Mechanisms in endocrinology: autoimmune thyroid disease: old and new players.

The last 10 years have seen some progress in understanding the etiology of autoimmune thyroid disease (AITD). The female preponderance can now be explained - at least in part - by fetal microchimerism and X-chromosome inactivation. The number of identified susceptibility genes for AITD is increasing (among others now including TSHR, TG, HLA, CTLA4, PTPN22, CD40, FCRL3, IL2RA, and FOXP3), but these genes together probably do not explain more than about 10% of the heritability of AITD.

What is the aim of immunosuppressive treatment in patients with graves' orbitopathy?

Purpose: The EUGOGO criteria and the clinical activity score (CAS) have been used as outcome measures to report response rates for patients after pulsed intravenous methylprednisolone (PIM) therapy. This study compares the results after PIM for both criteria and evaluates the number of rehabilitative surgeries performed in relation to treatment outcome.

Methods: This was a retrospective review of patients with active moderate-to-severe Graves' orbitopathy (GO) treated with PIM (cumulative dose of 4.

Paradigm shifts in thyroid hormone replacement therapies for hypothyroidism.

Impaired psychological well-being, depression or anxiety are observed in 5-10% of hypothyroid patients receiving levothyroxine, despite normal TSH levels. Such complaints might hypothetically be related to increased free T₄ and decreased free T₃ serum concentrations, which result in the abnormally low free T₄:free T₃ ratios observed in 30% of patients on levothyroxine. Evidence is mounting that levothyroxine monotherapy cannot assure a euthyroid state in all tissues simultaneously, and that normal serum TSH levels in patients receiving levothyroxine reflect pituitary euthyroidism alone.

Mice lacking the lectin-like domain of thrombomodulin are protected against melioidosis.

Objective: Thrombomodulin is a multidomain receptor primarily expressed by vascular endothelium. The lectin-like domain of thrombomodulin has anti-inflammatory properties. In this study, we investigated the role of the thrombomodulin lectin-like domain in the host response to Gram-negative sepsis caused by Burkholderia pseudomallei, a "Tier 1" biothreat agent and the causative agent of melioidosis, a common form of community-acquired sepsis in Southeast Asia.

Deficiency of protease-activated receptor-1 limits bacterial dissemination during severe Gram-negative sepsis (melioidosis).

Protease-activated receptor-1 (PAR-1) is a G-coupled transmembrane receptor expressed by multiple cell types present in the lungs that can be activated by various proteases generated during acute inflammation. In this study we aimed to investigate the role of PAR-1 during melioidosis, a common cause of (pneumo)sepsis in Southeast Asia in a murine model of intranasal inoculation of the causative pathogen Burkholderia (B.) pseudomallei.

Glyburide reduces bacterial dissemination in a mouse model of melioidosis.

Background: Burkholderia pseudomallei infection (melioidosis) is an important cause of community-acquired Gram-negative sepsis in Northeast Thailand, where it is associated with a ~40% mortality rate despite antimicrobial chemotherapy. We showed in a previous cohort study that patients taking glyburide ( = glibenclamide) prior to admission have lower mortality and attenuated inflammatory responses compared to patients not taking glyburide. We sought to define the mechanism underlying this observation in a murine model of melioidosis.

Endogenous α2-antiplasmin is protective during severe gram-negative sepsis (melioidosis).

Rationale: α2-Antiplasmin (A2AP) is a major inhibitor of fibrinolysis by virtue of its capacity to inhibit plasmin. Although the fibrinolytic system is strongly affected by infection, the functional role of A2AP in the host response to sepsis is unknown.

Objectives: To study the role of A2AP in melioidosis, a common form of community-acquired sepsis in Southeast Asia and Northern Australia caused by the gram-negative bacterium Burkholderia pseudomallei.

Overexpression of activated protein C is detrimental during severe experimental gram-negative sepsis (melioidosis).

Objective: The interplay between inflammation and blood coagulation is an essential part of host defense during severe pneumosepsis. Melioidosis, instigated by the Gram-negative bacterium Burkholderia pseudomallei, is a frequent cause of pneumosepsis in Southeast Asia. Patients with severe pneumosepsis, including melioidosis, have decreased circulating levels of protein C.

