The hypothalamus–pituitary–thyroid feedback control is a dynamic, adaptive system. In situations of illness and deprivation of energy representing type 1 allostasis, the stress response operates to alter both its set point and peripheral transfer parameters. In contrast, type 2 allostatic load, typically effective in psychosocial stress, pregnancy, metabolic syndrome, and adaptation to cold, produces a nearly opposite phenotype of predictive plasticity. The non-thyroidal illness syndrome (NTIS) or thyroid allostasis in critical illness, tumors, uremia, and starvation (TACITUS), commonly observed in hospitalized patients, displays a historically well-studied pattern of allostatic thyroid response. This is characterized by decreased total and free thyroid hormone concentrations and varying levels of thyroid-stimulating hormone (TSH) ranging from decreased (in severe cases) to normal or even elevated (mainly in the recovery phase) TSH concentrations. An acute versus chronic stage (wasting syndrome) of TACITUS can be discerned. The two types differ in molecular mechanisms and prognosis. The acute adaptation of thyroid hormone metabolism to critical illness may prove beneficial to the organism, whereas the far more complex molecular alterations associated with chronic illness frequently lead to allostatic overload. The latter is associated with poor outcome, independently of the underlying disease. Adaptive responses of thyroid homeostasis extend to alterations in thyroid hormone concentrations during fetal life, periods of weight gain or loss, thermoregulation, physical exercise, and psychiatric diseases. The various forms of thyroid allostasis pose serious problems in differential diagnosis of thyroid disease. This review article provides an overview of physiological mechanisms as well as major diagnostic and therapeutic implications of thyroid allostasis under a variety of developmental and straining conditions.

Coronary heart disease is a major cause of death in the western world. Although essential for successful recovery, reperfusion of ischemic myocardium is inevitably associated with reperfusion injury. To investigate a potential protective role of ADAMTS13, a protease cleaving von Willebrand factor multimers, during myocardial ischemia/reperfusion, we used a mouse model of acute myocardial infarction. We found that Adamts13 ؊/؊ mice developed larger myocardial infarctions than wild-type control mice, whereas treatment of wild-type mice with recombinant human ADAMTS13 (rhADAMTS13) led to smaller infarctions. The protective effect of ADAMTS13 was further confirmed by a significant reduction of cardiac troponin-I release and less myocardial apoptosis in mice that received rhADAMTS13 compared with controls. Platelets adherent to the blood vessel wall were observed in few areas in the heart samples from mice treated with vehicle and were not detected in samples from mice treated with rhADAMTS13. However, we observed a 9-fold reduction in number of neutrophils infiltrating ischemic myocardium in mice that were treated with rhADAMTS13, suggesting a potent anti-inflammatory effect of ADAMTS13 during heart injury. Our data show that ADAMTS13 reduces myocardial ischemia/reperfusion injury in mice and indicate that rhADAMTS13 could be of therapeutic value to limit myocardial ischemia/reperfusion injury. (Blood. 2012;120(26):5217-5223) IntroductionCoronary heart disease is the leading cause of death in the western world with approximately 1 million myocardial infarctions (MIs) each year just in the United States. 1,2 Acute myocardial infarction (AMI) is caused by thrombotic occlusion of a coronary artery. Although rapid restoration of the coronary circulation is critical for successful treatment, reperfusion itself exacerbates injury of previously ischemic myocardium. 1 The exact mechanisms of myocardial ischemia/reperfusion (MI/R) injury are not fully understood. 1 Given that cardiac ischemia is either unpredictable (MI) or inevitable (in patients undergoing cardioplegic arrest), there is great interest in developing strategies to minimize injury. von Willebrand factor (VWF) and its cleaving protease ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type-1 motif, member 13) play a pivotal role in platelet adhesion and thrombus formation. By specifically cleaving the VWF A2 domain, ADAMTS13 digests the most thrombogenic ultra-large VWF multimers (UL-VWF) into smaller, less hemostatically active VWF molecules. In addition, ADAMTS13's action on VWF downregulates inflammatory responses. As a result, using experimental mouse models, ADAMTS13 was shown to reduce both thrombosis and inflammation, including atherosclerosis. [3][4][5] An increasing amount of clinical evidence points to the possibility that VWF and ADAMTS13 are involved in MI pathogenesis. 6 To test this experimentally, we used a mouse model of acute myocardial infarction. Using mice deficient in ADAMTS13 and treating wild-type mice with human rhADAM...

Deficiency of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13), a VWFcleaving protease, is the key factor in the pathogenesis of thrombotic thrombocytopenic purpura (TTP), a life-threatening thrombotic microangiopathy. It is well established that ADAMTS13 deficiency results in elevated plasma levels of ultralarge VWF multimers (ULVWF), which are prone to induce platelet aggregation; however, the actual trigger of TTP development remains uncertain. Here we de-

This trial provides first evidence of clinical efficacy of vidofludimus in IBD. Although the safety and tolerability profile seems favorable, long-term controlled studies are needed to further investigate its potential as novel IBD therapy.

1 Glycerol trinitrate (GTN) has been used in therapy for more than 100 years. Biological effects of GTN are due to the release of the biomediator nitric oxide (NO). However, the mechanism by which GTN provides NO, in particular in liver, is still unknown. In this study, we provide experimental evidence showing that cytoplasm, endoplasmic reticulum, and mitochondria are required for the release of NO from GTN in the liver. 2 NO and nitrite (NO 2 À ) were determined using low-temperature electron paramagnetic resonance and the Griess reaction, respectively. 3 The first step of GTN biotransformation is the release of NO 2 À . This step is performed in cytoplasm and catalyzed by glutathione-S-transferase. The second step is the rate-limiting step where NO 2 À is slowly reduced to NO. This is mainly catalyzed by cytochrome P-450. The second phase can be significantly enhanced by decreasing the pH value, a situation which occurs during ischemia. At high NADPH concentrations exceeding physiological values, cytochrome P-450 catalyzes GTN biotransformation without the involvement of cytoplasmic glutathione-S-transferase. 4 In conclusion, our data show that NO 2 À derived from the first step of biotransformation of GTN in the liver is the precursor of NO but not a product of NO degradation; consequently, NO 2 À levels are not likely to be a marker of NO release from GTN as earlier suggested.