Cognitive functioning in the schizophrenia prodrome

In the last decade, there has been an increasing interest in cognitive alterations during the early course of schizophrenia. From a clinical perspective, a better understanding of cognitive functioning in putative at-risk states for schizophrenia is essential for developing optimal early intervention models. Two approaches have more recently been combined to assess the entire course of the initial schizophrenia prodrome: the predictive "basic symptom at-risk" (BS) and the ultra high-risk (UHR) criteria. Basic symptoms are considered to be present during the entire disease progression, including the initial prodrome, while the onset of symptoms captured by the UHR criteria expresses further disease progression toward frank psychosis. The present study investigated the cognitive functioning in 93 subjects who met either BS or UHR criteria and thus were assumed to be at different points on the putative trajectory to psychosis. We compared them with 43 patients with a first episode of psychosis and to 49 help-seeking patient controls. All groups performed significantly below normative values. Both at-risk groups performed at intermediate levels between the first-episode (FE) group and normative values. The UHR group demonstrated intermediate performance between the FE and BS groups. Overall, auditory working memory, verbal fluency/processing speed, and declarative verbal memory were impaired the most. Our results suggest that cognitive impairments may still be modest in the early stages of the initial schizophrenia prodrome and thus support current efforts to intervene in the early course of impending schizophrenia because early intervention may prevent or delay the onset of frank psychosis and thus prevent further cognitive damage.

Calmodulin-binding transcription activator 1 (CAMTA1) alleles predispose human episodic memory performance

Little is known about the genes and proteins involved in the process of human memory. To identify genetic factors related to human episodic memory performance, we conducted an ultra-high-density genome-wide screen at > 500 000 single nucleotide polymorphisms (SNPs) in a sample of normal young adults stratified for performance on an episodic recall memory test. Analysis of this data identified SNPs within the calmodulin-binding transcription activator 1 (CAMTA1) gene that were significantly associated with memory performance. A follow up study, focused on the CAMTA1 locus in an independent cohort consisting of cognitively normal young adults, singled out SNP rs4908449 with a P-value of 0.0002 as the most significant associated SNP in the region. These validated genetic findings were further supported by the identification of CAMTA1 transcript enrichment in memory-related human brain regions and through a functional magnetic resonance imaging experiment on individuals matched for memory performance that identified CAMTA1 allele-specific upregulation of medial temporal lobe brain activity in those individuals harboring the 'at-risk' allele for poorer memory performance. The CAMTA1 locus encodes a purported transcription factor that interfaces with the calcium-calmodulin system of the cell to alter gene expression patterns. Our validated genomic and functional biological findings described herein suggest a role for CAMTA1 in human episodic memory.

Steady state free precession magnetization transfer imaging

The formerly proposed concept for magnetization transfer imaging (MTI) using balanced steady-state free precession (SSFP) image acquisitions is in this work extended to nonbalanced protocols. This allows SSFP-based MTI of targets with high susceptibility variation (such as the musculoskeletal system), or at ultra-high magnetic fields (where balanced SSFP suffers from considerable off-resonance related image degradations). In the first part, SSFP-based MTI in human brain is analyzed based on magnetization transfer ratio (MTR) histograms. High correlations are observed among all different SSFP MTI protocols and thereby ensure proper conceptual extension to nonbalanced SSFP. The second part demonstrates SSFP-based MTI allowing fast acquisition of high resolution volumetric MTR data from human brain and cartilage at low (1.5T) to ultra-high (7.0T) magnetic fields.

Dual-energy X-ray absorptiometry for measuring total bone mineral content in the rat: study of accuracy and precision

