Two Sides of Theory of Mind: Mental State Attribution to Moving Shapes in Paranoid Schizophrenia Is Independent of the Severity of Positive Symptoms.

BACKGROUND: Theory of Mind (ToM) impairment has repeatedly been found in paranoid schizophrenia. The current study aims at investigating whether this is related to a deficit in ToM (undermentalizing) or an increased ToM ability to hyperattribute others' mental states (overmentalizing). METHODS: Mental state attribution was examined in 24 patients diagnosed with schizophrenia (12 acute paranoid (APS) and 12 post-acute paranoid (PPS)) with regard to positive symptoms as well as matched healthy persons using a moving shapes paradigm. We used 3-T-functional magnetic resonance imaging (fMRI) to provide insights into the neural underpinnings of ToM due to attributional processes in different states of paranoid schizophrenia. RESULTS: In the condition that makes demands on theory of mind skills (ToM condition), in patients with diagnosed schizophrenia less appropriate mental state descriptions have been used, and they attributed mental states less often to the moving shapes than healthy persons. On a neural level, patients suffering from schizophrenia exhibited within the ToM network hypoactivity in the medial prefrontal cortex (MPFC) and hyperactivity in the temporo-parietal junction (TPJ) as compared to the healthy sample. CONCLUSIONS: Our results indicate both undermentalizing and hypoactivity in the MPFC and increased overattribution related to hyperactivity in the TPJ in paranoid schizophrenia, providing new implications for understanding ToM in paranoid schizophrenia.

Predictors of outcomes in low-flow, low-gradient aortic stenosis: results of the multicenter TOPAS Study.

BACKGROUND: Patients with low-flow, low-gradient aortic stenosis have a poor prognosis with conservative therapy but a high operative mortality if treated surgically. Recently, we proposed a new index of aortic stenosis severity derived from dobutamine stress echocardiography, the projected aortic valve area at a normal transvalvular flow rate, as superior to other conventional indices to differentiate true-severe from pseudosevere aortic stenosis. The objective of this study was to identify the determinants of survival, functional status, and change in left ventricular ejection fraction during follow-up of patients with low-flow, low-gradient aortic stenosis. METHODS AND RESULTS: One hundred one patients with low-flow, low-gradient aortic stenosis (aortic valve area

Systemic pressure does not directly affect pressure gradient and valve area estimates in aortic stenosis in vitro.

AIMS: Hypertension is a frequent finding in patients with aortic stenosis (AS). However, controversial data about the influence of systemic blood pressure on the quantification of AS have been published. METHODS AND RESULTS: Various models of AS (plates and biological valves) were studied in an in vitro circuit. Valve areas were calculated with the Doppler continuity equation and the Gorlin formula. Systolic systemic pressures were increased from 80 to 200 mmHg while flow rates were maintained constant. In addition, a computational fluid dynamics (CFD) model was constructed to test the effect of systemic pressures on pressure gradient and valve area estimates. When systemic pressure was raised, pressure gradients as well as valve areas did not change (mean difference 3.4 +/- 1.8 mmHg, range 0.4-6.8 mmHg; mean difference 0.01 +/- 0.03 cm(2), range -0.02 to 0.05 cm(2)). By multivariable analysis, neither valve area nor pressure gradient were independently affected by systemic pressure. In addition, CFD analysis revealed no effect of systemic pressure on pressure gradient and valve area. CONCLUSION: Our results suggest that blood pressure itself does not directly affect pressure gradients and valve area estimates in AS. Thus, when observed in vivo, these changes are most likely due to afterload-related variations of ejection fraction and, therefore, flow rate.

Real-Time fMRI Neurofeedback in Patients With Tobacco Use Disorder During Smoking Cessation: Functional Differences and Implications of the First Training Session in Regard to Future Abstinence or Relapse.

