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Schizophrenia is a psychotic disorder that affects approximately 1% of the global population. However, the etiology of this illness remains a subject of debate. One of the proposed mechanisms underlying schizophrenia is the synaptic pruning mediated by microglia in the brains of individuals with schizophrenia, although the precise mechanisms of this process remain elusive. In this regard, we propose that the potential development of the disease stems from both a genetic predisposition leading to an excessive production of GABAergic neurons and an exaggerated effort to maintain the E/I (excitation/inhibition) balance in the brain.

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Atrial fibrillation (AF) is the commonest cardiac arrhythmia, affecting 3 million people in the USA and 8 million in the EU (according to the European Society of Cardiology). So, why is it that even with the best medical care, around a third of the patients are treatment resistant. Extensive research of its etiology showed that AF and its mechanisms are still debatable. Some of the AF origins are ascribed to functional and ionic heterogeneities of the heart tissue and possibly to additional triggering agents. But, have all AF origins been detected? Are all accepted origins, in fact, arrhythmogenic? In order to study these questions and specifically to check our new idea of intermittency as an arrhythmogenesis agent, we chose to employ a mathematical model which was as simple as possible, but which could still be used to observe the basic network processes of AF development. At this point we were not interested in the detailed ionic propagations nor in the actual shapes of the induced action potentials (APs) during the AF outbreaks. The model was checked by its ability to exactly recapture the basic AF developmental stages known from experimental cardiac observations and from more elaborate mathematical models. We use a simple cellular automata 2D mathematical model of N × N matrices to elucidate the field processes leading to AF in a tissue riddled with randomly distributed heterogeneities of different types, under sinus node operation, simulated by an initial line of briefly stimulated cells inducing a propagating wave, and with or without an additional active ectopic action potential pulse, in turn simulated by a transitory operation of a specific cell. Arrhythmogenic contributions, of three different types of local heterogeneities in myocytes and their collaborations, in inducing AF are examined. These are: a heterogeneity created by diffuse fibrosis, a heterogeneity created by myocytes having different refractory periods, and a new heterogeneity type, created by intermittent operation of some myocytes. The developmental stages (target waves and spirals) and the different probabilities of AF occurring under each condition, are shown. This model was established as being capable of reproducing the known AF origins and their basic development stages, and in addition has shown: (1) That diffuse fibrosis on its own is not arrhythmogenic but in combination with other arrhythmogenic agents it can either enhance or limit AF. (2) In general, combinations of heterogeneities can act synergistically, and, most importantly, (3) The new type of intermittency heterogeneity proves to be extremely arrhythmogenic. Both the intermittency risk and the fibrosis role in AF generation were established. Knowledge of the character of these arrhythmogenesis agents can be of real importance in AF treatment.

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In the last several years, quite a few papers on the joint question of transport, tortuosity and percolation have appeared in the literature, dealing with passage of miscellaneous liquids or electrical currents in different media. However, these methods have not been applied to the passage of action potential in heart fibrosis (HF), which is crucial for problems of heart arrhythmia, especially of atrial tachycardia and fibrillation. In this work we address the HF problem from these aspects. A cellular automaton model is used to analyze percolation and transport of a distributed-fibrosis inflicted heart-like tissue. Although based on a rather simple mathematical model, it leads to several important outcomes: (1) It is shown that, for a single wave front (as the one emanated by the heart's sinus node), the percolation of heart-like matrices is exactly similar to the forest fire case. (2) It is shown that, on the average, the shape of the transport (a question not dealt with in relation to forest fire, and deals with the delay of action potential when passing a fibrotic tissue) behaves like a Gaussian. (3) Moreover, it is shown that close to the percolation threshold the parameters of this Gaussian behave in a critical way. From the physical point of view, these three results are an important contribution to the general percolation investigation. The relevance of our results to cardiological issues, specifically to the question of reentry initiation, are discussed and it is shown that: (A) Without an ectopic source and under a mere sinus node operation, no arrhythmia is generated, and (B) A sufficiently high refractory period could prevent some reentry mechanisms, even in partially fibrotic heart tissue.