Sequential studies of osteopenic bone disease in small animals require the availability of non-invasive, accurate and precise methods to assess bone mineral content (BMC) and bone mineral density (BMD). Dual-energy X-ray absorptiometry (DXA), which is currently used in humans for this purpose, can also be applied to small animals by means of adapted software. Precision and accuracy of DXA was evaluated in 10 rats weighing 50-265 g. The rats were anesthetized with a mixture of ketamine-xylazine administrated intraperitoneally. Each rat was scanned six times consecutively in the antero-posterior incidence after repositioning using the rat whole-body software for determination of whole-body BMC and BMD (Hologic QDR 1000, software version 5.52). Scan duration was 10-20 min depending on rat size. After the last measurement, rats were sacrificed and soft tissues were removed by dermestid beetles. Skeletons were then scanned in vitro (ultra high resolution software, version 4.47). Bones were subsequently ashed and dissolved in hydrochloric acid and total body calcium directly assayed by atomic absorption spectrophotometry (TBCa[chem]). Total body calcium was also calculated from the DXA whole-body in vivo measurement (TBCa[DXA]) and from the ultra high resolution measurement (TBCa[UH]) under the assumption that calcium accounts for 40.5% of the BMC expressed as hydroxyapatite. Precision error for whole-body BMC and BMD (mean +/- S.D.) was 1.3% and 1.5%, respectively. Simple regression analysis between TBCa[DXA] or TBCa[UH] and TBCa[chem] revealed tight correlations (n = 0.991 and 0.996, respectively), with slopes and intercepts which were significantly different from 1 and 0, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Basic symptoms in the general population and in psychotic and non-psychotic psychiatric adolescents

Cognitive-perceptive 'basic symptoms' are used complementary to ultra-high-risk criteria in order to predict onset of psychosis in the pre-psychotic phase. The aim was to investigate the prevalence of a broad selection of 'basic symptoms' in a representative general adolescent population sample (GPS; N=96) and to compare it with adolescents first admitted for early onset psychosis (EOP; N=87) or non-psychotic psychiatric disorders (NP; N=137).

Stable two-element control of dTph1 transposition in mutator strains of Petunia by an inactive ACT1 introgression from a wild species

The high copy dTph1 transposon system of Petunia (Solanaceae) is one of the most powerful insertion mutagens in plants, but its activity cannot be controlled in the commonly used mutator strains. We analysed the regulation of dTph1 activity by QTL analysis in recombinant inbred lines of the mutator strain W138 and a wild species (P. integrifolia spp. inflata). Two genetic factors were identified that control dTph1 transposition. One corresponded to the ACT1 locus on chromosome I. A second, previously undescribed locus ACT2 mapped on chromosome V. As a 6-cM introgression in W138, the P. i. inflata act1(S6) allele behaved as a single recessive locus that fully eliminated transposition of all dTph1 elements in all stages of plant development and in a heritable fashion. Weak dTph1 activity was restored in act1(S6)/ACT2(S6) double introgression lines, indicating that the P. i. inflata allele at ACT2 conferred a low level of transposition. Thus, the act1(S6) allele is useful for simple and predictable control of transposition of the entire dTph1 family when introgressed into an ultra-high copy W138 mutator strain. We demonstrate the use of the ACT1(W138)/act1(S6) allele pair in a two-element dTph1 transposition system by producing 10 000 unique and fixed dTph1 insertions in a population of 1250 co-isogenic lines. This Petunia system produces the highest per plant insertion number of any known two-element system, providing a powerful and logistically simple tool for transposon mutagenesis of qualitative as well as quantitative traits.

Self-reported attenuated psychotic-like experiences in help-seeking adolescents and their association with age, functioning and psychopathology

OBJECTIVE Self-rated attenuated psychotic-like experiences (APLEs) are increasingly used to screen for ultra-high-risk (UHR) across all ages. However, self-rated psychotic-like experiences (PLEs), in particular perception-related ones, were more frequent in children and adolescents, in which they possessed less clinical significance. We therefore explored the prevalence of different factors of APLEs in help-seeking adolescents, and their relationship with age, functioning and psychopathology METHOD As a part of the "Liberiamo il Futuro" project, help-seeking adolescents (N=171; 11-18years, 53% male) were screened with the 92-item Prodromal Questionnaire (PQ-92). A factor analysis was performed on the PQ-92 positive items (i.e., APLEs) to identify different APLE-factors. These were assessed for their association with age, functioning and psychopathology using regression analyses. RESULTS APLEs were very common in help-seeking adolescents, and formed four factors: "Conceptual Disorganization and Suspiciousness", "Perceptual Abnormalities", "Bizarre Experiences", and "Magical Ideation". Associations with age and functioning but not psychopathology were found for "Perceptual Abnormalities" that was significantly more severe in 11-12-year-olds, while "Conceptual Disorganization and Suspiciousness" was significantly related to psychopathology. CONCLUSION In line with findings on PLEs, prevalence and clinical significance of APLEs, especially perception-related ones, might depend on age and thus neurodevelopmental stage, and may fall within the normal spectrum of experience during childhood. This should be considered when screening for UHR status in younger age groups

