Functional study of CD4+CD25+ regulatory T cells in health and autoimmune hepatitis

Regulatory CD4(+)CD25(+) T cells (Tregs) are defective numerically and functionally in autoimmune hepatitis (AIH). We have investigated and compared the mechanism of action of Tregs in healthy subjects and in AIH patients using Transwell experiments, where Tregs are cultured either in direct contact with or separated from their targets by a semipermeable membrane. We also studied Treg FOXP3 expression and effect on apoptosis. Direct contact is necessary for Tregs to suppress proliferation and IFN-gamma production by CD4(+)CD25(-) and CD8(+) T cells in patients and controls. Moreover, in both, direct contact of Tregs with their targets leads to increased secretion of regulatory cytokines IL-4, IL-10, and TGF-beta, suggesting a mechanism of linked immunosuppression. Tregs/CD4(+)CD25(-) T cell cocultures lead to similar changes in IFN-gamma and IL-10 secretion in patients and controls, whereas increased TGF-beta secretion is significantly lower in patients. In contrast, in patients, Tregs/CD8(+) T cell cocultures lead to a higher increase of IL-4 secretion. In AIH, Treg FOXP3 expression is lower than in normal subjects. Both in patients and controls, FOXP3 expression is present also in CD4(+)CD25(-) T cells, although at a low level and not associated to suppressive function. Both in patients and controls, addition of Tregs does not influence target cell apoptosis, but in AIH, spontaneous apoptosis of CD4(+)CD25(-) T cells is reduced. In conclusion, Tregs act through a direct contact with their targets by modifying the cytokine profile and not inducing apoptosis. Deficient CD4(+)CD25(-) T cell spontaneous apoptosis may contribute to the development of autoimmunity.     

Modeling the contribution of lamina 5 neuronal and network dynamics to low frequency EEG phenomena

The Electroencephalogram (EEG) is an important clinical and research tool in neurophysiology. With the advent of recording techniques, new evidence is emerging on the neuronal populations and wiring in the neocortex. A main challenge is to relate the EEG generation mechanisms to the underlying circuitry of the neocortex. In this paper, we look at the principal intrinsic properties of neocortical cells in layer 5 and their network behavior in simplified simulation models to explain the emergence of several important EEG phenomena such as the alpha rhythms, slow-wave sleep oscillations, and a form of cortical seizure. The models also predict the ability of layer 5 cells to produce a resonance-like neuronal recruitment known as the augmenting response. While previous models point to deeper brain structures, such as the thalamus, as the origin of many EEG rhythms (spindles), the current model suggests that the cortical circuitry itself has intrinsic oscillatory dynamics which could account for a wide variety of EEG phenomena.Electronic Supplementary Material Supplementary material is available for this article at Sensorimotor Control Project- MIT Harvard NeuroEngineering Research Collaborative.     

An Approximate EM Algorithm for Nonlinear Mixed Effects Models

In this article, we construct an approximate EM algorithm to estimate the parameters of a nonlinear mixed effects model. The iterative procedure can be viewed as an iterative method of moments procedure for estimating the variance components and an iterative reweighted least squares estimates for estimating the fixed effects. Therefore, it is valid without the normality assumptions on the random components. A computationally simple method of moments estimates of the model parameters are used as the starting values for our iterative procedure. A simulation study was conducted to compare the performances of the proposed procedure with the procedure proposed by Lindstrom and Bates (1990) for some normal models and nonnormal models.     

Simultaneous determination of triprolidine and pseudoephedrine in human plasma by liquid chromatography–ion trap mass spectrometry

A highly efficient, selective and specific method for simultaneous quantitation of triprolidine and pseudoephedrine in human plasma by liquid chromatography–ion trap-tandem mass spectrometry coupled with electro spray ionization (LC–ESI-ion trap-tandem MS) has been validated and successfully applied to a clinical pharmacokinetic study. Both targeted compounds together with the internal standard (gabapentin) were extracted from the plasma by direct protein precipitation. Chromatographic separation was achieved on a C₁₈ ACE^® column (50.0 mm × 2.1 mm, 5 μm, Advance Chromatography Technologies, Aberdeen, UK), using an isocratic mobile phase, consisting of water, methanol and formic acid (55:45:0.5, v/v/v), at a flow-rate of 0.3 mL/min. The transition monitored (positive mode) was m/z 279.1 → m/z 208.1 for triprolidine, m/z 165.9 → m/z 148.0 for pseudoephedrine and m/z 172.0 → m/z 154.0 for gabapentin (IS). This method had a chromatographic run time of 5.0 min and a linear calibration curves ranged from 0.2 to 20.0 ng/mL for triprolidine and 5.0–500.0 ng/mL for pseudoephedrine. The within- and between-batch accuracy and precision (expressed as coefficient of variation, %C.V.) evaluated at four quality control levels were within 94.3–106.3% and 1.0–9.6% respectively. The mean recoveries of triprolidine, pseudoephedrine and gabapentin were 93.6, 76.3 and 82.0% respectively. Stability of triprolidine and pseudoephedrine was assessed under different storage conditions. The validated method was successfully employed for the bioequivalence study of triprolidine and pseudoephedrine formulation in twenty six volunteers under fasting conditions.     

