Citations

Background: Thyrotoxicosis has multiple etiologies, manifestations, and potential therapies. Appropriate treatment requires an accurate diagnosis and is influenced by coexisting medical conditions and patient preference. This document describes evidence-based clinical guidelines for the management of thyrotoxicosis that would be useful to generalist and subspecialty physicians and others providing care for patients with this condition. Methods: The American Thyroid Association (ATA) previously cosponsored guidelines for the management of thyrotoxicosis that were published in 2011. Considerable new literature has been published since then, and the ATA felt updated evidence-based guidelines were needed. The association assembled a task force of expert clinicians who authored this report. They examined relevant literature using a systematic PubMed search supplemented with additional published materials. An evidence-based medicine approach that incorporated the knowledge and experience of the panel was used to update the 2011 text and recommendations. The strength of the recommendations and the quality of evidence supporting them were rated according to the approach recommended by the Grading of Recommendations, Assessment, Development, and Evaluation Group. Results: Clinical topics addressed include the initial evaluation and management of thyrotoxicosis; management of Graves' hyperthyroidism using radioactive iodine, antithyroid drugs, or surgery; management of toxic multinodular goiter or toxic adenoma using radioactive iodine or surgery; Graves' disease in children, adolescents, or pregnant patients; subclinical hyperthyroidism; hyperthyroidism in patients with Graves' orbitopathy; and management of other miscellaneous causes of thyrotoxicosis. New paradigms since publication of the 2011 guidelines are presented for the evaluation of the etiology of thyrotoxicosis, the management of Graves' hyperthyroidism with antithyroid drugs, the management of pregnant hyperthyroid patients, and the preparation of patients for thyroid surgery. The sections on less common causes of thyrotoxicosis have been expanded. Conclusions: One hundred twenty-four evidence-based recommendations were developed to aid in the care of patients with thyrotoxicosis and to share what the task force believes is current, rational, and optimal medical practice.

Background: Traditionally, ultrasound has been used to evaluate musculoskeletal injuries in athletes; however, ultrasound applications extend well beyond musculoskeletal conditions, many of which are pertinent to athletes. Evidence Acquisition: Articles were identified in PubMed using the search terms ultrasound, echocardiogram, preparticipation physical examination, glycogen, focused assessment with sonography of trauma, optic nerve, and vocal cord dysfunction. No date restrictions were placed on the literature search. Study Design: Clinical review. Level of Evidence: Level 4. Results: Several potential applications of nonmusculoskeletal ultrasound in sports medicine are presented, including extended Focused Assessment with Sonography for Trauma (eFAST), limited echocardiographic screening during preparticipation physical examinations, assessment of muscle glycogen stores, optic nerve sheath diameter measurements in athletes with increased intracranial pressure, and assessment of vocal cord dysfunction in athletes. Conclusion: Ultrasound can potentially be used to assist athletes with monitoring their muscle glycogen stores and the diagnosis of multiple nonmusculoskeletal conditions within sports medicine.

Abstract CD8 T cells must integrate antigenic and inflammatory signals to differentiate into efficient effector and memory T cells able to protect us from infections. The mechanisms by which TCR signaling and proinflammatory cytokine receptor signaling cooperate in these processes are poorly defined. In this study, we show that IL-12 and other proinflammatory cytokines transduce signals through the TCR signalosome in a manner that requires Fyn activity and self-peptide–MHC (self-pMHC) interactions. This mechanism is crucial for CD8 innate T cell functions. Loss of Fyn activity or blockade of self-pMHC interactions severely impaired CD8 T cell IFN-γ and NKG2D expression, proliferation, and cytotoxicity upon cytokine-mediated bystander activation. Most importantly, in the absence of self-pMHC interactions, CD8 memory T cells fail to undergo bystander activation upon an unrelated infection. Thus, CD8 T cell bystander activation, although independent of cognate Ag, still requires self-pMHC and TCR signaling.

