Intermittent spike-wave dynamics in a heterogeneous, spatially extended neural mass model

Generalised epileptic seizures are frequently accompanied by sudden, reversible transitions from low amplitude, irregular background activity to high amplitude, regular spike-wave discharges (SWD) in the EEG. The underlying mechanisms responsible for SWD generation and for the apparently spontaneous transitions to SWD and back again are still not fully understood. Specifically, the role of spatial cortico-cortical interactions in ictogenesis is not well studied. We present a macroscopic, neural mass model of a cortical column which includes two distinct time scales of inhibition. This model can produce both an oscillatory background and a pathological SWD rhythm. We demonstrate that coupling two of these cortical columns can lead to a bistability between out-of-phase, low amplitude background dynamics and in-phase, high amplitude SWD activity. Stimuli can cause state-dependent transitions from background into SWD. In an extended local area of cortex, spatial heterogeneities in a model parameter can lead to spontaneous reversible transitions from a desynchronised background to synchronous SWD due to intermittency. The deterministic model is therefore capable of producing absence seizure-like events without any time dependent adjustment of model parameters. The emergence of such mechanisms due to spatial coupling demonstrates the importance of spatial interactions in modelling ictal dynamics, and in the study of ictogenesis.

Self-organised transients in a neural mass model of epileptogenic tissue dynamics

Stimulation of human epileptic tissue can induce rhythmic, self-terminating responses on the EEG or ECoG. These responses play a potentially important role in localising tissue involved in the generation of seizure activity, yet the underlying mechanisms are unknown. However, in vitro evidence suggests that self-terminating oscillations in nervous tissue are underpinned by non-trivial spatio-temporal dynamics in an excitable medium. In this study, we investigate this hypothesis in spatial extensions to a neural mass model for epileptiform dynamics. We demonstrate that spatial extensions to this model in one and two dimensions display propagating travelling waves but also more complex transient dynamics in response to local perturbations. The neural mass formulation with local excitatory and inhibitory circuits, allows the direct incorporation of spatially distributed, functional heterogeneities into the model. We show that such heterogeneities can lead to prolonged reverberating responses to a single pulse perturbation, depending upon the location at which the stimulus is delivered. This leads to the hypothesis that prolonged rhythmic responses to local stimulation in epileptogenic tissue result from repeated self-excitation of regions of tissue with diminished inhibitory capabilities. Combined with previous models of the dynamics of focal seizures this macroscopic framework is a first step towards an explicit spatial formulation of the concept of the epileptogenic zone. Ultimately, an improved understanding of the pathophysiologic mechanisms of the epileptogenic zone will help to improve diagnostic and therapeutic measures for treating epilepsy.

[Calculating the basal metabolic rate and severe and morbid obesity]

The aim of this study was to evaluate the currently available predictive equations for basal metabolic rate (BMR) in subjects with obesity class II and III, and to assess the contribution by the components of a two-compartment model of body composition, namely the lean body mass (LBM) and the fat mass (FM) to the prediction. A second objective was to examine the reliability of the Harris Benedict equation in obese subjects, especially with a weight > or = 120 kg.

Dominance and the maintenance of polymorphism in multiallelic migration-selection models with two demes

The maintenance of genetic variation in a spatially heterogeneous environment has been one of the main research themes in theoretical population genetics. Despite considerable progress in understanding the consequences of spatially structured environments on genetic variation, many problems remain unsolved. One of them concerns the relationship between the number of demes, the degree of dominance, and the maximum number of alleles that can be maintained by selection in a subdivided population. In this work, we study the potential of maintaining genetic variation in a two-deme model with deme-independent degree of intermediate dominance, which includes absence of G x E interaction as a special case. We present a thorough numerical analysis of a two-deme three-allele model, which allows us to identify dominance and selection patterns that harbor the potential for stable triallelic equilibria. The information gained by this approach is then used to construct an example in which existence and asymptotic stability of a fully polymorphic equilibrium can be proved analytically. Noteworthy, in this example the parameter range in which three alleles can coexist is maximized for intermediate migration rates. Our results can be interpreted in a specialist-generalist context and (among others) show when two specialists can coexist with a generalist in two demes if the degree of dominance is deme independent and intermediate. The dominance relation between the generalist allele and the specialist alleles play a decisive role. We also discuss linear selection on a quantitative trait and show that G x E interaction is not necessary for the maintenance of more than two alleles in two demes.

