Clinical OtolaryngologyVolume 43, Issue 4 p. 1130-1131 CORRESPONDENCE: OUR EXPERIENCE Cochlear dead regions: Using the Threshold Equalising Noise (TEN) test to improve the assessment of potential cochlear implant candidates—The Oxford experience D. Moualed, Corresponding Author D. Moualed daniel.moualed@ouh.nhs.uk orcid.org/0000-0002-5590-5451 Department of Otolaryngology - Head and Neck Surgery, Oxford University Hospitals, Oxford, UK Correspondence D. Moualed, Department of Otolaryngology - Head and Neck Surgery, John Radcliffe Hospital, Oxford, UK. Email: daniel.moualed@ouh.nhs.ukSearch for more papers by this authorJ. Humphries, J. Humphries Department of Audiology, Oxford University Hospitals, Oxford, UKSearch for more papers by this authorJ.D. Ramsden, J.D. Ramsden Department of Otolaryngology - Head and Neck Surgery, Oxford University Hospitals, Oxford, UKSearch for more papers by this author D. Moualed, Corresponding Author D. Moualed daniel.moualed@ouh.nhs.uk orcid.org/0000-0002-5590-5451 Department of Otolaryngology - Head and Neck Surgery, Oxford University Hospitals, Oxford, UK Correspondence D. Moualed, Department of Otolaryngology - Head and Neck Surgery, John Radcliffe Hospital, Oxford, UK. Email: daniel.moualed@ouh.nhs.ukSearch for more papers by this authorJ. Humphries, J. Humphries Department of Audiology, Oxford University Hospitals, Oxford, UKSearch for more papers by this authorJ.D. Ramsden, J.D. Ramsden Department of Otolaryngology - Head and Neck Surgery, Oxford University Hospitals, Oxford, UKSearch for more papers by this author First published: 24 February 2018 https://doi.org/10.1111/coa.13088Citations: 1Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume43, Issue4August 2018Pages 1130-1131 RelatedInformation

In goiter, increased expression of growth factors and their receptors occurs. We have inhibited the action of some of these growth factors, alone and in combination, to determine which are important in goitrogenesis. Recombinant adenovirus vectors ( RAds) expressing truncated, secreted forms of human Tie2 (RAd-sTie2) and vascular endothelial growth factor receptor 1 (RAd-sVEGFR1) or a truncated, dominant-negative fibroblast growth factor receptor 1 (RAdDN-FGFR1) were used. Goiters in mice were induced by feeding an iodide-deficient diet, containing methimazole and sodium perchlorate. RAds were administered to mice simultaneously with the goitrogenic regimen, which was continued for 14 d. RAd treatment did not significantly affect increases in TSH or reductions in thyroid hormone or thyroid hyperactivity seen in goitrogen-treated controls mice, suggesting no effect on pituitary or thyroid responses to hypothyroidism. In control goiters, a 4-fold increase in vascular volume accompanied a 2-fold increase in thyroid mass. Complete inhibition of these increases was found when animals were treated with the three RAds in combination. In thyroids from three RAd-treated animals, there was marked, significant inhibition of Tie2, FGFR1, VEGFR1, FGF-2, and VEGF expression, compared with control goiters. When used individually, RAdDN-FGFR1 partially prevented goiter and RAd-sVEGFR1 partially reduced vascular volume. Their effects were not additive. RAd-sTie2 did not reduce goiter mass or vascular volume when used alone but was essential for complete goiter inhibition. VEGF and VEGFR1 expression was reduced in these thyroids. Limitation of physiologic organ growth is complex, requiring inhibition of multiple, interdependent growth factor axes.

Levels of fibroblast growth factor 2 (FGF-2) and its receptor, FGFR1, are elevated in goiter, but whether this is a direct effect of TSH is unknown. We have determined the regulation of FGF-2 and FGFR1 synthesis by TSH in a rat thyroid cell line (FRTL5) and have used a replication-defective adenovirus (RAd) expressing dominant negative FGFR1 (RAdDN-FGFR1) to examine the role of FGFR signaling in vitro and in goiter induced in mice. TSH induced FGF-2 and increased the expression of FGFR1 in FRTL5 cells. Infection of TSH-stimulated FRTL5 cells with RAdDN-FGFR1 inhibited growth and prevented FGF-2-mediated inhibition of (125)I uptake. Similar effects were found in primary cultures of human thyroid follicular cells. For in vivo experiments, male BALB/c mice were injected systemically with RAdDN-FGFR1 or RAd encoding green fluorescent protein, and goiter was simultaneously induced. Mouse thyroid follicles were shown to be transduced with RAd encoding green fluorescent protein. Circulating TSH was elevated comparably in the two groups. In the RAdDN-FGFR1-injected animals, goiter induced over 14 d was significantly smaller, and the vascular volume increase seen in goiter was also diminished. We conclude that the FGF axis is important in thyroid growth and that RAdDN-FGFR1 effectively blocks FGF actions, offering a means to control goitrogenesis.