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The origin of post-ictal malfunctions is debatable. We want to propose a novel idea of a cause of these adverse results occurring following epileptic seizures and anesthesia. Previously we have put forward the idea that epileptic seizures termination is caused by the function of the glymphatic system in the brain. A new measurement shows that this system can be much faster than what was estimated before. Moreover, the method enabling this speeding was actually measured in brains of epilepsy subjects. So, the main objection to our model is relegated. As a possible consequence of the glymphatic process, there can be an excess cleaning of the brain's interstitial fluid. We discuss possible adverse results of this process. This over-cleaning (that can, to a lower extent, occur also during anesthesia) which results post-ictally from the previous overexpression of fluid materials by the neurons during their seizure operation, can reduce ingredients essential for regular neuronal functioning, thereby leading to function reduction and EEG suppression which last until those materials are replenished. We argue that this ingredients' scarcity is the cause of post-ictal generalized EEG suppression (PGES), of post-ictal immobility (PI) and possibly of Sudden Unexpected Death in Epilepsy Patients (SUDEP). Similarly, such cleaning can lead to morbidity and even mortality problems following anesthesia. If our assumption is correct, this understanding of the process of the problems' origin can lead to a method to remedy them by judicial supplement of the lost materials.

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Two recent postictal EEG measurements demonstrate somewhat conflicting results of epileptic behavior clearance in different brain parts. Both measurements observed two modes of seizure cessation, an abrupt and a gradual one, with slightly different statistics. No explanations were given for the appearance of these modes. Both measurements differ also in assessing the postictal brain activity or lack thereof, specifically the gamma activity. Using our G-Lymphatic clearance hypothesis, these results can be explained theoretically. The presence of two modes can be related to the order of ISF-CSF cleaning of brain parts. The reduced activity can be ascribed to neuronal ingredients deficiency brought about by the seizure related excess brain activity and by an over cleaning by the G-Lymphatic system.

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The aim of the study is to understand in depth the meaning of "reentry", and to decipher if and how it can lead to malfunctions of the heart and possibly of the brain. A simple model is used to reveal the mechanism by which a single pulse of action potential rotating around a ring of excitable medium, the latter simulating a reentry circuit, can generate spirals (single and/or double) when the pulse can emerge from and develop outside the ring. Two mechanisms of spiral generation are demonstrated: (1) a mechanism in which a source of single spirals is created at the contact with the core soon after the pulse freeing action, their chirality being due to the sense of the preceding pulse rotation. Interestingly, these spirals, adhering to the core, become "double-spiral patterns" while leaving behind the seeds of the new single spirals. (2) A second possible mechanism, similar to the known "arms encountering methods", in which a double spiral (a figure of eight) is repeatedly created on the other side of the core. Similar procedures are assumed to occur in the heart, leading to tachycardia and fibrillation and possibly in the brain leading to epilepsy. The exact processes of the hitherto assumed spiral generations by reentry were established. The novel deep understanding of the mechanisms involved in these processes can lead to new methods of treating heart fibrillation (e.g., by judicial ablation).

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OBJECTIVE: The objective of this study was to estimate and to characterize the actual patterns of ergot use and overuse in France using a drug reimbursement database. METHODS: We included all people covered by the French General Health Insurance System (GHIS) from the Provence-Alpes-Côte-d'Azur (PACA) and Corsica administrative areas who had at least one prescription of ergot between May 2010 and December 2011. All prescriptions of ergots, migraine prophylactic treatment, and psychotropic medications were extracted from the GHIS database. We defined occasional ergot users (<3 months of prescription) and regular ergot users (>3 months of prescription). Among regular ergot users, we identified overusers and nonoverusers. RESULTS: We included 4358 patients who had at least one prescription of ergots (oral ergotamine tartrate, dihydroergotamine mesilate nasal spray, intravenous dihydroergotamine mesilate). Among ergot overusers, a large majority of patients had ergotamine tartrate overuse. The proportion of ergotamine tartrate overusers is maximum after 55 years. Compared with regular users, overusers use more frequently a prophylactic treatment (93/165 [56.4%] versus 398/1057, OR = 2.15, P < .001), antidepressants (72/165 [43.6%] versus 326/1057 [30.8%] OR = 1.79, P < .001), benzodiazepines (111/165 [67.3%] versus 613/1057 [58.0%], OR = 1.50, P < .001), weak opioids (95/165 [57.6%] versus 463/1057 [43.8], OR = 1.77, P < .001) and strong opioids (13/165 [7.9%] versus 24/1057 [2.3%], OR = 3.86, P < .001). The coexistence of ergot consumption and triptan overuse, and the possibility of both triptan and ergot overuse was described; triptan overusers were more described in ergotamine overusers than in nonoverusers. CONCLUSIONS: This work outlines a high prevalence of ergotamine tartrate overuse (11.1%). As ergotamine tartrate users are mostly aged more than 55 years, an evaluation of ergotamine cardiovascular risk profile is necessary in the elderly population.