Overexpression of the endothelial protein C receptor is detrimental during pneumonia-derived gram-negative sepsis (Melioidosis).

Background: The endothelial protein C receptor (EPCR) enhances anticoagulation by accelerating activation of protein C to activated protein C (APC) and mediates anti-inflammatory effects by facilitating APC-mediated signaling via protease activated receptor-1. We studied the role of EPCR in the host response during pneumonia-derived sepsis instigated by Burkholderia (B.) pseudomallei, the causative agent of melioidosis, a common form of community-acquired Gram-negative (pneumo)sepsis in South-East Asia.

Selenite supplementation in euthyroid subjects with thyroid peroxidase antibodies.

Context: Euthyroid thyroid peroxidase (TPO-Ab)-positive subjects are at risk for progression to subclinical and overt autoimmune hypothyroidism. Previous studies have shown a decrease in TPO-Ab and improvement of quality-of-life (QoL) in L-T4-treated hypothyroid patients upon selenium supplementation.

Objectives: To evaluate in euthyroid TPO-Ab-positive women without thyroid medication whether selenite decreases TPO-Ab and improves QoL.

Host innate immune responses to sepsis.

The immune response to sepsis can be seen as a pattern recognition receptor-mediated dysregulation of the immune system following pathogen invasion in which a careful balance between inflammatory and anti-inflammatory responses is vital. Invasive infection triggers both pro-inflammatory and anti-inflammatory host responses, the magnitude of which depends on multiple factors, including pathogen virulence, site of infection, host genetics, and comorbidities. Toll-like receptors, the inflammasomes, and other pattern recognition receptors initiate the immune response after recognition of danger signals derived from microorganisms, so-called pathogen-associated molecular patterns or derived from the host, so-called danger-associated molecular patterns.

Smoking and thyroid.

Current smoking in population surveys is associated with a slight dose-dependent fall of serum TSH, likely secondary to a rise of serum FT4 and FT3 induced by activation of the sympathetic nervous system; it is independent of iodine intake. In contrast, the slightly greater thyroid size in smokers is observed in iodine-deficient but not in iodine-sufficient areas and caused by competitive inhibition of thyroidal iodide uptake by thiocyanate. Smokers have an increased prevalence of nontoxic goitre and thyroid multinodularity, at least in iodine-deficient areas.

Graves' orbitopathy: Management of difficult cases.

Management of Graves' ophthalmopathy (GO) is based on three pillars: to stop smoking, to restore and maintain euthyroidism, and to treat the eye changes according to severity and activity of GO. Difficulties are frequently encountered in each of these three management issues. The advice to discontinue smoking is straightforward, but just a small minority of smokers is able to quit smoking.

Changes in serum adhesion molecules, chemokines, cytokines, and tissue remodeling factors in euthyroid women without thyroid antibodies who are at risk for autoimmune thyroid disease: a hypothesis on the early phases of the endocrine autoimmune reaction.

Background: The target glands in spontaneous animal models of endocrine autoimmune disease show, prior to the autoimmune reaction, growth and connective tissue abnormalities, whereas the autoimmune reaction is initiated by an early accumulation of macrophages and dendritic cells in the target glands.

Aim: The aim of the study was to test the hypothesis that serum factors related to these growth and connective tissue abnormalities and the early accumulation of immune cells, ie, tissue growth/remodeling factors, adhesion molecules, chemokines, and pro- and anti-inflammatory cytokines, are related to thyroid peroxidase autoantibodies (TPO-Abs) seroconversion in subjects at risk to develop autoimmune thyroid disease (AITD).

Design: A controlled study on 64 TPO-Ab-negative euthyroid female relatives with at least 1 first- or second-degree relative with documented autoimmune hyper- or hypothyroidism, 32 of whom did and 32 who did not seroconvert to TPO-Ab positivity in 5-year follow-up.

The intestinal microbiota and host immune interactions in the critically ill.

