Search

Therapy for thyroid-associated ophthalmopathy is evolving to specific biological molecules targeting putative and plausible disease mechanisms

IMPORTANCE: Thyroid eye disease (TED) results in varying degrees of proptosis and diplopia negatively affecting quality of life (QoL), producing possibly substantial visual changes, disfigurement, and disability. OBJECTIVE: To determine the association of varying TED severities with QoL in a non-TED population by assessing health state utility scores. DESIGN, SETTING, AND PARTICIPANTS: This qualitative study, conducted from April 20, 2020, to April 29, 2021, assessed health states for active, moderate-severe TED, and values were elicited using time trade-off methods. Six health states of varying severity were determined from 2 placebo-controlled clinical trials (171 patients with TED and clinical activity score ≥4, ±diplopia/proptosis) and refined using interviews with US patients with TED (n = 6). Each health state description was validated by interviews with additional TED patient advocates (n = 3) and physician experts (n = 3). Health state descriptions and a QOL questionnaire were piloted and administered to a general population. Visual analog scales (VASs) were also administered to detect concurrence of the findings. MAIN OUTCOMES AND MEASURES: TED health state utility scores and whether they differ from one another were assessed using Shapiro-Wilk, Kruskal-Wallis, pairwise Wilcoxon rank sum, and paired t tests. RESULTS: A total of 111 participants completed time trade-off interviews. The mean (SD) utility value was 0.44 (0.34). The lowest (worse) mean utility value was observed in the most severe disease state (constant diplopia/large proptosis) with 0.30 (95% CI, 0.24-0.36), followed by constant diplopia/small proptosis (0.34; 95% CI, 0.29-0.40), intermittent or inconstant diplopia/large proptosis (0.43; 95% CI, 0.36-0.49), no diplopia/large proptosis (0.46; 95% CI, 0.40-0.52), and intermittent or inconstant diplopia/small proptosis (0.52; 95% CI, 0.45-0.58). The highest (best) mean value, 0.60 (95% CI, 0.54-0.67), was observed for the least severe disease state (no diplopia/small proptosis). CONCLUSIONS AND RELEVANCE: These findings suggest that patients with active, moderate-severe TED may have substantial disutility, with increasing severity of proptosis/diplopia more likely to have detrimental associations with QoL. These health state scores may provide a baseline for determining QoL improvement in these TED health states (utility gains) treated with new therapies.

BackgroundThe novel optic neuritis (ON) diagnostic criteria include intereye differences (IED) of optical coherence tomography (OCT) parameters. IED has proven valuable for ON diagnosis in multiple sclerosis but has not been evaluated in aquaporin-4 antibody seropositive neuromyelitis optica spectrum disorders (AQP4+NMOSD). We evaluated the diagnostic accuracy of intereye absolute (IEAD) and percentage difference (IEPD) in AQP4+NMOSD after unilateral ON >6 months before OCT as compared with healthy controls (HC).MethodsTwenty-eight AQP4+NMOSD after unilateral ON (NMOSD-ON), 62 HC and 45 AQP4+NMOSD without ON history (NMOSD-NON) were recruited by 13 centres as part of the international Collaborative Retrospective Study on retinal OCT in Neuromyelitis Optica study. Mean thickness of peripapillary retinal nerve fibre layer (pRNFL) and macular ganglion cell and inner plexiform layer (GCIPL) were quantified by Spectralis spectral domain OCT. Threshold values of the ON diagnostic criteria (pRNFL: IEAD 5 µm, IEPD 5%; GCIPL: IEAD: 4 µm, IEPD: 4%) were evaluated using receiver operating characteristics and area under the curve (AUC) metrics.ResultsThe discriminative power was high for NMOSD-ON versus HC for IEAD (pRNFL: AUC 0.95, specificity 82%, sensitivity 86%; GCIPL: AUC 0.93, specificity 98%, sensitivity 75%) and IEPD (pRNFL: AUC 0.96, specificity 87%, sensitivity 89%; GCIPL: AUC 0.94, specificity 96%, sensitivity 82%). The discriminative power was high/moderate for NMOSD-ON versus NMOSD-NON for IEAD (pRNFL: AUC 0.92, specificity 77%, sensitivity 86%; GCIP: AUC 0.87, specificity 85%, sensitivity 75%) and for IEPD (pRNFL: AUC 0.94, specificity 82%, sensitivity 89%; GCIP: AUC 0.88, specificity 82%, sensitivity 82%).ConclusionsResults support the validation of the IED metrics as OCT parameters of the novel diagnostic ON criteria in AQP4+NMOSD.