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Clinical trials in psychiatry allow to build the regulatory dossiers for market authorization but also to document the mechanism of action of new drugs, to build pharmacodynamics models, evaluate the treatment effects, propose prognosis, efficacy or tolerability biomarkers and altogether to assess the impact of drugs for patient, caregiver and society. However, clinical trials have shown some limitations. Number of recent dossiers failed to convince the regulators. The clinical and biological heterogeneity of psychiatric disorders, the pharmacokinetic and pharmacodynamics properties of the compounds, the lack of translatable biomarkers possibly explain these difficulties. Several breakthrough options are now available: quantitative system pharmacology analysis of drug effects variability, pharmacometry and pharmacoepidemiology, Big Data analysis, brain modelling. In addition to more classical approaches, these opportunities lead to a paradigm change for clinical trials in psychiatry.

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Our progress of understanding how cellular and structural factors contribute to the arrhythmia is hampered in part because of controversies whether a fibrillating heart is driven by a single, several, or multiple number of sources, and whether they are focal or reentrant, and how to localize them. Here we demonstrate how a novel usage of the neutral singular value decomposition (SVD) method enables the extraction of the governing spatial and temporal modes of excitation from a rotor and fibrillatory waves. Those modes highlight patterns and regions of organization in the midst of the otherwise seemingly-randomly propagating excitation waves. We apply the method to experimental models of cardiac fibrillation in rabbit hearts. We show that the SVD analysis is able to enhance the classification of the heart electrical patterns into regions harboring drivers in the form of fast reentrant activity and other regions of by-standing activity. This enhancement is accomplished without any prior assumptions regarding the spatial, temporal or spectral properties of those drivers. The analysis corroborates that the dominant mode has the highest activation rate and further reveals a new feature: A transfer of modes from the driving to the passive regions resulting in a partial reaction of the passive region to the driving region.

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We state that the autonomic part of the brain controls the blood pressure (BP) and the heart rate (HR) via the baroreflex mechanism in all situations of human activity (at sleep, at rest, during exercise, fright etc.), in a way which is not, as was hitherto assumed, a mere homeostatic tool or even a resetting device, designed to bring these variables on the road to preset values. The baroreflex is rather a continuous feedback mechanism commanded by the autonomic part of the brain, leading to values appropriate to the situation at hand. Feasibility of this assertion is demonstrated here by using the Seidel-Herzel feedback system outside of its regular practice. Results show indeed that the brain can, and we claim that it does, control the HR and BP throughout life. New responses are demonstrated, e.g., to a sudden fear or apnea. In this event, large BP and HR overshoots are expected before the variables can relax to a new level. Response to abrupt downward change in the controlling parameter shows an undershoot in HR and just a gradual resetting in the BP. The relaxation from sudden external changes to various expected states are calculated and discussed and properties of the Rheos test are explained. Experimental findings for orthostatic tests and for babies under translations and rotations reveal complete qualitative agreement with our model and show no need to invoke the operation of additional body systems. Our method should be the preferred one by the Occam Razor approach. The outcomes may lead to beneficial clinical implication.

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INTRODUCTION: Prescription drug abuse and dependence is a widespread phenomenon in many countries. The use of disproportionality measures in drug abuse surveillance is rarely performed. PURPOSE: The aim of this study is to determine the occurrence of signals of abuse and dependence for different psychoactive drugs in real-life settings. METHODS: Disproportionality analysis was realised from a database specifically constructed for the monitoring of drug abuse and dependence. This database provides information on approximately 5000 patients and 8000 consumption modalities for more than 100 distinct psychoactive medications for 2010 and 2011. Proportional reporting ratio (PRR) was computed in two population groups: subjects under an opiate maintenance treatment (OMT) versus those not under OMT, and focused on four types of behaviours: abuse and dependence, illegal acquisition, diverted route of administration and concomitant alcohol use. RESULTS: Among the 100 psychoactive drugs for which a signal could be detected, those presenting the highest signals were the following: flunitrazepam, clonazepam, methylphenidate, ketamine, morphine sulfate, codeine and buprenorphine. CONCLUSIONS: The present study shows an innovative application of disproportionality measures for drug abuse monitoring based on two cross-national, annual studies. The disproportionality analysis provided the opportunity to reveal and compare the magnitude of signals between 100 psychoactive drugs. This approach helps to compare the magnitude of abuse and dependence behaviours for a large number of drugs, and allows prioritizing actions in a context where such events are usually underreported.