Developing Psychosis and Its Risk States Through the Lens of Schizotypy

Starting from the early descriptions of Kraepelin and Bleuler, the construct of schizotypy was developed from observations of aberrations in nonpsychotic family members of schizophrenia patients. In contemporary diagnostic manuals, the positive symptoms of schizotypal personality disorder were included in the ultra high-risk (UHR) criteria 20 years ago, and nowadays are broadly employed in clinical early detection of psychosis. The schizotypy construct, now dissociated from strict familial risk, also informed research on the liability to develop any psychotic disorder, and in particular schizophrenia-spectrum disorders, even outside clinical settings. Against the historical background of schizotypy it is surprising that evidence from longitudinal studies linking schizotypy, UHR, and conversion to psychosis has only recently emerged; and it still remains unclear how schizotypy may be positioned in high-risk research. Following a comprehensive literature search, we review 18 prospective studies on 15 samples examining the evidence for a link between trait schizotypy and conversion to psychosis in 4 different types of samples: general population, clinical risk samples according to UHR and/or basic symptom criteria, genetic (familial) risk, and clinical samples at-risk for a nonpsychotic schizophrenia-spectrum diagnosis. These prospective studies underline the value of schizotypy in high-risk research, but also point to the lack of evidence needed to better define the position of the construct of schizotypy within a developmental psychopathology perspective of emerging psychosis and schizophrenia-spectrum disorders

Declining transition rates to psychosis: The role of diagnostic spectra and symptom overlaps in individuals with attenuated psychosis syndrome

Transition to psychosis in at-risk individuals has markedly declined in recent years. So far it has never been discussed in detail that with the growing awareness and increasing availability of early psychosis services, a much broader diagnostic spectrum is now being seen in these services. Subsequently, subjects present with symptoms that meet psychosis risk on a purely psychometric basis but may be the phenotypical expression of another underlying mental disorder. Here we critically review four groups of symptoms and clinical features that are frequently reported by individuals with suspected psychosis risk states, yet share strong commonalities with other mental disorders and conditions: isolated hallucinations; unusual bodily perceptions, hypochondriatic fears and cenesthetic psychotic symptoms; depersonalization; obsessive–compulsive, overvalued and delusional ideas. Of the 616 individuals so far assessed in the Bruderholz Early Psychosis Outpatient Service for Adolescents and Young Adults, 218 (30.5%) met ultra-high risk (UHR) criteria, 188 (86.2%) of whom suffered from one of the four above-mentioned symptom groups. The appraisal of the diagnostic spectra and their overlapping symptoms constitute a tremendous challenge in the clinical assessment of each referred individual. The final conclusion of a clinical assessment should not end with the mere assignment – or non-assignment – to a presumed psychosis risk group, but needs to take into account the ‘Gestalt’ of these particular symptoms and clinical features and thus be based on many more facets than solely a psychometric or nosological approach. Such an approach may break down the heterogeneous psychosis risk group and enable appropriate treatment regimes.

Dissecting abdominal aortic aneurysm in Ang II-infused mice: suprarenal branch ruptures and apparent luminal dilatation.

