Untangling thyroid autoimmunity through modeling and simulation

Thyroid autoimmunity is characterized by a large number of identified factors, and determining the relative importance of genetics and environment, for instance, can be difficult. In addition, the definition and progression of the individual diseases can also be challenging, and questions such as “when to begin treatment” or even “should treatment be begun” can be problematic. One approach to handling situations in which there are many factors is utilizing mathematical modeling. In a model, quantities that are clinically measurable are related through equations, based on known and inferred relationships between the systems involved. In situations where these relationships are complicated, the resulting simulations can provide information not previous recognized as logically resulting from those relationships. One advantage of this approach is that patient-specific parameter estimates can be used to personalize disease monitoring and treatment. In this paper, models involving Hashimoto’s (autoimmune) thyroiditis, Graves’ disease, and the roles of leptin, vitamin D3, and adipose tissue are described. In the case of Hashimoto’s, a model consisting of a system of differential equations is presented which allows a patient specific description of the progression of the disease. The conditions leading to Hashitoxicosis are also described through that model. The patient specific model of the treatment of Graves’ disease is also described. Finally, the roles of the inflammatory adipokines, especially leptin, and vitamin D3 is explored as it relates to the initiation of thyroid autoimmunity. The result of this approach is an enhanced view of the initiation and progression of autoimmunity in the thyroid

The control of CD4+CD25+Foxp3+ regulatory T cell survival

CD4+CD25+Foxp3+ regulatory T (Treg) cells are believed to play an important role in suppressing autoimmunity and maintaining peripheral tolerance. How their survival is regulated in the periphery is less clear. Here we show that Treg cells express receptors for gamma chain cytokines and are dependent on an exogenous supply of these cytokines to overcome cytokine withdrawal apoptosis in vitro. This result was validated in vivo by the accumulation of Treg cells in Bim-/- and Bcl-2 tg mice which have arrested cytokine deprivation apoptosis. We also found that CD25 and Foxp3 expression were down-regulated in the absence of these cytokines. CD25+ cells from Scurfy mice do not depend on cytokines for survival demonstrating that Foxp3 increases their dependence on cytokines by suppressing cytokine production in Treg cells. Our study reveals that the survival of Treg cells is strictly dependent on cytokines and cytokine producing cells because they do not produce cytokines. Our study thus, demonstrates that different gamma chain cytokines regulate Treg homeostasis in the periphery by differentially regulating survival and proliferation. These findings may shed light on ways to manipulate Treg cells that could be utilized for their therapeutic applications

A Patient-Specific Treatment Model for Graves’ Hyperthyroidism

Background: Graves’ is disease an autoimmune disorder of the thyroid gland caused by circulating anti-thyroid receptor antibodies (TRAb) in the serum. TRAb mimics the action of thyroid stimulating hormone (TSH) and stimulates the thyroid hormone receptor (TSHR), which results in hyperthyroidism (overactive thyroid gland) and goiter. Methimazole (MMI) is used for hyperthyroidism treatment for patients with Graves’ disease. Methods: We have developed a model using a system of ordinary differential equations for hyperthyroidism treatment with MMI. The model has four state variables, namely concentration of MMI (in mg/L), concentration of free thyroxine - FT4 (in pg/mL), and concentration of TRAb (in U/mL) and the functional size of the thyroid gland (in mL) with thirteen parameters. With a treatment parameter, we simulate the time-course of patients’ progression from hyperthyroidism to euthyroidism (normal condition). We validated the model predictions with data from four patients. Results: When there is no MMI treatment, there is a unique asymptotically stable hyperthyroid state. After the initiation of MMI treatment, the hyperthyroid state moves towards subclinical hyperthyroidism and then euthyroidism. Conclusion: We can use the model to describe or test and predict patient treatment schedules. More specifically, we can fit the model to individual patients’ data including loading and maintenance doses and describe the mechanism, hyperthyroidism → euthyroidism. The model can be used to predict when to discontinue the treatment based on FT4 levels within the physiological range, which in turn help maintain the remittance of euthyroidism and avoid relapses of hyperthyroidism. Basically, the model can guide with decision-making on oral intake of MMI based on FT4 levels

