Analyzing spatio-temporal patterns of genuine cross-correlations

In multivariate time series analysis, the equal-time cross-correlation is a classic and computationally efficient measure for quantifying linear interrelations between data channels. When the cross-correlation coefficient is estimated using a finite amount of data points, its non-random part may be strongly contaminated by a sizable random contribution, such that no reliable conclusion can be drawn about genuine mutual interdependencies. The random correlations are determined by the signals' frequency content and the amount of data points used. Here, we introduce adjusted correlation matrices that can be employed to disentangle random from non-random contributions to each matrix element independently of the signal frequencies. Extending our previous work these matrices allow analyzing spatial patterns of genuine cross-correlation in multivariate data regardless of confounding influences. The performance is illustrated by example of model systems with known interdependence patterns. Finally, we apply the methods to electroencephalographic (EEG) data with epileptic seizure activity.

Macrophages and dendritic cells express tight junction proteins and exchange particles in an in vitro model of the human airway wall

The human airway epithelium serves as structural and functional barrier against inhaled particulate antigen. Previously, we demonstrated in an in vitro epithelial barrier model that monocyte derived dendritic cells (MDDC) and monocyte derived macrophages (MDM) take up particulate antigen by building a trans-epithelial interacting network. Although the epithelial tight junction (TJ) belt was penetrated by processes of MDDC and MDM, the integrity of the epithelium was not affected. These results brought up two main questions: (1) Do MDM and MDDC exchange particles? (2) Are those cells expressing TJ proteins, which are believed to interact with the TJ belt of the epithelium to preserve the epithelial integrity? The expression of TJ and adherens junction (AJ) mRNA and proteins in MDM and MDDC monocultures was determined by RT-PCR, and immunofluorescence, respectively. Particle uptake and exchange was quantified by flow cytometry and laser scanning microscopy in co-cultures of MDM and MDDC exposed to polystyrene particles (1 μm in diameter). MDM and MDDC constantly expressed TJ and AJ mRNA and proteins. Flow cytometry analysis of MDM and MDDC co-cultures showed increased particle uptake in MDDC while MDM lost particles over time. Quantitative analysis revealed significantly higher particle uptake by MDDC in co-cultures of epithelial cells with MDM and MDDC present, compared to co-cultures containing only epithelial cells and MDDC. We conclude from these findings that MDM and MDDC express TJ and AJ proteins which could help to preserve the epithelial integrity during particle uptake and exchange across the lung epithelium.

Optical properties of a nanomatch-like plasmonic structure

The optical properties of a match-like plasmonic nanostructure are numerically investigated using full-wave finite-difference time-domain analysis in conjunction with dispersive material models. This work is mainly motivated by the developed technique enabling reproducible fabrication of nanomatch structures as well as the growing applications that utilize the localized field enhancement in plasmonic nanostructures. Our research revealed that due to the pronounced field enhancement and larger resonance tunabilities, some nanomatch topologies show potentials for various applications in the field of, e.g., sensing as well as a novel scheme for highly reproducible tips in scanning near field optical microscopy, among others. Despite the additional degrees of freedom that are offered by the composite nature of the proposed nanomatch topology, the paper also reflects on a fundamental complication intrinsic to the material interfaces especially in the nanoscale: stoichiometric mixing. We conclude that the specificity in material modeling will become a significant issue in future research on functionalized composite nanostructures.

Rivaroxaban: Quantification by anti-FXa assay and influence on coagulation tests A study in 9 Swiss laboratories

INTRODUCTION: Rivaroxaban (RXA) is licensed for prophylaxis of venous thromboembolism after major orthopaedic surgery of the lower limbs. Currently, no test to quantify RXA in plasma has been validated in an inter-laboratory setting. Our study had three aims: to assess i) the feasibility of RXA quantification with a commercial anti-FXa assay, ii) its accuracy and precision in an inter-laboratory setting, and iii) the influence of 10mg of RXA on routine coagulation tests. METHODS: The same chromogenic anti-FXa assay (Hyphen BioMed) was used in all participating laboratories. RXA calibrators and sets of blinded probes (aim ii.) were prepared in vitro by spiking normal plasma. The precise RXA content was assessed by high-pressure liquid chromatography-tandem mass spectrometry. For ex-vivo studies (aim iii), plasma samples from 20 healthy volunteers taken before and 2 - 3hours after ingestion of 10mg of RXA were analyzed by participating laboratories. RESULTS: RXA can be assayed chromogenically. Among the participating laboratories, the mean accuracy and the mean coefficient of variation for precision of RXA quantification were 7.0% and 8.8%, respectively. Mean RXA concentration was 114±43?g/L .RXA significantly altered prothrombin time, activated partial thromboplastin time, factor analysis for intrinsic and extrinsic factors. Determinations of thrombin time, fibrinogen, FXIII and D-Dimer levels were not affected. CONCLUSIONS: RXA plasma levels can be quantified accurately and precisely by a chromogenic anti-FXa assay on different coagulometers in different laboratories. Ingestion of 10mg RXA results in significant alterations of both PT- and aPTT-based coagulation assays.

