Glutathione Precursor, N-Acetyl-Cysteine, Modulates EEG Synchronization in Schizophrenia Patients

Background: Glutathione (GSH) dysregulation at the gene, protein and functional levels observed in schizophrenia patients, and schizophrenia-like anomalies in GSH deficit experimental models, suggest that genetic glutathione synthesis impairments represent one major risk factor for the disease (Do et al., 2009). In a randomized, double blind, placebo controlled, add-on clinical trial of 140 patients, the GSH precursor N-Acetyl-Cysteine (NAC, 2g/day, 6 months) significantly improved the negative symptoms and reduced sideeffects due to antipsychotics (Berk et al., 2008). In a subset of patients (n=7), NAC (2g/day, 2 months, cross-over design) also improved auditory evoked potentials, the NMDA-dependent mismatch negativity (Lavoie et al, 2008). Methods: To determine whether increased GSH levels would modulate the topography of functional brain connectivity, we applied a multivariate phase synchronization (MPS) estimator (Knyazeva et al, 2008) to dense-array EEGs recorded during rest with eyes closed at the protocol onset, the point of crossover, and at its end. Results: The whole-head imaging revealed a specific synchronization landscape in NAC compared to placebo condition. In particular, NAC increased MPS over frontal and left temporal regions in a frequency-specific manner. The topography and direction of MPS changes were similar and robust in all 7 patients. Moreover, these changes correlated with the changes in the Liddle's score of disorganization, thus linking EEG synchronization to the improvement of the clinical picture. Conclusions: The data suggest an important pathway towards new therapeutic strategies that target GSH dysregulation in schizophrenia. They also show the utility of MPS mapping as a marker of treatment efficacy.

Positive feedback in the transition from sexual reproduction to parthenogenesis.

Understanding how new phenotypes evolve is challenging because intermediate stages in transitions from ancestral to derived phenotypes often remain elusive. Here we describe and evaluate a new mechanism facilitating the transition from sexual reproduction to parthenogenesis. In many sexually reproducing species, a small proportion of unfertilized eggs can hatch spontaneously ('tychoparthenogenesis') and develop into females. Using an analytical model, we show that if females are mate-limited, tychoparthenogenesis can result in the loss of males through a positive feedback mechanism whereby tychoparthenogenesis generates female-biased sex ratios and increasing mate limitation. As a result, the strength of selection for tychoparthenogenesis increases in concert with the proportion of tychoparthenogenetic offspring in the sexual population. We then tested the hypothesis that mate limitation selects for tychoparthenogenesis and generates female-biased sex ratios, using data from natural populations of sexually reproducing Timema stick insects. Across 41 populations, both the tychoparthenogenesis rates and the proportions of females increased exponentially as the density of individuals decreased, consistent with the idea that low densities of individuals result in mate limitation and selection for reproductive insurance through tychoparthenogenesis. Our model and data from Timema populations provide evidence for a simple mechanism through which parthenogenesis can evolve rapidly in a sexual population.

Identification of factors associated with diagnostic error in primary care.

BACKGROUND Missed, delayed or incorrect diagnoses are considered to be diagnostic errors. The aim of this paper is to describe the methodology of a study to analyse cognitive aspects of the process by which primary care (PC) physicians diagnose dyspnoea. It examines the possible links between the use of heuristics, suboptimal cognitive acts and diagnostic errors, using Reason's taxonomy of human error (slips, lapses, mistakes and violations). The influence of situational factors (professional experience, perceived overwork and fatigue) is also analysed. METHODS Cohort study of new episodes of dyspnoea in patients receiving care from family physicians and residents at PC centres in Granada (Spain). With an initial expected diagnostic error rate of 20%, and a sampling error of 3%, 384 episodes of dyspnoea are calculated to be required. In addition to filling out the electronic medical record of the patients attended, each physician fills out 2 specially designed questionnaires about the diagnostic process performed in each case of dyspnoea. The first questionnaire includes questions on the physician's initial diagnostic impression, the 3 most likely diagnoses (in order of likelihood), and the diagnosis reached after the initial medical history and physical examination. It also includes items on the physicians' perceived overwork and fatigue during patient care. The second questionnaire records the confirmed diagnosis once it is reached. The complete diagnostic process is peer-reviewed to identify and classify the diagnostic errors. The possible use of heuristics of representativeness, availability, and anchoring and adjustment in each diagnostic process is also analysed. Each audit is reviewed with the physician responsible for the diagnostic process. Finally, logistic regression models are used to determine if there are differences in the diagnostic error variables based on the heuristics identified. DISCUSSION This work sets out a new approach to studying the diagnostic decision-making process in PC, taking advantage of new technologies which allow immediate recording of the decision-making process.