AIMS In this work, we provide novel insight into the morphology of dissecting abdominal aortic aneurysms in angiotensin II-infused mice. We demonstrate why they exhibit a large variation in shape and, unlike their human counterparts, are located suprarenally rather than infrarenally. METHODS AND RESULTS We combined synchrotron-based, ultra-high resolution ex vivo imaging (phase contrast X-Ray tomographic microscopy) with in vivo imaging (high-frequency ultrasound and contrast-enhanced micro-CT) and image-guided histology. In all mice, we observed a tear in the tunica media of the abdominal aorta near the ostium of the celiac artery. Independently we found that, unlike the gradual luminal expansion typical for human aneurysms, the outer diameter increase of angiotensin II-induced dissecting aneurysms in mice was related to one or several intramural haematomas. These were caused by ruptures of the tunica media near the ostium of small suprarenal side branches, which had never been detected by the established small animal imaging techniques. The tear near the celiac artery led to apparent luminal dilatation, while the intramural haematoma led to a dissection of the tunica adventitia on the left suprarenal side of the aorta. The number of ruptured branches was higher in those aneurysms that extended into the thoracic aorta, which explained the observed variability in aneurysm shape. CONCLUSION Our results are the first to describe apparent luminal dilatation, suprarenal branch ruptures, and intramural haematoma formation in dissecting abdominal aortic aneurysms in mice. Moreover, we validate and demonstrate the vast potential of phase contrast X-ray tomographic microscopy in cardiovascular small animal applications.

Anisotropy of magnetic susceptibility in natural olivine single crystals

Mantle flow dynamics can cause preferential alignment of olivine crystals that results in anisotropy of physical properties. To interpret anisotropy in mantle rocks, it is necessary to understand the anisotropy of olivine single crystals. We determined anisotropy of magnetic susceptibility (AMS) for natural olivine crystals. High-field AMS allows for the isolation of the anisotropy due to olivine alone. The orientations of the principal susceptibility axes are related to the olivine’s crystallographic structure as soon as it contains >3 wt % FeO. The maximum susceptibility is parallel to the c axis both at room temperature (RT) and at 77 K. The orientation of the minimum axis at RT depends on iron content; it is generally parallel to the a axis in crystals with 3–5 wt % FeO, and along b in samples with 6–10 wt % FeO. The AMS ellipsoid is prolate and the standard deviatoric susceptibility, k0, is on the order of 8*10210 m3/kg for the samples with <1wt % FeO, and ranges from 3.1*1029 m3/kg to 5.7*1029 m3/kg for samples with 3–10 wt % FeO. At 77 K, the minimum susceptibility is along b, independent of iron content. The shape of the AMS ellipsoid is prolate for samples with <5 wt % FeO, but can be prolate or oblate for higher iron content. The degree of anisotropy increases at 77 K with p0 7757.160.5. The results from this study will allow AMS fabrics to be used as a proxy for olivine texture in ultramafic rocks with high olivine content.

Magnetic anisotropy in clinopyroxene and orthopyroxene single crystals

Pyroxenes constitute an important component in mafic igneous and metamorphic rocks. They often possess a prismatic habit, and their long axis, the crystallographic c axis, helps define a lineation in a textured rock. Anisotropy of magnetic susceptibility (AMS) serves as a fabric indicator in igneous and metamorphic rocks. If a rock’s AMS is carried by pyroxenes, it can be related to their crystallographic preferred orientation and degree of alignment. This requires knowing the intrinsic AMS of pyroxene single crystals. This study provides a comprehensive low-field and high-field AMS investigation of chemically diverse orthopyroxene and clinopyroxene crystals in relation to crystal structure, chemical composition, oxidation state of Fe, and the possible presence of ferromagnetic inclusions. The paramagnetic anisotropy, extracted from high-field data, shows clear relationships to crystallographic directions and Fe concentration both in clinopyroxene and orthopyroxene. In the diopside-augite series, the intermediate susceptibility is parallel to b, and the maximum is at 45° to the c axis. In aegirine, the intermediate axis remains parallel to b, while the maximum susceptibility is parallel to c. The AMS of spodumene depends on Fe concentration. In enstatite, the maximum susceptibility aligns with c and the minimum with b, and in the case of hypersthene, the maximum susceptibility is normal to the exsolution lamellae. Magnetite inclusions within augite possess a ferromagnetic anisotropy with consistent orientation of the principal susceptibilities, which dominates the low-field anisotropy. These results provide better understanding of magnetic anisotropy in pyroxenes and form a solid basis for interpretation of magnetic fabrics in pyroxene-bearing rocks.