Anti-inflammatory and immunosuppressive drugs and reproduction

Rheumatic diseases in women of childbearing years may necessitate drug treatment during a pregnancy, to control maternal disease activity and to ensure a successful pregnancy outcome. This survey is based on a consensus workshop of international experts discussing effects of anti-inflammatory, immunosuppressive and biological drugs during pregnancy and lactation. In addition, effects of these drugs on male and female fertility and possible long-term effects on infants exposed to drugs antenatally are discussed where data were available. Recommendations for drug treatment during pregnancy and lactation are given.     

The DWEYS peptide in systemic lupus erythematosus

Current therapies for treating systemic lupus erythematosus (SLE) mainly rely upon nonspecific and toxic immunosuppression by corticosteroids and cytotoxics. Although biologics hold promise, many agents have yet to prove clinical efficiency in controlled trials, with further limitations related to safety and cost. The primary self-specificity in SLE is double-stranded (ds) DNA. Studying anti-dsDNA antibodies in animal models of lupus and SLE patients identified a neurotoxic and nephrotoxic subset, including the nephritogenic mouse monoclonal anti-dsDNA antibody R4 that crossreacts with a sequence present in subunits of the N-methyl-d-aspartate receptor. In this review, anti-dsDNA antibodies as a pathogenic factor in SLE and recent efforts for the creation of highly specific, nontoxic therapeutics against an extremely pathogenic subset of such antibodies is discussed.     

On several conjectures from evolution of dispersal

We address several conjectures raised in Cantrell et al. [Evolution of dispersal and ideal free distribution, Math. Biosci. Eng. 7 (2010), pp. 17-36 [ 9 ]] concerning the dynamics of a diffusion-advection-competition model for two competing species. A conditional dispersal strategy, which results in the ideal free distribution of a single population at equilibrium, was found in Cantrell et al. [ 9 ]. It was shown in [ 9 ] that this special dispersal strategy is a local evolutionarily stable strategy (ESS) when the random diffusion rates of the two species are equal, and here we show that it is a global ESS for arbitrary random diffusion rates. The conditions in [ 9 ] for the coexistence of two species are substantially improved. Finally, we show that this special dispersal strategy is not globally convergent stable for certain resource functions, in contrast with the result from [ 9 ], which roughly says that this dispersal strategy is globally convergent stable for any monotone resource function.     

Deconvolution of Serum Cortisol Levels by Using Compressed Sensing

The pulsatile release of cortisol from the adrenal glands is controlled by a hierarchical system that involves corticotropin releasing hormone (CRH) from the hypothalamus, adrenocorticotropin hormone (ACTH) from the pituitary, and cortisol from the adrenal glands. Determining the number, timing, and amplitude of the cortisol secretory events and recovering the infusion and clearance rates from serial measurements of serum cortisol levels is a challenging problem. Despite many years of work on this problem, a complete satisfactory solution has been elusive. We formulate this question as a non-convex optimization problem, and solve it using a coordinate descent algorithm that has a principled combination of (i) compressed sensing for recovering the amplitude and timing of the secretory events, and (ii) generalized cross validation for choosing the regularization parameter. Using only the observed serum cortisol levels, we model cortisol secretion from the adrenal glands using a second-order linear differential equation with pulsatile inputs that represent cortisol pulses released in response to pulses of ACTH. Using our algorithm and the assumption that the number of pulses is between 15 to 22 pulses over 24 hours, we successfully deconvolve both simulated datasets and actual 24-hr serum cortisol datasets sampled every 10 minutes from 10 healthy women. Assuming a one-minute resolution for the secretory events, we obtain physiologically plausible timings and amplitudes of each cortisol secretory event with R ² above 0.92. Identification of the amplitude and timing of pulsatile hormone release allows (i) quantifying of normal and abnormal secretion patterns towards the goal of understanding pathological neuroendocrine states, and (ii) potentially designing optimal approaches for treating hormonal disorders.     

Characteristics of honey bee and non-Apis bee (Hymenoptera) farms in Canada

Here, we present a farm-level, Canada-wide analysis of Canadian bee farms in 2006; this article is the first report to distinguish between honey bee (Apis mellifera L.) farms and non-Apis bee (Hymenoptera) farms. Farms are characterized according to bee species, bee stocks, and whether the farm makes 50% or more of gross sales from bee-related activities. Farm characteristics, including bee stocks, gross sales, capital investments, land base, specialization, location, and operator demographics, are reported for the different farm types and sizes. Non-Apis bee farms are revealed to be a nontrivial part of the Canadian bee industry: 21.2% of Canadian bee farms have non-Apis bees and 16.6% have exclusively non-Apis bees. Important differences between honey bee farms and non-Apis bee farms also are found. These differences include the more land-intensive nature of non-Apis bee farms and the finding that non-Apis bee farms have greater diversity in terms of their primary commodity, even at higher bee stock levels.