Dorsal rather than ventral visual pathways discriminate freezing status in Parkinson's disease

BACKGROUND: Although visuospatial deficits have been linked with freezing of gait (FOG) in Parkinson's disease (PD), the specific effects of dorsal and ventral visual pathway dysfunction on FOG is not well understood. METHOD: We assessed visuospatial function in FOG using an angle discrimination test (dorsal visual pathway bias) and overlapping figure test (ventral visual pathway bias), and recorded overall response time, mean fixation duration and dwell time. Covariate analysis was conducted controlling for disease duration, motor severity, contrast sensitivity and attention with Bonferroni adjustments for multiple comparisons. RESULTS: Twenty seven people with FOG, 27 people without FOG and 24 controls were assessed. Average fixation duration during angle discrimination distinguished freezing status: [F (1, 43) = 4.77 p < 0.05] (1-way ANCOVA). CONCLUSION: Results indicate a preferential dysfunction of dorsal occipito-parietal pathways in FOG, independent of disease severity, attentional deficit, and contrast sensitivity.

Alpine ibex (Capra i. ibex) is not a reservoir for chlamydial infections of domestic ruminants and humans

Chlamydophila (C.) abortus is the most common infectious abortigenic agent in small domestic ruminants in Switzerland. In contrast, the knowledge about chlamydiae in wild ruminants is scarce. As interactions between livestock and Alpine ibex (Capra i. ibex) occur on alpine pastures, the question raises if wild ruminants could play a role as carriers of chlamydiae. Thus, we investigated the prevalence of chlamydiae in Alpine ibex in Switzerland. In total, 624 sera, 676 eye swabs, 84 organ samples and 51 faecal samples from 664 ibex were investigated. Serum samples were tested by two commercial ELISA kits specific for C. abortus. Eye swabs, organs and faecal samples were examined by a Chlamydiaceae-specific real-time polymerase chain reaction (PCR). Positive cases were further investigated by the ArrayTube (AT) microarray method for chlamydial species determination. Of 624 serum samples investigated, 612 animals were negative, whereas nine sera (1.5%) reacted positively in one of the two tests and three sera showed an inconclusive result. Eye swabs of seven out of 412 ibex (1.7%) were tested positive for Chlamydiaceae by real-time PCR. By AT microarray, Chlamydophila (C.) pecorum was identified in two animals, Chlamydophila (C.) pneumoniae was detected in one animal and a mixed infection with C. abortus and C. pecorum was found in four animals. Organs and faecal samples were all negative by real-time PCR analysis. In summary, we conclude that C. abortus is not a common infectious agent in the Swiss ibex population. To our knowledge, this is the first description of C. pneumoniae in ibex. Further studies are necessary to elucidate the situation in other species of wild ruminants as chamois (Rupicapra r. rupicapra), red deer (Cervus elaphus) and roe deer (Capreolus c. capreolus) in Switzerland.

Change mechanisms of schema-centered group psychotherapy with personality disorder patients

Background This study addressed the temporal properties of personality disorders and their treatment by schema-centered group psychotherapy. It investigated the change mechanisms of psychotherapy using a novel method by which psychotherapy can be modeled explicitly in the temporal domain. Methodology and Findings 69 patients were assigned to a specific schema-centered behavioral group psychotherapy, 26 to social skills training as a control condition. The largest diagnostic subgroups were narcissistic and borderline personality disorder. Both treatments offered 30 group sessions of 100 min duration each, at a frequency of two sessions per week. Therapy process was described by components resulting from principal component analysis of patients' session-reports that were obtained after each session. These patient-assessed components were Clarification, Bond, Rejection, and Emotional Activation. The statistical approach focused on time-lagged associations of components using time-series panel analysis. This method provided a detailed quantitative representation of therapy process. It was found that Clarification played a core role in schema-centered psychotherapy, reducing rejection and regulating the emotion of patients. This was also a change mechanism linked to therapy outcome. Conclusions/Significance The introduced process-oriented methodology allowed to highlight the mechanisms by which psychotherapeutic treatment became effective. Additionally, process models depicted the actual patterns that differentiated specific diagnostic subgroups. Time-series analysis explores Granger causality, a non-experimental approximation of causality based on temporal sequences. This methodology, resting upon naturalistic data, can explicate mechanisms of action in psychotherapy research and illustrate the temporal patterns underlying personality disorders.