We present the optical and mechanical designs of an optically-pluggable package for photonic integrated circuits (PICs). Using off-the-shelf micro-optical components, low-loss (∼2 dB) expanded-beam connection between an edge-coupled SiN-based PIC and standard optical fiber is demonstrated. High reproducibility of coupling efficiency is demonstrated over up to 80 mating/de-mating cycles.

What does it mean to think and act radically, and how does this relate to forms of radicalism connected to earlier moments, for example, in the 20th century? What can be the role of radical art and scholarship under the conditions of late capitalism? More generally, how can art and artists serve the ongoing struggle for social justice and the agendas of emancipatory social change? Finally, what kinds of art criticism and art historical scholarship are necessary to address the great challenges of our uncertain future?

National data indicate low intentions for COVID-19 vaccination among a substantial minority of Black Americans, and disproportionately lower vaccination rates among Black Americans than White Americans.

BackgroundPatients with anti-aquaporin-4 antibody seropositive (AQP4-IgG+) neuromyelitis optica spectrum disorders (NMOSDs) frequently suffer from optic neuritis (ON) leading to severe retinal neuroaxonal damage. Further, the relationship of this retinal damage to a primary astrocytopathy in NMOSD is uncertain. Primary astrocytopathy has been suggested to cause ON-independent retinal damage and contribute to changes particularly in the outer plexiform layer (OPL) and outer nuclear layer (ONL), as reported in some earlier studies. However, these were limited in their sample size and contradictory as to the localisation. This study assesses outer retinal layer changes using optical coherence tomography (OCT) in a multicentre cross-sectional cohort.Method197 patients who were AQP4-IgG+ and 32 myelin-oligodendrocyte-glycoprotein antibody seropositive (MOG-IgG+) patients were enrolled in this study along with 75 healthy controls. Participants underwent neurological examination and OCT with central postprocessing conducted at a single site.ResultsNo significant thinning of OPL (25.02±2.03 µm) or ONL (61.63±7.04 µm) were observed in patients who were AQP4-IgG+ compared with patients who were MOG-IgG+ with comparable neuroaxonal damage (OPL: 25.10±2.00 µm; ONL: 64.71±7.87 µm) or healthy controls (OPL: 24.58±1.64 µm; ONL: 63.59±5.78 µm). Eyes of patients who were AQP4-IgG+ (19.84±5.09 µm, p=0.027) and MOG-IgG+ (19.82±4.78 µm, p=0.004) with a history of ON showed parafoveal OPL thinning compared with healthy controls (20.99±5.14 µm); this was not observed elsewhere.ConclusionThe results suggest that outer retinal layer loss is not a consistent component of retinal astrocytic damage in AQP4-IgG+ NMOSD. Longitudinal studies are necessary to determine if OPL and ONL are damaged in late disease due to retrograde trans-synaptic axonal degeneration and whether outer retinal dysfunction occurs despite any measurable structural correlates.

The introduction of teprotumumab for the treatment of thyroid eye disease has dramatically improved management of this life-changing condition; however, clinical trials and experience in the clinic have revealed associated hearing abnormalities.

Thyroid eye disease manifests inflammation and treatment-resistant proptosis and diplopia. Teprotumumab, an insulin-like growth factor-1 receptor inhibiting monoclonal antibody, was approved in the USA on Jan 21, 2020, on the basis of two randomised trials. In this analysis we evaluated the short-term and long-term aggregate response to teprotumumab from the two trials, focusing on proptosis and diplopia.