One of the most prominent symptoms in addiction disorders is the strong desire to consume a particular substance or to show a certain behavior (craving). The strong association between craving and the probability of relapse emphasizes the importance of craving in the therapeutic process. Former studies have demonstrated that neuromodulation using real-time fMRI (rtfMRI) neurofeedback (NF) can be used as a treatment modality in patients with tobacco use disorder. The aim of the present project was to determine whether it is possible to predict the outcome of NF training plus group psychotherapy at the beginning of the treatment. For that purpose, neuronal responses during the first rtfMRI NF session of patients who remained abstinent for at least 3 months were compared to those of patients with relapse. All patients were included in a certified smoke-free course and took part in three NF sessions. During the rtfMRI NF sessions tobacco-associated and neutral pictures were presented. Subjects were instructed to reduce their neuronal responses during the presentation of smoking cues in an individualized region of interest for craving [anterior cingulate cortex (ACC), insula or dorsolateral prefrontal cortex]. Patients were stratified to different groups [abstinence (N = 10) vs. relapse (N = 12)] according to their individual smoking status 3 months after the rtfMRI NF training. A direct comparison of BOLD responses during the first NF-session of patients who had remained abstinent over 3 months after the NF training and patients who had relapsed after 3 months showed that patients of the relapse group demonstrated enhanced BOLD responses, especially in the ACC, the supplementary motor area as well as dorsolateral prefrontal areas, compared to abstinent patients. These results suggest that there is a probability of estimating a successful withdrawal in patients with tobacco use disorder by analyzing the first rtfMRI NF session: a pronounced reduction of frontal responses during NF training in patients might be the functional correlate of better therapeutic success. The results of the first NF sessions could be useful as predictor whether a patient will be able to achieve success after the behavioral group therapy and NF training in quitting smoking or not.

B-type natriuretic peptide in low-flow, low-gradient aortic stenosis: relationship to hemodynamics and clinical outcome: results from the Multicenter Truly or Pseudo-Severe Aortic Stenosis (TOPAS) study.

BACKGROUND: The prognostic value of B-type natriuretic peptide (BNP) is unknown in low-flow, low-gradient aortic stenosis (AS). We sought to evaluate the relationship between AS and rest, stress hemodynamics, and clinical outcome. METHODS AND RESULTS: BNP was measured in 69 patients with low-flow AS (indexed effective orifice area < 0.6 cm2/m2, mean gradient < or = 40 mm Hg, left ventricular ejection fraction < or = 40%). All patients underwent dobutamine stress echocardiography and were classified as truly severe or pseudosevere AS by their projected effective orifice area at normal flow rate of 250 mL/s (effective orifice area < or = 1.0 cm2 or > 1.0 cm2). BNP was inversely related to ejection fraction at rest (Spearman correlation coefficient r(s)=-0.59, P<0.0001) and at peak stress (r(s)=-0.51, P<0.0001), effective orifice area at rest (r(s)=-0.50, P<0.0001) and at peak stress (r(s)=-0.46, P=0.0002), and mean transvalvular flow (r(s)=-0.31, P=0.01). BNP was directly related to valvular resistance (r(s)=0.42, P=0.0006) and wall motion score index (r(s)=0.36, P=0.004). BNP was higher in 29 patients with truly severe AS versus 40 with pseudosevere AS (median, 743 pg/mL [Q1, 471; Q3, 1356] versus 394 pg/mL [Q1, 191 to Q3, 906], P=0.012). BNP was a strong predictor of outcome. In the total cohort, cumulative 1-year survival of patients with BNP > or = 550 pg/mL was only 47+/-9% versus 97+/-3% with BNP < 550 (P<0.0001). In 29 patients who underwent valve replacement, postoperative 1-year survival was also markedly lower in patients with BNP > or = 550 pg/mL (53+/-13% versus 92+/-7%). CONCLUSIONS: BNP is significantly higher in truly severe than pseudosevere low-gradient AS and predicts survival of the whole cohort and in patients undergoing valve replacement.

À côté calibration - Making optimal use of time and space in quantitative high performance thin layer chromatography.

Quantitative High Performance Thin Layer Chromatography (HPTLC) requires the application of several standards to each plate, reducing the number of actual samples that can be analyzed in a single run. Using pure standard compounds and a selective detection method, the standards for quantitation can be applied besides - à côté - the chromatography area. This frees the sample application space to accommodate the maximal number of sample on each plate. Also, analysis time is spent exclusively on samples, drastically shortening the effective analysis time per sample and increasing sample throughput. Using this new calibration approach, the sample capacity of regular HPTLC methods can be increased or their scope be extended by an additional quantitative analysis. As a limitation, changes to the distribution of samples and standards within the plate as well as interferences from matrix compounds must be observed. We demonstrate the feasibility of this method by complementing an HPTLC method with a quantitative analysis of total anthocyanin content in colored wheat varieties. The quantitation was validated and compared to the conventional photometric analysis. As outcome, the additional photometric analysis could be replaced and rendered unnecessary, saving time, effort and equipment. This approach could also be employed to quantify highly retained substances, which are usually inaccessible for quantitative analysis.