Insulin-like growth factors (IGFs) are implicated in the development of diabetic nephropathy (DN) and are shown to increase proliferation and extracellular matrix production in mesangial cells. The IGF system is complex and is composed of ligands, receptors, six binding proteins (IGF BPs) and a novel zinc metalloproteinase – pregnancy-associated plasma protein (PAPP)-A. PAPP-A increases the local bioavailability of IGF through the cleavage of IGF BP-4. Mesangial expansion is a major component of DN, and PAPP-A is shown to be increased in the glomeruli of patients with DN. Therefore, we determined the expression of PAPP-A and components of the IGF system in normal human mesangial cells (HMCs) and their regulation by factors known to be involved in DN. Under basal conditions, HMCs expressed PAPP-A, IGF1 receptor and all six IGF BPs. Interleukin (IL)-1β was the most potent stimulus for PAPP-A expression (5-fold) followed by tumor necrosis factor (TNF)-α (2.5-fold). This PAPP-A was secreted, cell associated and proteolytically active. IL1β also increased IGF BP-1expression (3-fold) with either reduction or no effect on other IGF BPs. Generally, TNF-α treatment decreased IGF BP expression. No treatment effect on PAPP-A or IGF BPs was seen with IL6, IGFs, advanced glycation end products or prolonged hyperglycemia. In addition, stimulation of HMCs with IGF1 alone or IGF1 complexed to wild-type, but not protease-resistant, IGF BP-4 led to increased [ 3 H]-thymidine incorporation. In conclusion, these novel findings of PAPP-A and its regulation by proinflammatory cytokines, as well as the comprehensive analysis of the IGF system regulation in HMCs, suggest a mechanism by which inflammatory states such as DN can impact IGF activity in the kidney.

Although the majority of giant cell tumors (GCTs) of the bone occur in adult patients, occasionally they arise in the pediatric population. In this setting they may be mistaken for tumors more commonly seen in this age group, including osteosarcoma, aneurysmal bone cyst, and chondroblastoma. All cases of primary GCT of the bone arising in patients 18 years and below were retrieved from our institutional archives and examined with emphasis on the evaluation of various morphologic patterns. Clinical/radiologic records were reviewed when available. Analysis for H3F3A/H3F3B mutations was performed in a subset of cases. Sixty-three (of 710) patients treated at our institution for GCT were 18 years of age and below. The following morphologic patterns were identified: fibrosis (31 cases, 49%), reactive-appearing bone (26, 41%), cystic change (7, 11%), foamy histiocytes (6, 10%), secondary aneurysmal bone cyst (3, 5%), and cartilage (2, 3%). Infarct-like necrosis was present in 17 tumors (27%), and the mitotic rate ranged from 0 to 35 mitoses/10 high-power fields (median 5 mitoses/10 high-power field). Follow-up information (n=55; 6 mo to 69.6 y; median, 11.6 y) showed 21 patients with local recurrence (38%) and 2 patients with lung metastasis (4%). Polymerase chain reaction with sequencing showed that 5 of 5 tested cases harbored H3F3A mutations. In summary, GCT arising in the pediatric population is rare, representing 9% of GCTs seen at our institution. The morphologic spectrum of these tumors is broad and similar to that seen in patients above 18 years of age. It is important to recognize that matrix formation may be observed in GCT, including reactive-appearing bone and cartilage, as well as areas of fibrosis mimicking osteoid production, to avoid misclassification as osteosarcoma or other giant cell–rich lesions common in children.

Background— Previously published evidence on ischemic mitral regurgitation (IMR) and its adverse prognosis after myocardial infarction has been based on the severity of IMR in the subacute or chronic period of myocardial infarction. However, the state of IMR can vary from the early stage to the chronic stage as a result of various responses of myocardium after primary percutaneous coronary intervention (PCI). Methods and Results— Standard echocardiography was serially performed in 546 consecutive patients with first-onset acute myocardial infarction (1) immediately after their arrival (pre-PCI), (2) before discharge (early post-PCI), and (3) 6 to 8 months after PCI (late post-PCI). The course of IMR after primary PCI and the prognostic impact of the IMR in each phase were investigated. IMR was found in 193/546 (35%) patients at the emergency room. In the acute phase after PCI, IMR improved in 63 patients. IMR worsened in 78 patients despite successful PCI. Shorter onset-to-reperfusion time and nontotal occlusion before PCI were the independent predictors of early improvement of IMR. In the chronic phase, IMR improved in 79 patients and worsened in 36 patients. Lower peak creatine kinase–myocardial band was an independent predictor of late improvement of IMR. IMR before PCI worsened 30-day prognosis ( P =0.02), and persistent IMR in the chronic phase worsened long-term prognosis ( P =0.04) after primary PCI. Conclusions— Degrees of IMR changed in the early and chronic phase after primary PCI for acute myocardial infarction. IMR on arrival and persistent IMR in the chronic phase worsened short-term and long-term prognosis after acute myocardial infarction, respectively.