Background:Thyroid-associated ophthalmopathy (TAO), an autoimmune process affecting the tissues surrounding the eye, most commonly develops in individuals with Graves’ disease. It is disfiguring, can cause vision loss, and dramatically lessens the quality of life in patients. There has been an absence of approved medical therapies for TAO with proven effectiveness and safety in multicenter, placebo-controlled, and adequately powered clinical trials. Summary:The following is a brief overview of the rationale for developing a monoclonal antibody inhibitor of the insulin-like growth factor-I receptor into a treatment for TAO. This area of fundamental research has yielded an effective and safe medication, namely teprotumumab, based on two multicenter, placebo-controlled trials. Teprotumumab, marketed as Tepezza, has been approved recently by the US Food and Drug Administration for the treatment of TAO. Given its remarkable effectiveness, Tepezza is poised to become the first-line standard of care for TAO. Key Messages:Introduction of Tepezza into our armamentarium of therapeutic strategies for TAO represents a paradigm shift in the management of the disease. I proffer that the drug will replace glucocorticoids as a first-line treatment for TAO.

Background:Thyroid-associated ophthalmopathy (TAO), an autoimmune process affecting the tissues surrounding the eye, most commonly develops in individuals with Graves’ disease. It is disfiguring, can cause vision loss, and dramatically lessens the quality of life in patients. There has been an absence of approved medical therapies for TAO with proven effectiveness and safety in multicenter, placebo-controlled, and adequately powered clinical trials. Summary:The following is a brief overview of the rationale for developing a monoclonal antibody inhibitor of the insulin-like growth factor-I receptor into a treatment for TAO. This area of fundamental research has yielded an effective and safe medication, namely teprotumumab, based on two multicenter, placebo-controlled trials. Teprotumumab, marketed as Tepezza, has been approved recently by the US Food and Drug Administration for the treatment of TAO. Given its remarkable effectiveness, Tepezza is poised to become the first-line standard of care for TAO. Key Messages:Introduction of Tepezza into our armamentarium of therapeutic strategies for TAO represents a paradigm shift in the management of the disease. I proffer that the drug will replace glucocorticoids as a first-line treatment for TAO.

Coumarin and oxadiazole moieties ubiquitously occur in a wide range of natural products and are valued for their varied and beneficial pharmacological activities. Herein, this review focuses on various documented techniques used by researchers to synthesize an assortment of biologically active coumarin-oxadiazole scaffolds. Also, the common techniques discussed are used to establish the wide-range of biological activities of the synthesized coumarin and oxadiozole derivatives, including; antioxidant, anthelmintic, antimicrobial, anti-tuberculosis, analgesic, anti-inflammatory, cytotoxicity and anticonvulsant. Additionally, the current, well-established drugs synthesized using coumarin-oxadiazole scaffolds are typically dispensed in regular clinical practice are also highlighted in this review paper.

ABSTRACTIntroductionThyroid-associated ophthalmopathy (TAO) is a disfiguring, potentially blinding, and sub-optimally managed autoimmune condition. Current therapy of active TAO consists most frequently of glucocorticoid steroids, orbital radiation, or B-cell depletion; all of which are associated with substantial side effects. Teprotumumab (Tepezza) is a human monoclonal antibody against the insulin-like growth factor type I receptor (IGF-IR), recently evaluated in two clinical trials for active moderate-to-severe TAO that was recently approved by the United States Food and Drug Administration (FDA) for use in TAO.Areas coveredThis article reviews phase II and III placebo-controlled, double-masked, prospective, multicenter studies assessing the efficacy and safety of teprotumumab for the treatment of active, moderate-to-severe TAO.Expert opinionTeprotumumab has demonstrated substantial and rapid improvement in Clinical Activity Score and proptosis reduction in TAO compared to placebo. Subjective diplopia and quality of life were also improved in both clinical trials. Teprotumumab exhibited a favorable safety profile, with transient hyperglycemia, muscle cramps, and auditory side effects being associated with the drug; these were usually transient. The trial findings indicate that teprotumumab is a promising, potential first-line therapy for treating TAO.