Use of Two-Part Regression Calibration Model to Correct for Measurement Error in Episodically Consumed Foods in a Single-Replicate Study Design: EPIC Case Study.

In epidemiologic studies, measurement error in dietary variables often attenuates association between dietary intake and disease occurrence. To adjust for the attenuation caused by error in dietary intake, regression calibration is commonly used. To apply regression calibration, unbiased reference measurements are required. Short-term reference measurements for foods that are not consumed daily contain excess zeroes that pose challenges in the calibration model. We adapted two-part regression calibration model, initially developed for multiple replicates of reference measurements per individual to a single-replicate setting. We showed how to handle excess zero reference measurements by two-step modeling approach, how to explore heteroscedasticity in the consumed amount with variance-mean graph, how to explore nonlinearity with the generalized additive modeling (GAM) and the empirical logit approaches, and how to select covariates in the calibration model. The performance of two-part calibration model was compared with the one-part counterpart. We used vegetable intake and mortality data from European Prospective Investigation on Cancer and Nutrition (EPIC) study. In the EPIC, reference measurements were taken with 24-hour recalls. For each of the three vegetable subgroups assessed separately, correcting for error with an appropriately specified two-part calibration model resulted in about three fold increase in the strength of association with all-cause mortality, as measured by the log hazard ratio. Further found is that the standard way of including covariates in the calibration model can lead to over fitting the two-part calibration model. Moreover, the extent of adjusting for error is influenced by the number and forms of covariates in the calibration model. For episodically consumed foods, we advise researchers to pay special attention to response distribution, nonlinearity, and covariate inclusion in specifying the calibration model.

A positive FGFR3/FOXN1 feedback loop underlies benign skin keratosis versus squamous cell carcinoma formation in humans.

Seborrheic keratoses (SKs) are common, benign epithelial tumors of the skin that do not, or very rarely, progress into malignancy, for reasons that are not understood. We investigated this by gene expression profiling of human SKs and cutaneous squamous cell carcinomas (SCCs) and found that several genes previously connected with keratinocyte tumor development were similarly modulated in SKs and SCCs, whereas the expression of others differed by only a few fold. In contrast, the tyrosine kinase receptor FGF receptor-3 (FGFR3) and the transcription factor forkhead box N1 (FOXN1) were highly expressed in SKs, and close to undetectable in SCCs. We also showed that increased FGFR3 activity was sufficient to induce FOXN1 expression, counteract the inhibitory effect of EGFR signaling on FOXN1 expression and differentiation, and induce differentiation in a FOXN1-dependent manner. Knockdown of FOXN1 expression in primary human keratinocytes cooperated with oncogenic RAS in the induction of SCC-like tumors, whereas increased FOXN1 expression triggered the SCC cells to shift to a benign SK-like tumor phenotype, which included increased FGFR3 expression. Thus,we have uncovered a positive regulatory loop between FGFR3 and FOXN1 that underlies a benign versus malignant skin tumor phenotype.

Can neurally adjusted ventilatory assist (NAVA) improve patient-ventilator interaction? A preliminary study

INTRODUCTION. NAVA is a new spontaneous-assisted ventilatory mode based on thedetection of diaphragmatic electrical activity (Eadi) and its feedback to adjust ventilatorsettings. NAVA uses the Eadi, an expression of the respiratory center's activity, to initiatepressurization, set the level of pressure support and cycle the ventilator into exhalation.Therefore, NAVA should theoretically allow near-perfect synchronization between the patientand the ventilator. However there are few data documenting these effects in intensive carepatients.OBJECTIVES. To determine whether NAVA can improve patient-ventilator synchronycompared to standard pressure support (PS) in intubated intensive care patients.METHODS. Comparative study of patient-ventilator interaction during PS with cliniciandetermined ventilator settings and NAVA with NAVA gain (proportionality factor betweenEadi and the amount of delivered inspiratory pressure) set as to obtain the same peak airwaypressure as the total pressure obtained in PS. A 20 min continuous recording with eachventilatory mode was performed allowing determination of trigger delay (Td), patient neuralinspiratory time (Tin), duration of pressurization by the ventilator (Tiv), excess durationof pressurization (Ti excess = Tiv - Tin/Tin 9 100) and number of asynchrony events byminute: non-triggering breaths, auto-triggering, double triggering, premature and delayedcycling.Results are given in mean ± SD. p is considered significant if\0.05.RESULTS. Preliminary results (mean ± SD): five patients (age 75 ± 12 years, 1 M/4F,BMI 25.7 ± 4.1 kg m-2), two pts with COPD, 1 with restrictive disease, initial settings: PS14.6 ± 1.7 cm H2O, PEEP 6.4 ± 1.5 cm H2O, NAVA gain 2.8 ± 1.3PS NAVA % reduction NAVAversus PSTd (ms) 210.4 ± 63.0 51.8 ± 12.1* 74.5 ± 5.0Ti excess (%) 12.9 ± 19.6 2.2 ± 0.6 70.8 ± 37.8n asynchrony/minute 7.6 ± 6.4 4.1 ± 3.7* 47.5 ± 17.0Respiratory rate (min-1) 16.8 ± 2.6 20.4 ± 4.7 NA* p\0.05CONCLUSION. Compared to standard PS, NAVA improves patient ventilator interaction byreducing Td and the overall incidence of asynchrony events. There is also a strong trend inreducing delayed cycling. This ongoing trial should provide evidence that NAVA can indeedimprove patient-ventilator synchrony in intubated patients undergoing PS.REFERENCE(S). 1. Sinderby C, Navalesi P et al (1995) Neural control of mechanicalventilation in respiratory failure. Nat Med 5(12):1433-1436.2. Colombo D, Cammarota G et al (2008) Physiologic response to varying levels of pressuresupport and neurally adjusted ventilator assist in patients with acute respiratory failure.Intensive Care Med 34(11):2010-2018.