Metabolomics reveals herbivore-induced metabolites of resistance and susceptibility in maize leaves and roots

Plants respond to herbivory by reprogramming their metabolism. Most research in this context has focused on locally induced compounds that function as toxins or feeding deterrents. We developed an ultra-high-pressure liquid chromatography time-of-flight mass spectrometry (UHPLC-TOF-MS)-based metabolomics approach to evaluate local and systemic herbivore-induced changes in maize leaves, sap, roots and root exudates without any prior assumptions about their function. Thirty-two differentially regulated compounds were identified from Spodoptera littoralis-infested maize seedlings and isolated for structure assignment by microflow nuclear magnetic resonance (CapNMR). Nine compounds were quantified by a high throughput direct nano-infusion tandem mass spectrometry/mass spectrometry (MS/MS) method. Leaf infestation led to a marked local increase of 1,3-benzoxazin-4-ones, phospholipids, N-hydroxycinnamoyltyramines, azealic acid and tryptophan. Only few changes were found in the root metabolome, but 1,3-benzoxazin-4-ones increased in the vascular sap and root exudates. The role of N-hydroxycinnamoyltyramines in plant–herbivore interactions is unknown, and we therefore tested the effect of the dominating p-coumaroyltyramine on S. littoralis. Unexpectedly, p-coumaroyltyramine was metabolized by the larvae and increased larval growth, possibly by providing additional nitrogen to the insect. Taken together, this study illustrates that herbivore attack leads to the induction of metabolites that can have contrasting effects on herbivore resistance in the leaves and roots.

The CHEOPS mission

Ground based radial velocity (RV) searches continue to discover exoplanets below Neptune mass down to Earth mass. Furthermore, ground- based transit searches now reach milli-mag photometric precision and can dis- cover Neptune size planets around bright stars. These searches will find exo- planets around bright stars anywhere on the sky, their discoveries representing prime science targets for further study due to the proximity and brightness of their host stars. A mission for transit follow-up measurements of these prime targets is currently lacking. The first ESA S-class mission CHEOPS (CHarac- terizing ExoPlanet Satellite) will fill this gap. It will perform ultra-high preci- sion photometric monitoring of selected bright target stars almost anywhere on the sky with sufficient precision to detect Earth-sized transits. It will be able to detect transits of RV-planets by photometric monitoring if the geometric con- figuration results in a transit. For Hot Neptunes discovered from the ground, CHEOPS will be able to improve the transit light curve so that the radius can be determined precisely. Because of the host stars’ brightness, high precision RV measurements will be possible for all targets. All planets observed in tran- sit by CHEOPS will be validated and their masses will be known. This will provide valuable data for constraining the mass-radius relation of exoplanets, especially in the Neptune-mass regime. During the planned 3.5 year mission, about 500 targets will be observed. There will be 20% of open time available for the community to develop new science programmes.

Time-Resolved Ultra–High Resolution Optical Coherence Tomography for Real-Time Monitoring of Selective Retina Therapy

Purpose: Selective retina therapy (SRT) is a novel treatment for retinal pathologies, solely targeting the retinal pigment epithelium (RPE). During SRT, the detection of an immediate tissue reaction is challenging as tissue effects remain limited to intracellular RPE photodisruption. Time-resolved ultra-high axial resolution optical coherence tomography (OCT) is thus evaluated for the monitoring of dynamic optical changes at and around the RPE during SRT. Methods: An experimental OCT system with an ultra-high axial resolution of 1.78 µm was combined with an SRT system and time-resolved OCT M-scans of the target area were recorded from four patients undergoing SRT. OCT scans were analyzed and OCT morphology was correlated with findings in fluorescein angiography, fundus photography and cross-sectional OCT. Results: In cases where the irradiation caused RPE damage proven by fluorescein angiography, the lesions were well discernible in time-resolved OCT images but remained invisible in fundus photography and cross-sectional OCT acquired after treatment. If RPE damage was introduced, all applied SRT pulses led to detectable signal changes in the time-resolved OCT images. The extent of optical signal variation seen in the OCT data appeared to scale with the applied SRT pulse energy. Conclusion: The first clinical results proved that successful SRT irradiation induces detectable changes in the OCT M-scan signal while it remains invisible in conventional ophthalmoscopic imaging. Thus, real-time high-resolution OCT is a promising modality to monitor and analyze tissue effects introduced by selective retina therapy and may be used to guide SRT in an automatic feedback mode.