Change in the history of art has many causes, but one often overlooked by art historical institutions is the complex, unequal set of relationships that subsist between art centers and peripheries. These take many forms, from powerful penetration of peripheral art by the subjects, styles and modes of the relevant center, through accommodation to this penetration to various degrees and kinds of resistance to it. Mapping these relationships should be a major task for art historians, especially those committed to tracing the reception of works of art and the dissemination of ideas about art. This lecture, delivered by Nicos Hadjinicolaou in 1982, outlines a “political art geography” approach to these challenges, and demonstrates it by exploring four settings: the commissioning of paintings commemorating key battles during the Greek War of Independence; the changes in Diego Rivera's style on his return to Mexico from Paris in the 1920s; the impact on certain Mexican artists in the 1960s of “hard edge” painting from the United States; and the differences between Socialist Realism in Moscow and in the Soviet Republics of Asia during the mid-twentieth century. The lecture is here translated into English for the first time and is introduced by Terry Smith, who relates it to its author's long-term art historical quest, as previously pursued in his book Art History and Class Struggle(1973).

Loop-mediated isothermal amplification (LAMP) provides effective diagnostic technology for infectious disease pathogen identification and is compatible with inexpensive instrumentation for use in disease-prevalent developing regions. However, simultaneous multiple-target detection and single-nucleotide polymorphism (SNP) identification, essential properties of nucleic acid diagnostics, are difficult to achieve using LAMP. This study introduces loop-primer endonuclease cleavage (LEC)–LAMP, a singleplex or multiplex LAMP technology with single-base specificity for variable SNP identification. We developed a singleplex LEC-LAMP Neisseria meningitidisassay that demonstrated complete analytical specificity and a limit of detection of 3.1 genome copies per reaction. Small-scale clinical testing of this assay demonstrated 100% diagnostic specificity and sensitivity when assessed with anonymized DNA extracts from confirmed cases of bacterial meningitis infection. The single-base specificity of this assay indicated effective SNP identification properties when challenged with DNA templates containing SNPs located within a specific six-base region. This assay was modified to generate an allele-specific LEC-LAMP N. meningitidisassay that successfully demonstrated single-tube differentiation of wild-type and mutant allele templates. The singleplex assay was further modified to generate a multiplex LEC-LAMP assay that successfully demonstrated simultaneous multiple-target detection of three bacterial targets, N. meningitidis, Streptococcus pneumonia, and Hemophilus influenzae. LEC-LAMP is the first report of single-tube, real-time, singleplex or multiplex LAMP technology with single-base specificity for variable SNP identification.

Background/objectives: Thyroid-associated ophthalmopathy (TAO), an autoimmune component of Graves’ disease, remains a disfiguring and potentially blinding condition. Here, the author reviews the role of insulin-like growth factor-I receptor pathway in TAO and how it might be therapeutically targeted. Methods: The recent literature is reviewed. Results: TAO involves reactivity of orbital connective tissues and their remodeling. While many of the details concerning the pathogenesis of TAO remain to be determined, several insights have come to light recently. Among them is the apparent involvement of IGF-IR. This receptor protein, a membrane-spanning tyrosine kinase receptor can form both physical and functional complexes with the thyrotropin receptor (TSHR). This is notable because TSHR is the established primary autoantigen in Graves’ disease. IGF-IR activity is critical to signaling downstream from both IGF-IR and TSHR. In addition, antibodies against IGF-IR have been detected in patients with Graves’ disease and in rodent models of TAO. Evidence has been put forward that these antibodies may act directly on IGF-IR, perhaps in some manner activating the receptor. These experimental observations have led to the development of a novel therapy for active TAO, utilizing a monoclonal anti-IGF-IR inhibitory antibody which had been produced originally as treatment for cancer. The agent, teprotumumab was recently evaluated in a clinical trial and found to be highly effective and relatively well-tolerated. It is currently undergoing assessment in a follow-up trial. Conclusions: Should the current study yield similarly encouraging results, it is possible that teprotumumab will emerge as a paradigm-shifting medical therapy for TAO.

Orbital tissues in thyroid-associated ophthalmopathy exhibit particular reactivity and undergo characteristic remodeling. Mechanisms underlying these changes have remained largely unexplained. Studies have characterized orbital connective tissues and derivative fibroblasts to gain insights into local manifestations of a systemic autoimmune syndrome.