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The feasibility of a spiral-type solution, periodic both in time and in space, of a reaction-diffusion equation (specifically the FitzHugh-Nagumo system) in an excitable medium is numerically demonstrated. The solution consists of arrays of interacting spiral pairs, which repeatedly create by partial annihilation a system of residual portions (RPs). The latter behaves as a source to the next generation of the spiral-pair array. If basic (highest) translational symmetry is not conserved, pointwise perturbations, above a certain threshold, are shown to be able to destroy the pattern after a certain transient time by changing its symmetry. If the basic translational symmetry is preserved, such perturbations do not cause destruction unless occurring at the nearest vicinity of the RP site. Singular value decomposition methods are used to analyze the structure of the pattern, revealing the importance of the spiral pairs and the RPs.

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AIMS: To evaluate auxological parameters in children and adults with a 22q11.2 microdeletion syndrome (22q11.2 DS) and to compare prevalence of obesity to that in the French general population. METHODS: 102 patients with 22q11.2 DS (49 males, 53 females) were recruited from birth to adulthood through a reference center in southern France. RESULTS: Mean BMI Z score and mean height were normal (0.07 ± 1.49 SD, -0.87 ± 1.36 SDS, respectively). 16.1% of patients were overweight (including obese), 57% out of them being born small for gestational age for length versus 25% of non-overweight patients. During infancy, BMI increased in girls (+0.89 SD Z score). Childhood: 14.7% were overweight, prevalence similar to that of the in French children population. Adulthood: 19.2% were overweight. BMI Z scores were inversely correlated with neonatal length (p = 0.026) and female sex (p = 0.032) but positively associated with neonatal weight (p = 0.036). From analysis of neonatal data, 22q11.2 DS newborns were significantly shorter with regard to their weight (p < 0.01), even though mean neonatal measures were above -2 SDS. CONCLUSIONS: Our study did not find a higher prevalence of overweight in 22q11.2 DS to that in the French population. The BMI Z score was inversely correlated with neonatal length and female gender but positively associated with neonatal weight.

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Pericardial cysts are rare mediastinal cysts occurring with an incidence of 1 in 100, 000. Characteristically, they occur along the right border of the heart. Their size varies from 1.0 cm to 15 cm, and they are often asymptomatic. Patients with symptoms usually have atypical chest pain. In the case reported here, a 37-year-old man complained of nonproductive cough. Chest x-ray film revealed a pericardial cyst that appeared as a large echolucent unilocular mass along the left border of the heart. Diagnosis was confirmed with the use of both computed tomography and transthoracic echocardiography.

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Scanning force microscopy was used to image rat basophilic leukemia (RBL-2H3) cell surfaces under different stimulation conditions that either permit or inhibit secretion. Cross-linking the surface IgE receptors with dinitrophenol-conjugated bovine serum albumin initiates secretion in RBL cells with concomitant spreading of the cell body. Structures at the cell surface approximately 1.5 microns in diameter relate to secretion both spatially and temporally. The position of these surface pits and their sizes suggest that they may be related to the dense-core granules positioned along the cytoskeletal filaments in detergent-extracted, unactivated RBL cell processes. Topographic scanning force microscopy images of RBL cell surfaces at 2, 5, and 35 min after activation show that these structures persist and change in cross-sectional profile with time after activation. These structures may be related to the membrane retrieval mechanism of cells after intense stimulation.

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Surface and subsurface dynamics of Rat Basophilic Leukemia cells, a model system of stimulated secretion, were imaged using Scanning Force Microscopy (SFM) at a rate of 50-60 s/image. Cytoskeletal elements and organelles were tracked within quiescent cells and those activated after IgE receptor crosslinking. In addition, surface waves were observed moving within the plasma membrane. The structures seen in quiescent and activated cells can be correlated with those seen in electron micrographs and topographic SFM images of fixed detergent-extracted cells. Furthermore, images of the detergent-extracted nuclei reveal the presence of numerous nuclear pore complexes. High-magnification images of the nuclear pore complexes show evidence of subunit structure and exhibit dimensions consistent with those reported previously using electron microscopy. The behavior and overall change in morphology of cells observed during activation was consistent with that observed under similar conditions with Differential Interference Contrast microscopy. This study demonstrates that SFM, unlike other techniques, can be used to provide high-resolution information in both fixed and living cells.