Profiling and quantification of grain anthocyanins in purple pericarp × blue aleurone wheat crosses by high-performance thin-layer chromatography and densitometry.

BACKGROUND: Anthocyanins are abundant secondary metabolites responsible for most blue to blue-black, and red to purple colors of various plant organs. In wheat grains, anthocyanins are accumulated in the pericarp and/or aleurone layer. Anthocyanin pigmented wheat grains can be processed into functional foods with potential health benefits due to the antioxidant properties of the anthocyanins. The grain anthocyanin content can be increased by pyramidizing the different genes responsible for the accumulation of anthocyanins in the different grain layers. Our objective was to develop a high-performance thin-layer chromatography (HPTLC) method that allows the determination of both the anthocyanin profile and the total pigment concentration. Thereby, selection of breeding lines with significantly higher grain anthocyanin content from purple pericarp × blue aleurone wheat crosses should become more efficient than selection based on only visual scoring of grain color and the unspecific determination of anthocyanin concentration by UV/Vis spectroscopy. RESULTS: A wide variability in the grain anthocyanin content was observed in breeding lines and check varieties. The highest concentration of anthocyanins was observed in deep purple (i.e. combination of the purple pericarp and blue aleurone genetics) grained breeding lines, followed by blue aleurone and purple pericarp genotypes. Determination of the total anthocyanin content was included into the chromatographic analysis, rendering an additional photometric analysis unnecessary. Ten target zones were identified in anthocyanin pigmented wheat grains; four of these zones were typically for blue aleurone types, five for purple pericarp types, and one (i.e. kuromanin glucoside) was characteristic for both. Chemometrics applied to the anthocyanin profile recorded by scanning densitometry revealed that peak heights and peak areas are highly correlated and that seven out of the ten target zones were responsible for about 90% of the total variation in the germplasm. Multivariate analysis of these seven target zones allowed not only a separation of the genetic material into purple, blue and deep purple grained genotypes, but also the identification of genotypes with a specific anthocyanin pattern. Thereby, the original classification by visual scoring was overruled in about one-third of the breeding lines. CONCLUSIONS: The presented HPTLC method with à côté calibration allowed the profiling of the pigments and quantification of wheat grain anthocyanin content in a single analysis, replacing UV/Vis spectroscopy with subsequent HPLC analysis. Moreover, no sample preparation apart from extraction and filtration is required, and more than 15 samples can be evaluated in one analysis run, corresponding to several dozens of samples per day. Hence, the method fulfills the requirements for screening methods in early generations of a plant breeding program such as high-throughput, small sample size, high repeatability, fast determination, and reasonable costs per sample. Combined with multivariate statistical analysis, the anthocyanin pattern allowed the validation of the genetic background in the offspring of purple × blue wheat crosses and, therefore, the efficient selection of genotypes exhibiting both the cyanidin and delphinidin aglycon.

A hierarchical 3D segmentation method and the definition of vertebral body coordinate systems for QCT of the lumbar spine.

We have developed a new hierarchical 3D technique to segment the vertebral bodies in order to measure bone mineral density (BMD) with high trueness and precision in volumetric CT datasets. The hierarchical approach starts with a coarse separation of the individual vertebrae, applies a variety of techniques to segment the vertebral bodies with increasing detail and ends with the definition of an anatomic coordinate system for each vertebral body, relative to which up to 41 trabecular and cortical volumes of interest are positioned. In a pre-segmentation step constraints consisting of Boolean combinations of simple geometric shapes are determined that enclose each individual vertebral body. Bound by these constraints viscous deformable models are used to segment the main shape of the vertebral bodies. Volume growing and morphological operations then capture the fine details of the bone-soft tissue interface. In the volumes of interest bone mineral density and content are determined. In addition, in the segmented vertebral bodies geometric parameters such as volume or the length of the main axes of inertia can be measured. Intra- and inter-operator precision errors of the segmentation procedure were analyzed using existing clinical patient datasets. Results for segmented volume, BMD, and coordinate system position were below 2.0%, 0.6%, and 0.7%, respectively. Trueness was analyzed using phantom scans. The bias of the segmented volume was below 4%; for BMD it was below 1.5%. The long-term goal of this work is improved fracture prediction and patient monitoring in the field of osteoporosis. A true 3D segmentation also enables an accurate measurement of geometrical parameters that may augment the clinical value of a pure BMD analysis.