Thyroid-associated ophthalmopathy (TAO) is a complex disease process presumed to emerge from autoimmunity occurring in the thyroid gland, most frequently in Graves disease (GD). It is disfiguring and potentially blinding, culminating in orbital tissue remodeling and disruption of function of structures adjacent to the eye. There are currently no medical therapies proven capable of altering the clinical outcome of TAO in randomized, placebo-controlled multicenter trials. The orbital fibroblast represents the central target for immune reactivity. Recent identification of fibroblasts that putatively originate in the bone marrow as monocyte progenitors provides a plausible explanation for why antigens, the expressions of which were once considered restricted to the thyroid, are detected in the TAO orbit. These cells, known as fibrocytes, express relatively high levels of functional TSH receptor (TSHR) through which they can be activated by TSH and the GD-specific pathogenic antibodies that underpin thyroid overactivity. Fibrocytes also express insulin-like growth factor I receptor (IGF-IR) with which TSHR forms a physical and functional signaling complex. Notably, inhibition of IGF-IR activity results in the attenuation of signaling initiated at either receptor. Some studies suggest that IGF-IR-activating antibodies are generated in GD, whereas others refute this concept. These observations served as the rationale for implementing a recently completed therapeutic trial of teprotumumab, a monoclonal inhibitory antibody targeting IGF-IR in TAO. Results of that trial in active, moderate to severe disease revealed dramatic and rapid reductions in disease activity and severity. The targeting of IGF-IR with specific biologic agents may represent a paradigm shift in the therapy of TAO.

Thyroid-associated orbitopathy (TAO) is a disfiguring periocular connective tissue disease associated with autoimmune thyroid disorders. It is a potentially blinding condition, for which no effective pharmacological treatment has been established. Despite a suggested role played by autoimmune thyrotropin receptor activation in the pathogenesis of TAO, the cellular and molecular events contributing to the fibrotic and inflammatory disease process of TAO are not fully defined. By developing a three-dimensional organoid culture of human orbital fibroblasts (OFs), we sought to determine the molecular mechanism underlying the fibrotic disease process of TAO. In this ex vivo model, we have demonstrated that hypoxia-inducible factor (HIF) 2α (HIF2A), but not its paralog HIF1A, accelerates extracellular matrix (ECM) deposition by inducing a collagen-cross-linking enzyme, lysyl oxidase (LOX). Inhibiting HIF2A and LOX with short hairpin RNA or small molecular antagonists effectively ameliorated fibrotic disease process within TAO organoids. Conversely, the overexpression of a constitutively active HIF2A in mouse OFs was sufficient to initiate LOX-dependent fibrotic tissue remodeling in OF organoids. Consistent with these findings, HIF2A and LOX were highly expressed in human TAO tissues paralleling excess ECM deposition. We propose that the HIF2A-LOX pathway can be a potential therapeutic target for the prevention and treatment of TAO.

The trypanosomatids, Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp, are causative agents of important human diseases such as African sleeping sickness, Chagas’ disease and Leishmaniasis, respectively. The high impact of these diseases on human health and economy worldwide, the unsatisfactory available chemotherapeutic options and the absence of human effective vaccines, strongly justifies the search for new drugs. The pentose phosphate pathway has been proposed to be a viable strategy to defeat several infectious diseases, including those from trypanosomatids, as it includes an oxidative branch, important in the maintenance of cell redox homeostasis, and a non-oxidative branch in which ribose 5-phosphate and erythrose 4-phosphate, precursors of nucleic acids and aromatic amino acids, are produced. This review provides an overview of the available chemotherapeutic options against these diseases and discusses the potential of genetically validated enzymes from the pentose phosphate pathway of trypanosomatids to be explored as potential drug targets.

Neglected tropical diseases caused by trypanosomatid parasites are a continuing and escalating problem, which devastate the less economically developed cultures in countries in which they are endemic by impairing both human and animal health. Current drugs for these diseases are regarded as out-of-date and expensive, with unacceptable side-effects and mounting parasite resistance, meaning there is an urgent need for new therapeutics. Natural products have long been a source of potent, structurally diverse bioactive molecules. Herein are reviewed natural products with reported trypanocidal activity, which have been clustered based on core structural similarities, to aid the future discovery of new trypanocidal core motifs with potential routes to synthetically accessible natural product cores suggested.