Angiostatin, a 38 kDa fragment of plasminogen, potently inhibits the growth of blood vessels. Angiostatin is generated from plasminogen by urokinase-type (uPA) and tissue-type (tPA) plasminogen activators in the presence of free sulphydryl donors. Angiogenesis inhibitors may be important in regulating angiogenesis in developing goitre. We have examined angiostatin formation in human primary thyrocyte cultures and a rat thyrocyte cell line (FRTL-5). We found that human thyroid cells in culture secrete plasminogen activators (both tPA and uPA) as well as matrix metalloproteinase 2 into the medium. When human thyrocyte conditioned medium was incubated with plasminogen (10 microg/ml) and N-acetylcysteine (100 microM) for 24 h, a 38 kDa fragment of plasminogen, which is consistent with angiostatin, was generated. The appearance of the 38 kDa fragment was increased by agents that increase cAMP (forskolin and 8 BrcAMP). FRTL-5 cells, which do not secrete uPA or tPA, did not generate angiostatin. Thyroid cells produce several angiogenic growth factors, and human thyrocyte conditioned medium stimulated growth of endothelial cells. When the conditioned medium was incubated with plasminogen and N-acetylcysteine, this stimulatory effect was lost, consistent with the production of a growth inhibitory factor. We conclude that thyroid cells can produce angiostatin from plasminogen in vitro, and this may play a role in vivo in limiting goitre size.

Thyroid surgery has been traditionally a general surgical practice, but recently more otolaryngologists have been offering a thyroid service. We have quantified thyroid surgery performed by the different specialties, and looked more closely at the practice of otolaryngologists. Data was obtained from the Department of Health for UK thyroid surgery in all specialties for the year 1998-99 and validated against a survey of members of the British Association of Otolaryngologists-Head & Neck Surgeons (BAO-HNS). The use of investigations of a simple clinical case (solitary thyroid nodule) was compared with best practice. General surgeons still perform the majority of thyroid surgery (83%) but ENT surgeons now perform significant numbers (15.4% of all cases), which translates to 1499 cases per annum. A total of 102 BAO-HNS members were performing thyroid surgery with an average case-load of 19.1 per year. In total, 35% of ENT surgeons see thyroid patients in multidisciplinary clinics. The choice of investigation is consistent with European guidelines. ENT surgeons are doing significant amounts of thyroid surgery and the numbers appear to be increasing. The formation of multidisciplinary teams including general surgeons and otolaryngologists who are committed to subspecialization can only improve both training and treatment outcomes.

Angiogenesis is coordinated with follicular cell growth in goitrogenesis. The angiopoietins, Ang-1 and Ang-2, are angiogenic growth factors acting through Tie-2, a tyrosine kinase receptor. We have examined the expression and regulation of the angiopoietins and Tie-2 in human and rat thyroids. In human goiters there was increased Tie-2 immunostaining, compared with that in normal thyroids, on both follicular and endothelial cells. In an induced goiter in rats, in situ hybridization showed increased expression of messenger ribonucleic acids (mRNAs) for Tie-2 and Ang-1 in follicular cells. As Tie-2 has previously been believed to be restricted to cells of endothelial lineage in adults, we examined its expression further in isolated follicular cells. Tie-2 and Ang-1 mRNA expression in human thyrocytes was confirmed by ribonuclease protection assay. Ang-2 mRNA was not detected in human cultures or rat thyroids. In both human follicular cell cultures and FRTL-5 cells, immunoblotting showed that Tie-2 expression was increased by TSH and agents that increased intracellular cAMP. In conclusion, we have demonstrated the expression of Tie-2 and Ang-1 in thyroid epithelial and endothelial cells, and have shown the regulation of Tie-2 by TSH and cAMP in follicular cells. Tie-2 expression is increased in goiter in both humans and rats, consistent with a role in goitrogenesis.

Angiogenesis is the mechanism of blood vessel formation after the first few days of embryogenesis, and is essential for all tissue growth. In adults, angiogenesis occurs in the thyroid during disease processes including goitre, Graves disease, thyroiditis and cancer. The molecular mechanisms controlling angiogenesis are becoming clearer, and therapy targeting these processes is coming closer to clinical fruition. Both promoters and inhibitors of angiogenesis have been identified in the thyroid, including vascular endothelial growth factor (VEGF), fibroblast growth factor, and thrombospondin. This commentary will review the understanding of the control of angiogenesis within the context of the thyroid gland, and review the pre-eminent role of VEGF as the angiogenic signal from the follicular cells to the endothelial cells.

Clinical Otolaryngology & Allied SciencesVolume 25, Issue 1 p. 90-91 A Central Role for Angiopoietins in Goitre Formation J.D. Ramsden, (Divisions of Medical Sciences andSearch for more papers by this authorH.C. Cocks, (Divisions of Medical Sciences andSearch for more papers by this authorM.C. Sheppard, (Divisions of Medical Sciences andSearch for more papers by this authorJ. Franklyn, (Divisions of Medical Sciences andSearch for more papers by this authorJ.C. Watkinson, (Divisions of Medical Sciences andSearch for more papers by this authorA. Ahmed, (Divisions of Medical Sciences andSearch for more papers by this authorS. Nijjar, (Divisions of Medical Sciences andSearch for more papers by this authorM.C. Eggo, (Divisions of Medical Sciences andSearch for more papers by this author J.D. Ramsden, (Divisions of Medical Sciences andSearch for more papers by this authorH.C. Cocks, (Divisions of Medical Sciences andSearch for more papers by this authorM.C. Sheppard, (Divisions of Medical Sciences andSearch for more papers by this authorJ. Franklyn, (Divisions of Medical Sciences andSearch for more papers by this authorJ.C. Watkinson, (Divisions of Medical Sciences andSearch for more papers by this authorA. Ahmed, (Divisions of Medical Sciences andSearch for more papers by this authorS. Nijjar, (Divisions of Medical Sciences andSearch for more papers by this authorM.C. Eggo, (Divisions of Medical Sciences andSearch for more papers by this author First published: 10 August 2009 https://doi.org/10.1046/j.1365-2273.2000.00337-10.xRead the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinked InRedditWechat Volume25, Issue1February 2000Pages 90-91 RelatedInformation