Impact of suborbital climate changes in the North Atlantic on ice sheet dynamics at the Mid-Pleistocene Transition

[1] Early and Mid-Pleistocene climate, ocean hydrography and ice sheet dynamics have been reconstructed using a high-resolution data set (planktonic and benthicδ18O time series, faunal-based sea surface temperature (SST) reconstructions and ice-rafted debris (IRD)) record from a high-deposition-rate sedimentary succession recovered at the Gardar Drift formation in the subpolar North Atlantic (Integrated Ocean Drilling Program Leg 306, Site U1314). Our sedimentary record spans from late in Marine Isotope Stage (MIS) 31 to MIS 19 (1069–779 ka). Different trends of the benthic and planktonic oxygen isotopes, SST and IRD records before and after MIS 25 (∼940 ka) evidence the large increase in Northern Hemisphere ice-volume, linked to the cyclicity change from the 41-kyr to the 100-kyr that occurred during the Mid-Pleistocene Transition (MPT). Beside longer glacial-interglacial (G-IG) variability, millennial-scale fluctuations were a pervasive feature across our study. Negative excursions in the benthicδ18O time series observed at the times of IRD events may be related to glacio-eustatic changes due to ice sheets retreats and/or to changes in deep hydrography. Time series analysis on surface water proxies (IRD, SST and planktonicδ18O) of the interval between MIS 31 to MIS 26 shows that the timing of these millennial-scale climate changes are related to half-precessional (10 kyr) components of the insolation forcing, which are interpreted as cross-equatorial heat transport toward high latitudes during both equinox insolation maxima at the equator.

Antinociceptive effects, metabolism and disposition of ketamine in ponies under target-controlled drug infusion

Ketamine is widely used as an anesthetic in a variety of drug combinations in human and veterinary medicine. Recently, it gained new interest for use in long-term pain therapy administered in sub-anesthetic doses in humans and animals. The purpose of this study was to develop a physiologically based pharmacokinetic (PBPk) model for ketamine in ponies and to investigate the effect of low-dose ketamine infusion on the amplitude and the duration of the nociceptive withdrawal reflex (NWR). A target-controlled infusion (TCI) of ketamine with a target plasma level of 1 microg/ml S-ketamine over 120 min under isoflurane anesthesia was performed in Shetland ponies. A quantitative electromyographic assessment of the NWR was done before, during and after the TCI. Plasma levels of R-/S-ketamine and R-/S-norketamine were determined by enantioselective capillary electrophoresis. These data and two additional data sets from bolus studies were used to build a PBPk model for ketamine in ponies. The peak-to-peak amplitude and the duration of the NWR decreased significantly during TCI and returned slowly toward baseline values after the end of TCI. The PBPk model provides reliable prediction of plasma and tissue levels of R- and S-ketamine and R- and S-norketamine. Furthermore, biotransformation of ketamine takes place in the liver and in the lung via first-pass metabolism. Plasma concentrations of S-norketamine were higher compared to R-norketamine during TCI at all time points. Analysis of the data suggested identical biotransformation rates from the parent compounds to the principle metabolites (R- and S-norketamine) but different downstream metabolism to further metabolites. The PBPk model can provide predictions of R- and S-ketamine and norketamine concentrations in other clinical settings (e.g. horses).