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Fouier-transform infrared (FTIR) difference spectra of several His-E7 and Val-E11 mutants of sperm whale carbonmonoxymyoglobin were obtained by photodissociation at cryogenic temperatures. The IR absorption of the CO ligand shows characteristic features for each of the mutants, both in the ligand-bound (A) state and in the photodissociated (B) state. For most of the mutants, a single A substate band is observed, which points to the crucial role of the His-E7 residue in determining the A substrate spectrum of the bound CO in the native structure. The fact that some of the mutants show more than one stretch band of the bound CO indicates that the appearance of multiple A substates is not exclusively connected to the presence of His-E7. In all but one mutant, multiple stretch bands of the CO in the photodissociated state are observed; these B substates are thought to arise from discrete positions and/or orientations of the photodissociated ligand in the heme pocket. The red shifts of the B bands with respect to the free-gas frequency indicate weak binding in the heme pocket. The observation of similar red shifts in microperoxidase (MP-8), where there is no residue on the distal side, suggests that the photodissociated ligand is still associated with the heme iron. Photoselection experiments were performed to determine the orientation of the bound ligand with respect to the heme normal by photolyzing small fractions of the sample with linearly polarized light at 540 nm. The resulting linear dichroism in the CO stretch spectrum yielded angles alpha > 20 degrees between the CO molecular axis and the heme normal for all of the mutants. We conclude that the off-axis position of the CO ligand in the native structure does not arise from steric constraints imposed by the distal histidine. There is no clear correlation between the size of the distal residue and the alpha of the CO ligand.

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Phenomena occurring in the heme pocket after photolysis of carbonmonoxymyoglobin (MbCO) below about 100 K are investigated using temperature-derivative spectroscopy of the infrared absorption bands of CO. MbCO exists in three conformations (A substrates) that are distinguished by the stretch bands of the bound CO. We establish connections among the A substates and the substates of the photoproduct (B substates) using Fourier-transform infrared spectroscopy together with kinetic experiments on MbCO solution samples at different pH and on orthorhombic crystals. There is no one-to-one mapping between the A and B substates; in some cases, more than one B substate corresponds to a particular A substate. Rebinding is not simply a reversal of dissociation; transitions between B substates occur before rebinding. We measure the nonequilibrium populations of the B substates after photolysis below 25 K and determine the kinetics of B substate transitions leading to equilibrium. Transitions between B substates occur even at 4 K, whereas those between A substates have only been observed above about 160 K. The transitions between the B substates are nonexponential in time, providing evidence for a distribution of substates. The temperature dependence of the B substate transitions implies that they occur mainly by quantum-mechanical tunneling below 10 K. Taken together, the observations suggest that the transitions between the B substates within the same A substate reflect motions of the CO in the heme pocket and not conformational changes. Geminate rebinding of CO to Mb, monitored in the Soret band, depends on pH. Observation of geminate rebinding to the A substates in the infrared indicates that the pH dependence results from a population shift among the substates and not from a change of the rebinding to an individual A substate.

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Ligand binding to heme proteins is studied by using flash photolysis over wide ranges in time (100 ns-1 ks) and temperature (10-320 K). Below about 200 K in 75% glycerol/water solvent, ligand rebinding occurs from the heme pocket and is nonexponential in time. The kinetics is explained by a distribution, g(H), of the enthalpic barrier of height H between the pocket and the bound state. Above 170 K rebinding slows markedly. Previously we interpreted the slowing as a "matrix process" resulting from the ligand entering the protein matrix before rebinding. Experiments on band III, an inhomogeneously broadened charge-transfer band near 760 nm (approximately 13,000 cm-1) in the photolyzed state (Mb*) of (carbonmonoxy)myoglobin (MbCO), force us to reinterpret the data. Kinetic hole-burning measurements on band III in Mb* establish a relation between the position of a homogeneous component of band III and the barrier H. Since band III is red-shifted by 116 cm-1 in Mb* compared with Mb, the relation implies that the barrier in relaxed Mb is 12 kJ/mol higher than in Mb*. The slowing of the rebinding kinetics above 170 K hence is caused by the relaxation Mb*----Mb, as suggested by Agmon and Hopfield [(1983) J. Chem. Phys. 79, 2042-2053]. This conclusion is supported by a fit to the rebinding data between 160 and 290 K which indicates that the entire distribution g(H) shifts. Above about 200 K, equilibrium fluctuations among conformational substates open pathways for the ligands through the protein matrix and also narrow the rate distribution. The protein relaxations and fluctuations are nonexponential in time and non-Arrhenius in temperature, suggesting a collective nature for these protein motions. The relaxation Mb*----Mb is essentially independent of the solvent viscosity, implying that this motion involves internal parts of the protein. The protein fluctuations responsible for the opening of the pathways, however, depend strongly on the solvent viscosity, suggesting that a large part of the protein participates. While the detailed studies concern MbCO, similar data have been obtained for MbO2 and CO binding to the beta chains of human hemoglobin and hemoglobin Zürich. The results show that protein dynamics is essential for protein function and that the association coefficient for binding from the solvent at physiological temperatures in all these heme proteins is governed by the barrier at the heme.

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