An anatomic coordinate system of the femoral neck for highly reproducible BMD measurements using 3D QCT.

In this paper, a procedure for the determination of an anatomically oriented coordinate system of the femoral neck (NCS) in 3D spiral CT datasets is described. The origin of the NCS is centered in the minimal cross-sectional area of the neck. Its three axes are defined as follows: the so called neck axis is perpendicular to this area and points towards the femoral head, the second axis is the principal axis of the minimal cross-sectional area and the third axis is perpendicular to the other two. After a semi-automatic 3D segmentation of the proximal femur the NCS is automatically determined in a two-step minimization procedure. Relative to the coordinate system volumes of interest (VOIs) are positioned in which bone mineral density (BMD) and cortical thickness are analyzed. We investigated intra- and inter-operator precision of the position of the NCS, the BMD in cortical and trabecular VOIs, and cortical thickness in nine pelvic CT datasets obtained from clinical routine examinations. We further investigated the effect of increased noise by adding Gaussian distributed noise to measured projections before tomographic reconstruction. The mean precision error (averaged form the results of the nine datasets) of the NCS position was less than 0.5 mm and smaller than 2.25 degrees . There were no significant differences between inter- and intra-operator analyses. Precision errors in trabecular BMD were smaller than 3% in a stack of five 1 mm thin slices cut perpendicularly to the neck axis and smaller than 1% in a spherical VOI encompassing the neck. Relative precision errors for cortical BMD were smaller than 3% for both VOIs. An increase of noise up to a factor of 5 caused a maximal displacement of the NCS origin position by less than 1mm and a rotation by less than 2 degrees .

Tracing myelin protein zero (P0) in vivo by construction of P0-GFP fusion proteins.

BACKGROUND: Mutations in P0, the major protein of the myelin sheath in peripheral nerves, cause the inherited peripheral neuropathies Charcot-Marie-Tooth disease type 1B (CMT1B), Dejerine-Sottas syndrome (DSS) and congenital hypomyelination (CH). We reported earlier a de novo insertional mutation c.662_663GC (Ala221fs) in a DSS patient. The c.662_663GC insertion results in a frame shift mutation Ala221fs altering the C-terminal amino acid sequence. The adhesion-relevant intracellular RSTK domain is replaced by a sequence similar to Na+/K+ ATPase. To further clarify the molecular disease mechanisms in this sporadic patient we constructed wild type P0 and the c.662_663GC mutant expression cassettes by site-specific mutagenesis and transfected the constructs into insect cells (S2, High5). To trace the effects in live cells, green fluorescent protein (GFP) has been added to the carboxyterminus of the wild type and mutated P0 protein. RESULTS: In contrast to the membrane-localized wild type P0-GFP the Ala221fs P0-GFP protein was detectable almost only in the cytoplasm of the cells, and a complete loss of adhesion function was observed. CONCLUSIONS: The present study provides evidence that GFP is a versatile tool to trace in vivo effects of P0 and its mutations. Not only a loss of adhesion function as a result of the loss of the RSTK domain, but also altered intracellular trafficking indicated by a loss of membrane insertion are possible consequences of the Ala221fs mutation.

Valve tissue characterization by magnetic resonance imaging in calcific aortic valve disease.