A first look at maximally twisted mass lattice QCD calculations at the physical point

In this contribution, a first look at simulations using maximally twisted mass Wilson fermions at the physical point is presented. A lattice action including clover and twisted mass terms is presented and the Monte Carlo histories of one run with two mass-degenerate flavours at a single lattice spacing are shown. Measurements from the light and heavy-light pseudoscalar sectors are compared to previous Nf = 2 results and their phenomenological values. Finally, the strategy for extending simulations to Nf = 2+1+1 is outlined.

From stellar nebula to planets: The refractory components

Context. To date, calculations of planet formation have mainly focused on dynamics, and only a few have considered the chemical composition of refractory elements and compounds in the planetary bodies. While many studies have been concentrating on the chemical composition of volatile compounds (such as H2O, CO, CO2) incorporated in planets, only a few have considered the refractory materials as well, although they are of great importance for the formation of rocky planets. Aims. We computed the abundance of refractory elements in planetary bodies formed in stellar systems with a solar chemical composition by combining models of chemical composition and planet formation. We also considered the formation of refractory organic compounds, which have been ignored in previous studies on this topic. Methods. We used the commercial software package HSC Chemistry to compute the condensation sequence and chemical composition of refractory minerals incorporated into planets. The problem of refractory organic material is approached with two distinct model calculations: the first considers that the fraction of atoms used in the formation of organic compounds is removed from the system (i.e., organic compounds are formed in the gas phase and are non-reactive); and the second assumes that organic compounds are formed by the reaction between different compounds that had previously condensed from the gas phase. Results. Results show that refractory material represents more than 50 wt % of the mass of solids accreted by the simulated planets with up to 30 wt % of the total mass composed of refractory organic compounds. Carbide and silicate abundances are consistent with C/O and Mg/Si elemental ratios of 0.5 and 1.02 for the Sun. Less than 1 wt % of carbides are present in the planets, and pyroxene and olivine are formed in similar quantities. The model predicts planets that are similar in composition to those of the solar system. Starting from a common initial nebula composition, it also shows that a wide variety of chemically different planets can form, which means that the differences in planetary compositions are due to differences in the planetary formation process. Conclusions. We show that a model in which refractory organic material is absent from the system is more compatible with observations. The use of a planet formation model is essential to form a wide diversity of planets in a consistent way.

Modeling the formation and aging of secondary organic aerosols during CalNex 2010

Four different literature parameterizations for the formation and evolution of urban secondary organic aerosol (SOA) frequently used in 3-D models are evaluated using a 0-D box model representing the Los Angeles metropolitan region during the California Research at the Nexus of Air Quality and Climate Change (CalNex) 2010 campaign. We constrain the model predictions with measurements from several platforms and compare predictions with particle- and gas-phase observations from the CalNex Pasadena ground site. That site provides a unique opportunity to study aerosol formation close to anthropogenic emission sources with limited recirculation. The model SOA that formed only from the oxidation of VOCs (V-SOA) is insufficient to explain the observed SOA concentrations, even when using SOA parameterizations with multi-generation oxidation that produce much higher yields than have been observed in chamber experiments, or when increasing yields to their upper limit estimates accounting for recently reported losses of vapors to chamber walls. The Community Multiscale Air Quality (WRF-CMAQ) model (version 5.0.1) provides excellent predictions of secondary inorganic particle species but underestimates the observed SOA mass by a factor of 25 when an older VOC-only parameterization is used, which is consistent with many previous model–measurement comparisons for pre-2007 anthropogenic SOA modules in urban areas. Including SOA from primary semi-volatile and intermediate-volatility organic compounds (P-S/IVOCs) following the parameterizations of Robinson et al. (2007), Grieshop et al. (2009), or Pye and Seinfeld (2010) improves model–measurement agreement for mass concentration. The results from the three parameterizations show large differences (e.g., a factor of 3 in SOA mass) and are not well constrained, underscoring the current uncertainties in this area. Our results strongly suggest that other precursors besides VOCs, such as P-S/IVOCs, are needed to explain the observed SOA concentrations in Pasadena. All the recent parameterizations overpredict urban SOA formation at long photochemical ages (3 days) compared to observations from multiple sites, which can lead to problems in regional and especially global modeling. However, reducing IVOC emissions by one-half in the model to better match recent IVOC measurements improves SOA predictions at these long photochemical ages. Among the explicitly modeled VOCs, the precursor compounds that contribute the greatest SOA mass are methylbenzenes. Measured polycyclic aromatic hydrocarbons (naphthalenes) contribute 0.7% of the modeled SOA mass. The amounts of SOA mass from diesel vehicles, gasoline vehicles, and cooking emissions are estimated to be 16–27, 35–61, and 19–35 %, respectively, depending on the parameterization used, which is consistent with the observed fossil fraction of urban SOA, 71(+-3) %. The relative contribution of each source is uncertain by almost a factor of 2 depending on the parameterization used. In-basin biogenic VOCs are predicted to contribute only a few percent to SOA. A regional SOA background of approximately 2.1 μgm-3 is also present due to the long-distance transport of highly aged OA, likely with a substantial contribution from regional biogenic SOA. The percentage of SOA from diesel vehicle emissions is the same, within the estimated uncertainty, as reported in previous work that analyzed the weekly cycles in OA concentrations (Bahreini et al., 2012; Hayes et al., 2013). However, the modeling work presented here suggests a strong anthropogenic source of modern carbon in SOA, due to cooking emissions, which was not accounted for in those previous studies and which is higher on weekends. Lastly, this work adapts a simple two-parameter model to predict SOA concentration and O/C from urban emissions. This model successfully predicts SOA concentration, and the optimal parameter combination is very similar to that found for Mexico City. This approach provides a computationally inexpensive method for predicting urban SOA in global and climate models. We estimate pollution SOA to account for 26 Tg yr-1 of SOA globally, or 17% of global SOA, one third of which is likely to be non-fossil.

