect to both positive and negative symptoms. CONCLUSION: The results are compatible with the hypothesis that treatment response becomes less favorable during the course of schizophrenic illness. This finding might be associated with progressive neurobiological alterations. peerReviewed

Gas hydrate samples recovered from a cold vent field offshore Vancouver Island were studied in detail both by macroscopic observations and instrumental methods (powder X-ray diffraction method (PXRD), nuclear magnetic resonance (NMR), and Raman spectroscopy). It was found that gas hydrates were massive from 2.64 to 2.94 m below seafloor (mbsf), elongated, nodular and tabular from 4.60 to 4.81 mbsf, and vein-like from 5.48 to 5.68 mbsf, showing a trend of decreasing hydrate content with increasing depth. All samples were determined to be structure I hydrate from PXRD, NMR, and Raman spectroscopies. The hydration numbers were estimated to be 6.1 ± 0.2 on average as determined from the methane distribution over the cage sites from NMR and Raman analytical results. Estimates of conversion levels indicated that ∼78% of the water in the massive samples was hydrate, down to a low value of ∼0.4% for the pore hydrate samples. The results are compared with measurements on synthetic hydrates and samples recovered from below the permafrost on the Mallik site. Differences in methane content and lattice parameters for synthetic and natural samples are relatively minor. Additional work is needed to address the presence of minor gas components and the heterogeneity of natural hydrate samples.