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Peter Kopp

The large family of G protein-coupled receptors (GPCRs) transduces signals of a bewildering variety of extracellular stimuli including hormones, neurotransmitters, ions, cytokines and photons. Many GPCRs undergo a rapid, but reversible decrease or loss of responsiveness upon exposure to their ligand, a phenomenon referred to as homologous desensitization. This process involves an inhibition of the GPCR-interaction with the appropriate G protein and is therefore also coined 'receptor uncoupling'. This rapid form of modulation in responsiveness has to be differentiated from the long-term desensitization caused by transcriptional downregulation (1).

Primarily from studies with rhodopsin and the β-adrenergic receptors, it became apparent that the rapid uncoupling of these GPCRs from the interacting G protein is initiated by phosphorylation of the agonistoccupied, stimulated receptor. Phosphorylation of GPCRs is induced by G protein-coupled receptor kinases (GRKs), a family of serine/threonine kinases with, currently, six known members (2). Once a GPRC is phosphorylated by a

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Peter Kopp

Adrenal hypoplasia congenita (AHC) is an inherited disorder that presents at different time points in childhood with adrenal insufficiency and severe saltwasting (1). Its eponym, AHC, frequently creates some confusion with CAH, congenital adrenal hyperplasia. Two distinct entities of AHC have been described: the X-linked form and the autosomal recessive form. In the X-linked variant, also referred to as the cytomegalic form, the fetal cortex is intact but the permanent zone of the adrenal cortex does not develop and is replaced by large vacuolated cells (2).

Clinically, affected boys suffering from X-linked AHC present with cortisol and mineralocorticoid deficiency but, in contrast to CAH, there are no signs of androgen excess. Moreover, there is no increase in steroid precursors in response to adrenocorticotropin (ACTH) stimulation. AHC is lethal if untreated. Once treatment with steroids allowed survival beyond childhood, it became apparent that one of the additional features of this syndrome

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Ides M Colin, Peter Kopp, Jakob Zbären, André Häberli, William E Grizzle and J Larry Jameson

Abstract

Nitric oxide mediates a wide array of cellular functions in many tissues. It is generated by three known isoforms of nitric oxide synthases (NOS). Recently, the endothelial isoform, NOSIII, was shown to be abundantly expressed in the rat thyroid gland and its expression increased in goitrous glands.

In this study, we analyzed whether NOSIII is expressed in human thyroid tissue and whether levels of expression vary in different states of thyroid gland function. Semiquantitative RT-PCR was used to assess variations in NOSIII gene expression in seven patients with Graves' disease, one with a TSH-receptor germline mutation and six hypothyroid patients (Hashimoto's thyroiditis). Protein expression and subcellular localization were determined by immunohistochemistry (two normal thyroids, five multinodular goiters, ten hyperthyroid patients and two hypothyroid patients).

NOSIII mRNA was detected in all samples: the levels were significantly higher in tissues from hyperthyroid patients compared with euthyroid and hypothyroid patients. NOSIII immunoreactivity was detected in vascular endothelial cells, but was also found in thyroid follicular cells. In patients with Graves' disease, the immunostaining was diffusely enhanced in all follicular cells. A more intense signal was observed in toxic adenomas and in samples obtained from a patient with severe hyperthyroidism due to an activating mutation in the TSH receptor. In multinodular goiters, large follicles displayed a weak signal whereas small proliferative follicles showed intense immunoreactivity near the apical plasma membrane. In hypothyroid patients, NOSIII immunoreactivity was barely detectable.

In summary, NOSIII is expressed both in endothelial cells and thyroid follicular cells. The endothelial localization of NOSIII is consistent with a role for nitric oxide in the vascular control of the thyroid. NOSIII expression in thyroid follicular cells and the variations in its immunoreactivity suggest a possible role for nitric oxide in thyrocyte function and/or growth.

European Journal of Endocrinology 136 649–655

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Massimo Bongiovanni, William C Faquin, Luca Giovanella, Cosimo Durante, Peter Kopp and Pierpaolo Trimboli

Objective

The second version of The Bethesda System for Reporting Thyroid Cytopathology endorsed the introduction of non-invasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) as a distinct entity with low malignant potential into clinical practice. Consequently, the risk of malignancy (ROM) of cytological diagnoses has changed, but the magnitude of the change remains uncertain. The present systematic review was undertaken to obtain more robust information about the true impact of NIFTP on the ROM among patients undergoing surgery following a fine-needle aspiration cytology (FNAC) diagnosis of suspicious for malignancy (Bethesda V) or malignant (Bethesda VI). As they are managed surgically, these two diagnostic categories are the primary entities that are clinically impacted by the advent of NIFTP.

Design

Systematic review and meta-analysis.

Methods

A comprehensive literature search of online databases was performed in November 2018. The search was conducted looking for data of histologically proven NIFTP with preoperative FNAC.

Results

One-hundred fifty-seven articles were identified and nine were included in the study. Overall, there were 13,752 thyroidectomies with a cancer prevalence of 45.7%. When NIFTP was considered non-malignant, the pooled risk difference for ROM was 5.5%. Applying meta-analysis, the pooled prevalence of NIFTP among nodules with FNAC of Bethesda V or Bethesda VI was 14 and 3%, respectively.

Conclusion

This meta-analysis shows that the inclusion of NIFTP leads to a reduction in the ROM for the Bethesda V and Bethesda VI FNAC diagnostic categories by 14 and 3%, respectively. Clinicians should be aware of these data to avoid overtreatment.