Factor Structure of the Neck Disability Index

BACKGROUND CONTEXT: The Neck Disability Index frequently is used to measure outcomes of the neck. The statistical rigor of the Neck Disability Index has been assessed with conflicting outcomes. To date, Confirmatory Factor Analysis of the Neck Disability Index has not been reported for a suitably large population study. Because the Neck Disability Index is not a condition-specific measure of neck function, initial Confirmatory Factor Analysis should consider problematic neck patients as a homogenous group. PURPOSE: We sought to analyze the factor structure of the Neck Disability Index through Confirmatory Factor Analysis in a symptomatic, homogeneous, neck population, with respect to pooled populations and gender subgroups. STUDY DESIGN: This was a secondary analysis of pooled data. PATIENT SAMPLE: A total of 1,278 symptomatic neck patients (67.5% female, median age 41 years), 803 nonspecific and 475 with whiplash-associated disorder. OUTCOME MEASURES: The Neck Disability Index was used to measure outcomes. METHODS: We analyzed pooled baseline data from six independent studies of patients with neck problems who completed Neck Disability Index questionnaires at baseline. The Confirmatory Factor Analysis was considered in three scenarios: the full sample and separate sexes. Models were compared empirically for best fit. RESULTS: Two-factor models have good psychometric properties across both the pooled and sex subgroups. However, according to these analyses, the one-factor solution is preferable from both a statistical perspective and parsimony. The two-factor model was close to significant for the male subgroup (p<.07) where questions separated into constructs of mental function (pain, reading headaches and concentration) and physical function (personal care, lifting, work, driving, sleep, and recreation). CONCLUSIONS: The Neck Disability Index demonstrated a one-factor structure when analyzed by Confirmatory Factor Analysis in a pooled, homogenous sample of neck problem patients. However, a two-factor model did approach significance for male subjects where questions separated into constructs of mental and physical function. Further investigations in different conditions, subgroup and sex-specific populations are warranted.

Phosphocreatine interacts with phospholipids, affects membrane properties and exerts membrane-protective effects

A broad spectrum of beneficial effects has been ascribed to creatine (Cr), phosphocreatine (PCr) and their cyclic analogues cyclo-(cCr) and phospho-cyclocreatine (PcCr). Cr is widely used as nutritional supplement in sports and increasingly also as adjuvant treatment for pathologies such as myopathies and a plethora of neurodegenerative diseases. Additionally, Cr and its cyclic analogues have been proposed for anti-cancer treatment. The mechanisms involved in these pleiotropic effects are still controversial and far from being understood. The reversible conversion of Cr and ATP into PCr and ADP by creatine kinase, generating highly diffusible PCr energy reserves, is certainly an important element. However, some protective effects of Cr and analogues cannot be satisfactorily explained solely by effects on the cellular energy state. Here we used mainly liposome model systems to provide evidence for interaction of PCr and PcCr with different zwitterionic phospholipids by applying four independent, complementary biochemical and biophysical assays: (i) chemical binding assay, (ii) surface plasmon resonance spectroscopy (SPR), (iii) solid-state (31)P-NMR, and (iv) differential scanning calorimetry (DSC). SPR revealed low affinity PCr/phospholipid interaction that additionally induced changes in liposome shape as indicated by NMR and SPR. Additionally, DSC revealed evidence for membrane packing effects by PCr, as seen by altered lipid phase transition. Finally, PCr efficiently protected against membrane permeabilization in two different model systems: liposome-permeabilization by the membrane-active peptide melittin, and erythrocyte hemolysis by the oxidative drug doxorubicin, hypoosmotic stress or the mild detergent saponin. These findings suggest a new molecular basis for non-energy related functions of PCr and its cyclic analogue. PCr/phospholipid interaction and alteration of membrane structure may not only protect cellular membranes against various insults, but could have more general implications for many physiological membrane-related functions that are relevant for health and disease.