The Molecular Mechanisms of Regulatory T Cell Immunosuppression

CD4+CD25+Foxp3+ T lymphocytes, known as regulatory T cells or Tregs, have been proposed to be a lineage of professional immune suppressive cells that exclusively counteract the effects of the immunoprotective “helper” and “cytotoxic” lineages of T lymphocytes. Here we discuss new concepts on the mechanisms and functions of Tregs. There are several key points we emphasize: 1. Tregs exert suppressive effects both directly on effector T cells and indirectly through antigen-presenting cells; 2. Regulation can occur through a novel mechanism of cytokine consumption to regulate as opposed to the usual mechanism of cytokine/chemokine production; 3. In cases where CD4+ effector T cells are directly inhibited by Tregs, it is chiefly through a mechanism of lymphokine withdrawal apoptosis leading to polyclonal deletion; and 4. Contrary to the current view, we discuss new evidence that Tregs, similar to other T-cells lineages, can promote protective immune responses in certain infectious contexts (Chen et al., 2011; Pandiyan et al., 2011). Although these points are at variance to varying degrees with the standard model of Treg behavior, we will recount developing findings that support these new concepts

A Pediatric Diabetic Ketoacidosis Patient with Multisystem Complications and a Prolonged Course

The prevalence of diabetic ketoacidosis (DKA) in children with type 1 diabetes mellitus (T1DM) is 30% at the time of diagnosis.1 Cerebral edema is a rare, but life-threatening complication of DKA, occurring in only 0.3 - 1% of cases.2 Deep vein thrombosis and acute pancreatitis are other rare complications of DKA. Supraventricular tachycardia (SVT) as a complication of pediatric DKA has been reported.3 A unique case of a pediatric patient who had multiple rare complications of DKA including cerebral edema, venous thrombosis, and hypertriglyceridemia associated acute pancreatitis is presented.The SVT episode encountered during the admission was due to complications arising from a procedure and not due to DKA itself

Divacancy superstructures in thermoelectric calcium-doped sodium cobaltate

We have grown single crystals of Na$_x$Ca$_y$CoO$_2$ and determined their superstructures as a function of composition using neutron and x-ray diffraction. Inclusion of Ca$^{2+}$ stabilises a single superstructure across a wide range of temperatures and concentrations. The superstructure in the Na$^+$ layers is based on arrays of divacancy clusters with Ca$^{2+}$ ions occupying the central site, and it has an ideal concentration Na$_{4/7}$Ca$_{1/7}$CoO$_2$. Previous measurements of the thermoelectric properties on this system are discussed in light of this superstructure. Na$_{4/7}$Ca$_{1/7}$CoO$_2$ corresponds to the maximum in thermoelectric performance of this system.Comment: Produced using Revtex 4.1 and pdflatex. 7 Pages, 6 figure

Synthesis, photophysical properties and DFT analysis of highly substituted pyrido carbazole-based "push pull'' chromophores

A series of new fluorescent pyrido[2,3-a]carbazole derivatives were synthesized based on a four component reaction with 2,3,4,9-tetrahydro-1H-carbazol-1-one, malononitrile, and aryl/heteroaryl aldehydes in presence of NaOEt.</p

Plasma Driven Exsolution for Nanoscale Functionalization of Perovskite Oxides

Perovskite oxides with dispersed nanoparticles on their surface are considered instrumental in energy conversion and catalytic processes. Redox exsolution is an alternative method to the conventional deposition techniques for directly growing well-dispersed and anchored nanoarchitectures from the oxide support through thermochemical or electrochemical reduction. Herein, a new method for such nanoparticle nucleation through the exposure of the host perovskite to plasma is shown. The applicability of this new method is demonstrated by performing catalytic tests for CO2 hydrogenation over Ni exsolved nanoparticles prepared by either plasma or conventional H2 reduction. Compared to the conventional thermochemical H2 reduction, there are plasma conditions that lead to the exsolution of a more than ten times higher Ni amount from a lanthanum titanate perovskite, which is similar to the reported values of the electrochemical method. Unlike the electrochemical method, however, plasma does not require the integration of the material in an electrochemical cell, and is thus applicable to a wide range of microstructures and physical forms. Additionally, when N2 plasma is employed, the nitrogen species are stripping out oxygen from the perovskite lattice, generating a key chemical intermediate, such as NO, rendering this technology even more appealing.</p