The prevalence of penicillin-non-susceptible Streptococcus pneumoniae among children aged < 5 years correlates with the biannual epidemic activity of respiratory syncytial virus

This study investigated whether the epidemiology of penicillin-non-susceptible pneumococci (PNSP) colonising small children correlated with the biannual epidemic activity of respiratory syncytial virus (RSV). Colonisation rates and the prevalence of PNSP among paediatric outpatients aged < 5 years was analysed between January 1998 and September 2003 using an established national surveillance network. Resistance trends were investigated using time-series analysis to assess the correlation with the biannual pattern of RSV infections and national sales of oral paediatric formulations of antibiotics and antibiotic prescriptions to children aged < 5 years for acute respiratory tract infections. PNSP rates exhibited a biannual cycle in phase with the biannual seasonal RSV epidemics (p < 0.05). Resistance rates were higher during the winter seasons of 1998-1999 (20.1%), 2000-2001 (16.0%) and 2002-2003 (19.1%), compared with the winter seasons of 1997-1998 (8.2%), 1999-2000 (11.6%) and 2001-2002 (9.5%). Antibiotic sales and prescriptions showed regular peaks during each winter, with no significant correlation with the biannual pattern of RSV activity and seasonal trends of PNSP. RSV is an important determinant of the spread of PNSP and must be considered in strategies aimed at antimicrobial resistance control.

Haematopoietic stem cell transplantation in Switzerland. Report from the Swiss Transplant Working Group Blood and Marrow Transplantation (STABMT) Registry 1997-2003

In 1997, the Swiss Transplant Working Group Blood and Marrow Transplantation (STABMT) initiated a mandatory national registry for all haematopoietic stem cell transplants (HSCT) in Switzerland. As of 2003, information was collected of 2010 patients with a first HSCT (577 allogeneic (29%) and 1433 autologous (71%) HSCT) and 616 additional re-transplants. This included 1167 male and 843 female patients with a median age of 42.4 years (range 0.2-76.6 years). Main indications were leukaemias (592; 29%) lymphoproliferative disorders (1,061; 53%), solid tumours (295; 15%) and non-malignant disorders (62; 3%). At the time of analysis 1,263 patients were alive (63%), 747 had died (37%). Probability of survival, transplant related mortality or relapse at 5 years was 52%, 21%, 36% for allogeneic and 54%, 5%, 60% for autologous HSCT. Outcome depended on indication, donor type, stem cell source and age of patient. HSCT is an established therapy in Switzerland. These data describe current practice and outcome.

A pharmaco-EEG study on antipsychotic drugs in healthy volunteers

RATIONALE: Both psychotropic drugs and mental disorders have typical signatures in quantitative electroencephalography (EEG). Previous studies found that some psychotropic drugs had EEG effects opposite to the EEG effects of the mental disorders treated with these drugs (key-lock principle). OBJECTIVES: We performed a placebo-controlled pharmaco-EEG study on two conventional antipsychotics (chlorpromazine and haloperidol) and four atypical antipsychotics (olanzapine, perospirone, quetiapine, and risperidone) in healthy volunteers. We investigated differences between conventional and atypical drug effects and whether the drug effects were compatible with the key-lock principle. METHODS: Fourteen subjects underwent seven EEG recording sessions, one for each drug (dosage equivalent of 1 mg haloperidol). In a time-domain analysis, we quantified the EEG by identifying clusters of transiently stable EEG topographies (microstates). Frequency-domain analysis used absolute power across electrodes and the location of the center of gravity (centroid) of the spatial distribution of power in different frequency bands. RESULTS: Perospirone increased duration of a microstate class typically shortened in schizophrenics. Haloperidol increased mean microstate duration of all classes, increased alpha 1 and beta 1 power, and tended to shift the beta 1 centroid posterior. Quetiapine decreased alpha 1 power and shifted the centroid anterior in both alpha bands. Olanzapine shifted the centroid anterior in alpha 2 and beta 1. CONCLUSIONS: The increased microstate duration under perospirone and haloperidol was opposite to effects previously reported in schizophrenic patients, suggesting a key-lock mechanism. The opposite centroid changes induced by olanzapine and quetiapine compared to haloperidol might characterize the difference between conventional and atypical antipsychotics.

Identifying mechanisms of treatment effects and recovery in rehabilitation of schizophrenia: longitudinal analytic methods

The longitudinal dimension of schizophrenia and related severe mental illness is a key component of theoretical models of recovery. However, empirical longitudinal investigations have been underrepresented in the psychopathology of schizophrenia. Similarly, traditional approaches to longitudinal analysis of psychopathological data have had serious limitations. The utilization of modern longitudinal methods is necessary to capture the complexity of biopsychosocial models of treatment and recovery in schizophrenia. The present paper summarizes empirical data from traditional longitudinal research investigating recovery in symptoms, neurocognition, and social functioning. Studies conducted under treatment as usual conditions are compared to psychosocial intervention studies and potential treatment mechanisms of psychosocial interventions are discussed. Investigations of rehabilitation for schizophrenia using the longitudinal analytic strategies of growth curve and time series analysis are demonstrated. The respective advantages and disadvantages of these modern methods are highlighted. Their potential use for future research of treatment effects and recovery in schizophrenia is also discussed.