BACKGROUND: Calcific aortic valve disease affects 10%-15% of the elderly population, causing considerable morbidity and mortality. There is no imaging technique that allows for the assessment of tissue composition of the valve in vivo. We thus investigated whether multiparametric magnetic resonance imaging (MRI) could characterize and quantify lipid, fibrous, and mineralized tissues within aortic valve (AV) cusps. METHODS: AV leaflets were explanted from patients with severe aortic stenosis at the time of valve replacement surgery. Aortic cusps were imaged ex vivo using 1.5 T MRI using 3 gradient-echo sequences with T1, moderate T2, and proton density weightings (T1w, T2w, and PDw). Histopathologic analysis was performed on coregistered slices to identify and measure mineralized tissue, fibrous tissue, and lipid-rich tissue. Area and mean grey values were measured in all 3 weightings by standardized software. RESULTS: Four hundred ninety-two regions of interest from 30 AV leaflets were studied. Total leaflet surface and the areas of mineralized (P < 0.0001), fibrous (P = 0.002), and lipid-rich (P = 0.0001) tissues measured by MRI matched closely those measured by histopathologic examination. All 3 weightings provided significant discrimination between median grey values for mineralized, fibrous, and lipid-rich tissues (P < 0.0001 for T1w, moderate T2w, and PDw). A best-fit equation integrating the grey value data from all 3 weightings allowed multiparametric MRI to identify valve leaflet components with areas under the receiver operating characteristic curve of 0.92, 0.81, and 0.72, respectively. CONCLUSIONS: AV leaflet characteristics, including tissue composition, distribution, and area, may be successfully measured by multiparametric MRI with good to excellent accuracy.

Predictors of outcome of non-ischemic mitral valve surgery.

BACKGROUND: Data on the risk stratification of patients undergoing mitral valve (MV) surgery for non-ischemic mitral disease are sparse. The present study seeks to define them in a contemporary cohort. METHODS: 193 consecutive patients referred to non-ischemic MV surgery were prospectively studied. Baseline characteristics and the type of surgery were analyzed with regard to operative and late mortality as well as functional outcome. RESULTS: 129 patients underwent MV replacement and 64 MV repair. MV replacement patients presented with more symptoms (p = 0.010), higher EuroSCORE (6.1 versus 5.6; p=0.009), more frequently underwent additional valve surgery (7.8 versus 0%; p = 0.003) and were more frequently female (p=0.048). Operative mortality was 3.1%, two thirds of operative deaths had additional surgery of the tricuspid valve (p = 0.019). Patients were followed for 5.2 ± 2.7 years. 1-, 3-, 5- and 7-year survival rates were 93-, 91-, 82-, and 79% in MV replacement patients versus 100-, 98-, 96-, and 89% in patients with MV repair (p = 0.015). However, by multivariate logistic regression, overall mortality was determined by additional surgery of the tricuspid valve (p = 0.0103), multivessel coronary disease (p = 0.026), and age (p<0.0001), but not by the type of surgery (p=0.066). Furthermore, the type of surgery did not influence functional outcome (p = 0.515). CONCLUSIONS: Apart from age and coronary artery disease the need for additional tricuspid valve surgery significantly determines the outcome of non-ischemic MV surgery. The type of operation appears less important when the need for additional valve surgery and co-morbidities like coronary artery disease are taken into consideration.

Gender differences in clinical presentation and surgical outcome of aortic stenosis.

BACKGROUND: Little is known about the gender differences of patients undergoing aortic valve replacement (AVR) for isolated severe aortic stenosis. METHODS AND RESULTS: 408 consecutive patients (215 women and 193 men; p=0.9) were analysed. At presentation, women were older (73.7+/-9.3 years vs men 66.5+/-11.5 years; p<0.001), more symptomatic (New York Heart Association (NYHA) class: women 2.3+/-0.7 vs men 2.0+/-0.65; p<0.001), and presented with smaller valve areas (women 0.6+/-0.2 cm(2) vs men 0.7+/-0.2 cm(2); p<0.001) and higher mean pressure gradients (women 67.3+/-19.2 mm Hg vs men 62.2+/-20.0 mm Hg, p=0.001). Despite older age and more advanced disease in women, operative mortality did not differ. Survival after AVR by Kaplan-Meier analysis tended to be even better in women (92.8%, 89.8%, 81.4% vs men 89.1%, 86.6%, 76.3% at 1, 2 and 5 years, p=0.31). After division into age quintiles, the outcome of women was significantly better in patients older than 79 years (p=0.005). After adjustment for clinical characteristics, gender did not predict operative mortality and late outcome. Despite physical improvement in both groups after surgery, women remained more symptomatic (NYHA class: women 1.6+/-0.7 vs men 1.3+/-0.4; p=0.001). CONCLUSION: Although women referred to AVR are older and more symptomatic, operative and long-term mortality are not increased. In the oldest age group of 79 years and older, women even have a better outcome, presumably due to a longer mean life expectancy.