Altered Local Beta and Gamma Synchronization in Prefrontal Cortex of Mice with Redox Dysregulation or Maternal Immune Activation

Background: A developmental dysregulation of glutathione (GSH) synthesis leading to oxidative stress, when combined with environmental risk factors (viral infections) generating reactive oxygen species, can play a critical role in inducing schizophrenia phenotypes. GSH deficit induces morphological, physiological and behavioral anomalies analogous to those reported in schizophrenic patients, including disrupted parvalbumine (PV) inhibitory interneuron's integrity and neuronal synchrony (β/γ-oscillations). Methods: We assessed PV immunoreactivity (PV-IR) and local synchronization in prefrontal cortex of two mouse models: (1) mice with a genetic deficit in GSH (GCLM-/-) and (2) mice with prenatal immune activation at embryonic day17 (PolyI:C). Results: Adults from both mice models display reduced PV-IR in prefrontal cortex. In anterior cingulate (ACC) of GCLM-/-, appearance and maturation of PVI are delayed and worsened with peribubertal stress but not in adult one. This effect is reversed by treatment with the GSH precursor N-acetyl-cysteine. The power of beta and gamma oscillations are decreased in ACC of GCLM-/- while they increased in prelimbic cortex of PolyI:C mice. Conclusions: Despite reduced PV-IR in both models, alteration of the synchronization was different, indicating that the structural/functional disruption of the cortical circuitry was partly different in both models. Novel therapeutic strategies are proposed, based on interference with oxidative stress and inflammatory processes.

Robust synchronization of coupled circadian and cell cycle oscillators in single mammalian cells.

Circadian cycles and cell cycles are two fundamental periodic processes with a period in the range of 1 day. Consequently, coupling between such cycles can lead to synchronization. Here, we estimated the mutual interactions between the two oscillators by time-lapse imaging of single mammalian NIH3T3 fibroblasts during several days. The analysis of thousands of circadian cycles in dividing cells clearly indicated that both oscillators tick in a 1:1 mode-locked state, with cell divisions occurring tightly 5 h before the peak in circadian Rev-Erbα-YFP reporter expression. In principle, such synchrony may be caused by either unidirectional or bidirectional coupling. While gating of cell division by the circadian cycle has been most studied, our data combined with stochastic modeling unambiguously show that the reverse coupling is predominant in NIH3T3 cells. Moreover, temperature, genetic, and pharmacological perturbations showed that the two interacting cellular oscillators adopt a synchronized state that is highly robust over a wide range of parameters. These findings have implications for circadian function in proliferative tissues, including epidermis, immune cells, and cancer.

Selected configuration interaction with truncation energy error and application to the Ne atom