The gastrointestinal tract harbors a complex population of microbes that play a fundamental role in the development of the immune system and human health. Besides an important local contribution in the host defense against infections, it has become increasingly clear that intestinal bacteria also modulate immune responses at systemic sites. These new insights can be of profound clinical relevance especially for intensive care medicine where the majority of patients are treated with antibiotics, which have pervasive and long-term effects on the intestinal microbiota.

Differential involvement of orbital fat and extraocular muscles in graves' ophthalmopathy.

Graves' ophthalmopathy (GO) is characterized by swelling of orbital fat and extraocular muscles, but little attention has been given to differential involvement of fat and muscles. Advancements in imaging allow rather accurate measurements of orbital bony cavity volume (OV), fat volume (FV) and muscle volume (MV), and are the topics of this review. Ratios of FV/OV and MV/OV neutralize gender differences.

VEGF levels in plasma in relation to platelet activation, glycemic control, and microvascular complications in type 1 diabetes.

Objective: Increased levels of vascular endothelial growth factor (VEGF) in human plasma samples have suggested that circulating VEGF is a cause of endothelial dysfunction in diabetes mellitus. However, artificial release of VEGF from platelets as a source of VEGF in plasma samples, as also occurs in serum samples, has not been ruled out in these studies.

Research Design And Methods: We determined VEGF levels in plasma collected in both citrate and PECT, a medium that inactivates platelets, in a cross-sectional cohort of 21 healthy subjects and 64 patients with type 1 diabetes.

Circulating IgGs may modulate IGF-I receptor stimulating activity in a subset of patients with Graves' ophthalmopathy.

Context: There is a close association between levels of TSH binding inhibitory immunoglobulins (TBIIs) and Graves' ophthalmopathy (GO). In addition to the TSH receptor, the IGF-I receptor (IGF-IR) has been proposed to be a second autoantigen that plays a role in the pathogenesis of GO.

Objective: The aim was to study relationships between TBII and serum IGF-IR stimulating activity in relationship to age in patients with GO.

[Cardiovascular risks in patients with subclinical thyroid dysfunction].

Recent meta-analyses of population-based studies with long-term follow-up have clarified the risk of cardiovascular disorders in patients with subclinical thyroid dysfunction. Subclinical hyperthyroidism is associated with an increased risk of atrial fibrillation and cardiovascular morbidity and mortality; the risk is higher at a thyroid stimulating hormone (TSH) level < 0.1 mU/l than at 0.

Endogenous protein C has a protective role during Gram-negative pneumosepsis (melioidosis).

Background: Activated protein C (APC) exerts anticoagulant effects via inactivation of factors Va and VIIIa and cytoprotective effects via protease activated receptor (PAR)1. Inhibition of endogenous APC in endotoxemia and sepsis results in exacerbation of coagulation and inflammation, with consequent enhanced lethality.

Objectives: We here sought to dissect the distinct roles of the anticoagulant and cytoprotective functions of endogenous APC in severe Gram-negative pneumonia-derived sepsis (melioidosis).

Workshop on treatment of and postexposure prophylaxis for Burkholderia pseudomallei and B. mallei Infection, 2010.

The US Public Health Emergency Medical Countermeasures Enterprise convened subject matter experts at the 2010 HHS Burkholderia Workshop to develop consensus recommendations for postexposure prophylaxis against and treatment for Burkholderia pseudomallei and B. mallei infections, which cause melioidosis and glanders, respectively. Drugs recommended by consensus of the participants are ceftazidime or meropenem for initial intensive therapy, and trimethoprim/sulfamethoxazole or amoxicillin/clavulanic acid for eradication therapy.

Host-pathogen interaction in invasive Salmonellosis.

Salmonella enterica infections result in diverse clinical manifestations. Typhoid fever, caused by S. enterica serovar Typhi (S.

Efficacy and safety of three different cumulative doses of intravenous methylprednisolone for moderate to severe and active Graves' orbitopathy.

Background: Optimal doses of i.v. glucocorticoids for Graves' orbitopathy (GO) are undefined.