Gene expression in cultured endometrium from women with different outcomes following IVF

Estradiol and progesterone are crucial for the acquisition of receptivity and the change in transcriptional activity of target genes in the implantation window. The aim of this study was to differentiate the regulation of genes in the endometrium of patients with recurrent implantation failure (IF) versus those who became pregnant after in vitro fertilization (IVF) treatment. Moreover, the effect of embryo-derived factors on endometrial transcriptional activity was studied. Nine women with known IVF outcome (IF, M, miscarriage, OP, ongoing pregnancy) and undergoing hysteroscopy with endometrial biopsy were enrolled. Biopsies were taken during the midluteal phase. After culture in the presence of embryo-conditioned IVF media, total RNA was extracted and submitted to reverse transcription, target cDNA synthesis, biotin labelling, fragmentation and hybridization using the Affymetrix Human Genome U133A 2.0 Chip. Differential expression of selected genes was re-analysed by quantitative PCR, in which the results were calculated as threshold cycle differences between the groups and normalized to Glyceraldehyde phosphate dehydrogenase and beta-actin. Differences were seen for several genes from endometrial tissue between the IF and the pregnancy groups, and when comparing OP with M, 1875 up- and 1807 down-regulated genes were returned. Real-time PCR analysis confirmed up-regulation for somatostatin, PLAP-2, mucin 4 and CD163, and down-regulation of glycodelin, IL-24, CD69, leukaemia inhibitory factor and prolactin receptor between Op and M. When the different embryo-conditioned media were compared, no significant differential regulation could be demonstrated. Although microarray profiling may currently not be sensitive enough for studying the effects of embryo-derived factors on the endometrium, the observed differences in gene expression between M and OP suggest that it will become an interesting tool for the identification of fertility-relevant markers produced by the endometrium.

Combined ultrasmall superparamagnetic particles of iron oxide-enhanced and diffusion-weighted magnetic resonance imaging reliably detect pelvic lymph node metastases in normal-sized nodes of bladder and prostate cancer patients

BACKGROUND: Lymph node staging of bladder or prostate cancer using conventional imaging is limited. Newer approaches such as ultrasmall superparamagnetic particles of iron oxide (USPIO) and diffusion-weighted magnetic resonance imaging (DW-MRI) have inconsistent diagnostic accuracy and are difficult to interpret. OBJECTIVE: To assess whether combined USPIO and DW-MRI (USPIO-DW-MRI) improves staging of normal-sized lymph nodes in bladder and/or prostate cancer patients. DESIGN, SETTING, AND PARTICIPANTS: Twenty-one consecutive patients with bladder and/or prostate cancer were enrolled between May and October 2008. One patient was excluded secondary to bone metastases detected on DW-MRI with subsequent abstention from surgery. INTERVENTION: Patients preoperatively underwent 3-T MRI before and after administration of lymphotropic USPIO using conventional MRI sequences combined with DW-MRI. Surgery consisted of extended pelvic lymphadenectomy and resection of primary tumors. MEASUREMENTS: Diagnostic accuracies of the new combined USPIO-DW-MRI approach compared with the "classic" reading method evaluating USPIO images without and with DW-MRI versus histopathology were evaluated. Duration of the two reading methods was noted for each patient. RESULTS AND LIMITATIONS: Diagnostic accuracy (90% per patient or per pelvic side) was comparable for the classic and the USPIO-DW-MRI reading method, while time of analysis with 80 min (range 45-180 min) for the classic and 13 min (range 5-90 min) for the USPIO-DW-MRI method was significantly shorter (p<0.0001). Interobserver agreement (three blinded readers) was high with a kappa value of 0.75 and 0.84, respectively. Histopathological analysis showed metastases in 26 of 802 analyzed lymph nodes (3.2%). Of these, 24 nodes (92%) were correctly diagnosed as positive on USPIO-DW-MRI. In two patients, one micrometastasis each (1.0x0.2 mm; 0.7x0.4 mm) was missed in all imaging studies. CONCLUSIONS: USPIO-DW-MRI is a fast and accurate method for detecting pelvic lymph node metastases, even in normal-sized nodes of bladder or prostate cancer patients.