Selected configuration interaction (SCI) for atomic and molecular electronic structure calculations is reformulated in a general framework encompassing all CI methods. The linked cluster expansion is used as an intermediate device to approximate CI coefficients BK of disconnected configurations (those that can be expressed as products of combinations of singly and doubly excited ones) in terms of CI coefficients of lower-excited configurations where each K is a linear combination of configuration-state-functions (CSFs) over all degenerate elements of K. Disconnected configurations up to sextuply excited ones are selected by Brown's energy formula, ΔEK=(E-HKK)BK2/(1-BK2), with BK determined from coefficients of singly and doubly excited configurations. The truncation energy error from disconnected configurations, Δdis, is approximated by the sum of ΔEKS of all discarded Ks. The remaining (connected) configurations are selected by thresholds based on natural orbital concepts. Given a model CI space M, a usual upper bound ES is computed by CI in a selected space S, and EM=E S+ΔEdis+δE, where δE is a residual error which can be calculated by well-defined sensitivity analyses. An SCI calculation on Ne ground state featuring 1077 orbitals is presented. Convergence to within near spectroscopic accuracy (0.5 cm-1) is achieved in a model space M of 1.4× 109 CSFs (1.1 × 1012 determinants) containing up to quadruply excited CSFs. Accurate energy contributions of quintuples and sextuples in a model space of 6.5 × 1012 CSFs are obtained. The impact of SCI on various orbital methods is discussed. Since ΔEdis can readily be calculated for very large basis sets without the need of a CI calculation, it can be used to estimate the orbital basis incompleteness error. A method for precise and efficient evaluation of ES is taken up in a companion paper

Basis set superposition error-counterpoise corrected potential energy surfaces : application to hydrogen peroxide ... X (X=F-, Cl-, Br-, Li+, Na+) complexes

Møller-Plesset (MP2) and Becke-3-Lee-Yang-Parr (B3LYP) calculations have been used to compare the geometrical parameters, hydrogen-bonding properties, vibrational frequencies and relative energies for several X- and X+ hydrogen peroxide complexes. The geometries and interaction energies were corrected for the basis set superposition error (BSSE) in all the complexes (1-5), using the full counterpoise method, yielding small BSSE values for the 6-311 + G(3df,2p) basis set used. The interaction energies calculated ranged from medium to strong hydrogen-bonding systems (1-3) and strong electrostatic interactions (4 and 5). The molecular interactions have been characterized using the atoms in molecules theory (AIM), and by the analysis of the vibrational frequencies. The minima on the BSSE-counterpoise corrected potential-energy surface (PES) have been determined as described by S. Simón, M. Duran, and J. J. Dannenberg, and the results were compared with the uncorrected PES

A chemical Hamiltonian approach study of the basis set superposition error changes on electron densities and one- and two-center energy components

A comparision of the local effects of the basis set superposition error (BSSE) on the electron densities and energy components of three representative H-bonded complexes was carried out. The electron densities were obtained with Hartee-Fock and density functional theory versions of the chemical Hamiltonian approach (CHA) methodology. It was shown that the effects of the BSSE were common for all complexes studied. The electron density difference maps and the chemical energy component analysis (CECA) analysis confirmed that the local effects of the BSSE were different when diffuse functions were present in the calculations

Effect of basis set superposition error on the electron density of molecular complexes

The effect of basis set superposition error (BSSE) on molecular complexes is analyzed. The BSSE causes artificial delocalizations which modify the first order electron density. The mechanism of this effect is assessed for the hydrogen fluoride dimer with several basis sets. The BSSE-corrected first-order electron density is obtained using the chemical Hamiltonian approach versions of the Roothaan and Kohn-Sham equations. The corrected densities are compared to uncorrected densities based on the charge density critical points. Contour difference maps between BSSE-corrected and uncorrected densities on the molecular plane are also plotted to gain insight into the effects of BSSE correction on the electron density

Second-order Møller-Plesset perturbation theory without basis set superposition error : II : open-shell systems

The basis set superposition error-free second-order MØller-Plesset perturbation theory of intermolecular interactions was studied. The difficulties of the counterpoise (CP) correction in open-shell systems were also discussed. The calculations were performed by a program which was used for testing the new variants of the theory. It was shown that the CP correction for the diabatic surfaces should be preferred to the adiabatic ones

C-H···O H-bonded complexes: how does basis set superposition error change their potential-energy surfaces?

Geometries, vibrational frequencies, and interaction energies of the CNH⋯O3 and HCCH⋯O3 complexes are calculated in a counterpoise-corrected (CP-corrected) potential-energy surface (PES) that corrects for the basis set superposition error (BSSE). Ab initio calculations are performed at the Hartree-Fock (HF) and second-order Møller-Plesset (MP2) levels, using the 6-31G(d,p) and D95++(d,p) basis sets. Interaction energies are presented including corrections for zero-point vibrational energy (ZPVE) and thermal correction to enthalpy at 298 K. The CP-corrected and conventional PES are compared; the unconnected PES obtained using the larger basis set including diffuse functions exhibits a double well shape, whereas use of the 6-31G(d,p) basis set leads to a flat single-well profile. The CP-corrected PES has always a multiple-well shape. In particular, it is shown that the CP-corrected PES using the smaller basis set is qualitatively analogous to that obtained with the larger basis sets, so the CP method becomes useful to correctly describe large systems, where the use of small basis sets may be necessary