Noninvasive monitoring of chest wall movement in infants using laser

Traditionally, non-invasive monitoring of tidal volume in infants has been performed using impedance plethysmography analyzed using a one or two compartment model. We developed a new laser system for use in infants, which measures antero-posterior movement of the chest wall during quiet sleep. In 24 unsedated or sedated infants (11 healthy, 13 with respiratory disease), we examined whether the analysis of thoracoabdominal movement based on a three compartment model could more accurately estimate tidal volume in comparison to V(T) measured at the mouth. Using five laser signals, chest wall movements were measured at the right and left, upper and lower ribcage and the abdomen. Within the tidal volume range from 4.6 to 135.7 ml, a three compartment model showed good short term repeatability and the best agreement with tidal volume measured at mouth (r(2) = 0.86) compared to that of a single compartment model (r(2) = 0.62, P < 0.0001) and a two compartment model (r(2) = 0.82, P < 0.01), particularly in the presence of respiratory disease. Three compartment modeling of a 5 laser thoracoabdominal monitoring permits more accurate estimates of tidal volume in infants and potentially of regional differences of chest wall displacement in future studies.

Acute respiratory syndrome after inhalation of waterproofing sprays: a posteriori exposure-response assessment in 102 cases

Waterproofing agents are widely used to protect leather and textiles in both domestic and occupational activities. An outbreak of acute respiratory syndrome following exposure to waterproofing sprays occurred during the winter 2002-2003 in Switzerland. About 180 cases were reported by the Swiss Toxicological Information Centre between October 2002 and March 2003, whereas fewer than 10 cases per year had been recorded previously. The reported cases involved three brands of sprays containing a common waterproofing mixture, that had undergone a formulation change in the months preceding the outbreak. A retrospective analysis was undertaken in collaboration with the Swiss Toxicological Information Centre and the Swiss Registries for Interstitial and Orphan Lung Diseases to clarify the circumstances and possible causes of the observed health effects. Individual exposure data were generated with questionnaires and experimental emission measurements. The collected data was used to conduct numeric simulation for 102 cases of exposure. A classical two-zone model was used to assess the aerosol dispersion in the near- and far-field during spraying. The resulting assessed dose and exposure levels obtained were spread on large scales, of several orders of magnitude. No dose-response relationship was found between exposure indicators and health effects indicators (perceived severity and clinical indicators). Weak relationships were found between unspecific inflammatory response indicators (leukocytes, C-reactive protein) and the maximal exposure concentration. The results obtained disclose a high interindividual response variability and suggest that some indirect mechanism(s) predominates in the respiratory disease occurrence. Furthermore, no threshold could be found to define a safe level of exposure. These findings suggest that the improvement of environmental exposure conditions during spraying alone does not constitute a sufficient measure to prevent future outbreaks of waterproofing spray toxicity. More efficient preventive measures are needed prior to the marketing and distribution of new waterproofing agents.

Glycoprotein VI is a major collagen receptor for platelet activation: it recognizes the platelet-activating quaternary structure of collagen, whereas CD36, glycoprotein IIb/IIIa, and von Willebrand factor do not

Simple collagen-related peptides (CRPs) containing a repeat Gly-Pro-Hyp sequence are highly potent platelet agonists. Like collagen, they must exhibit tertiary (triple-helical) and quaternary (polymeric) structure to activate platelets. Platelet signaling events induced by the peptides are the same as most of those induced by collagen. The peptides do not recognize the alpha 2 beta 1 integrin. To identify the signaling receptor involved, we have evaluated the response to the CRP, Gly-Lys-Hyp(Gly-Pro-Hyp)10-Gly-Lys-Hyp-Gly of platelets with defined functional deficiencies. These studies exclude a primary recognition role for CD36, von Willebrand factor (vWF), or glycoprotein (GP) IIb/IIIa. Thus, both CD36 and vWF-deficient platelets exhibited normal aggregation, normal fibrinogen binding, and normal expression of CD62 and CD63, measured by flow cytometry, in response to the peptide, and there was normal expression of CD62 and CD63 on thrombasthenic platelets. In contrast, GPVI-deficient platelets were totally unresponsive to the peptide, indicating that this receptor recognizes the Gly-Pro-Hyp sequence in collagen. GPVI-deficient platelets showed some fibrinogen binding in response to collagen but failed to aggregate and to express CD62 and CD63. Collagen, but not CRP-XL, contains binding sites for alpha 2 beta 1. Therefore, it is possible that collagen still induces some signaling via alpha 2 beta 1, leading to activation of GPIIb/IIIa. Our findings are consistent with a two-site, two-step model of collagen interaction with platelets involving recognition of specific sequences in collagen by an adhesive receptor such as alpha 2 beta 1 to arrest platelets under flow and subsequent recognition of another specific collagen sequence by an activatory receptor, namely GPVI.

Stereoselective pharmacokinetics of ketamine and norketamine after racemic ketamine or S-ketamine administration during isoflurane anaesthesia in Shetland ponies

BACKGROUND: The arterial pharmacokinetics of ketamine and norketamine enantiomers after racemic ketamine or S-ketamine i.v. administration were evaluated in seven gelding ponies in a crossover study (2-month interval). METHODS: Anaesthesia was induced with isoflurane in oxygen via a face-mask and then maintained at each pony's individual MAC. Racemic ketamine (2.2 mg kg(-1)) or S-ketamine (1.1 mg kg(-1)) was injected in the right jugular vein. Blood samples were collected from the right carotid artery before and at 1, 2, 4, 8, 16, 32, 64, and 128 min after ketamine administration. Ketamine and norketamine enantiomer plasma concentrations were determined by capillary electrophoresis. Individual R-ketamine and S-ketamine concentration vs time curves were analysed by non-linear least square regression two-compartment model analysis using PCNonlin. Plasma disposition curves for R-norketamine and S-norketamine were described by estimating AUC, C(max), and T(max). Pulse rate (PR), respiratory rate (R(f)), tidal volume (V(T)), minute volume ventilation (V(E)), end-tidal partial pressure of carbon dioxide (PE'(CO(2))), and mean arterial blood pressure (MAP) were also evaluated. RESULTS: The pharmacokinetic parameters of S- and R-ketamine administered in the racemic mixture or S-ketamine administered separately did not differ significantly. Statistically significant higher AUC and C(max) were found for S-norketamine compared with R-norketamine in the racemic group. Overall, R(f), V(E), PE'(CO(2)), and MAP were significantly higher in the racemic group, whereas PR was higher in the S-ketamine group. CONCLUSIONS: Norketamine enantiomers showed different pharmacokinetic profiles after single i.v. administration of racemic ketamine in ponies anaesthetised with isoflurane in oxygen (1 MAC). Cardiopulmonary variables require further investigation.

A family of stage-specific alanine-rich proteins on the surface of epimastigote forms of Trypanosoma brucei

A 'two coat' model of the life cycle of Trypanosoma brucei has prevailed for more than 15 years. Metacyclic forms transmitted by infected tsetse flies and mammalian bloodstream forms are covered by variant surface glycoproteins. All other life cycle stages were believed to have a procyclin coat, until it was shown recently that epimastigote forms in tsetse salivary glands express procyclin mRNAs without translating them. As epimastigote forms cannot be cultured, a procedure was devised to compare the transcriptomes of parasites in different fly tissues. Transcripts encoding a family of glycosylphosphatidyl inositol-anchored proteins, BARPs (previously called bloodstream alanine-rich proteins), were 20-fold more abundant in salivary gland than midgut (procyclic) trypanosomes. Anti-BARP antisera reacted strongly and exclusively with salivary gland parasites and a BARP 3' flanking region directed epimastigote-specific expression of reporter genes in the fly, but inhibited expression in bloodstream and procyclic forms. In contrast to an earlier report, we could not detect BARPs in bloodstream forms. We propose that BARPs form a stage-specific coat for epimastigote forms and suggest renaming them brucei alanine-rich proteins.