Sober analyzes two paradigms of parsimony that have been used successfully in science. These are associated with two interpretations of probability: Bayesian and frequentist. Sober applies these paradigms to problems in biology, psychology, and philosophy. In the chapter on psychology, he argues that objective data consisting of environmental input and two or more concurrent responses could be used to refute empirically the radical behaviorist thesis that probability of learned responses can be accounted for solely on the basis of environmental variables. Sober believes that such data are readily available and offers a thought experiment to illustrate his point. Behavior analysts, however, would want actual experimental data, undoubtedly with animals, before accepting any such refutation. Nonetheless, Sober's philosophical point about the type of experiment that would be capable of refuting this thesis is valid. The behavior analytic program, however, does not depend upon the truth of this thesis.

Our hypothesis concerns the relative differences in gene expression found in extraocular muscles that may explain less severe involvement of the lateral rectus muscle plus patient variability in clinical presentation.

AbstractIn cities throughout the world, the Visual Arts Exhibitionary Complex (VAEC) is a constellation of exhibitionary venues that ranges from metropolitan museums to pop-up installations and Internet postings. This article maps VAECs as historical developments, as power hierarchies, and as consisting of distinct but internally dynamic elements that interact with each other constantly. VAECs are the primary contexts in which curating is done today, so this article also presents a series of charts that outline the historical evolution and the current forms of professional categorization within curating: types of exhibition, display formats, curatorial styles, projective publics and modes of collaboration.

A major hallmark of Alzheimer’s disease (AD) is the formation of neurotoxic aggregates composed of the amyloid-β peptide (Aβ). Aβ has been recognized to interact with numerous proteins, resulting in pathological changes to the metabolism of patients with AD. One such mitochondrial metabolic enzyme is amyloid-binding alcohol dehydrogenase (ABAD), where altered enzyme function caused by the Aβ-ABAD interaction is known to cause mitochondrial distress and cytotoxic effects, providing a feasible therapeutic target for AD drug development. Here we have established a high-throughput screening platform for the identification of modulators to the ABAD enzyme. A pilot screen with a total of 6759 compounds from the NIH Clinical Collections (NCC) and SelleckChem libraries and a selection of compounds from the BioAscent diversity collection have allowed validation and robustness to be optimized. The pilot screen revealed 16 potential inhibitors in the low µM range against ABAD with favorable physicochemical properties for blood-brain barrier penetration.

A major hallmark of Alzheimer’s disease (AD) is the formation of neurotoxic aggregates composed of the amyloid-β peptide (Aβ). Aβ has been recognized to interact with numerous proteins, resulting in pathological changes to the metabolism of patients with AD. One such mitochondrial metabolic enzyme is amyloid-binding alcohol dehydrogenase (ABAD), where altered enzyme function caused by the Aβ-ABAD interaction is known to cause mitochondrial distress and cytotoxic effects, providing a feasible therapeutic target for AD drug development. Here we have established a high-throughput screening platform for the identification of modulators to the ABAD enzyme. A pilot screen with a total of 6759 compounds from the NIH Clinical Collections (NCC) and SelleckChem libraries and a selection of compounds from the BioAscent diversity collection have allowed validation and robustness to be optimized. The pilot screen revealed 16 potential inhibitors in the low µM range against ABAD with favorable physicochemical properties for blood-brain barrier penetration.

Background: The mitochondrial enzyme amyloid beta-binding alcohol dehydrogenase (ABAD) also known as 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10) has been connected with the pathogenesis of Alzheimer’s disease (AD). ABAD/17β-HSD10 is a binding site for the amyloid-beta peptide (Aβ) inside the mitochondrial matrix where it exacerbates Aβtoxicity. Interaction between these two proteins triggers a series of events leading to mitochondrial dysfunction as seen in AD. Methods: As ABAD’s enzymatic activity is required for mediating Aβ toxicity, its inhibition presents a promising strategy for AD treatment. In this study, a series of new benzothiazolylurea analogues have been prepared and evaluated in vitro for their potency to inhibit ABAD/17β-HSD10 enzymatic activity. The most potent compounds have also been tested for their cytotoxic properties and their ability to permeate through blood-brain barrier has been predicted. To explain the structureactivity relationship QSAR and pharmacophore studies have been performed. Results and Conclusion: Compound 12 was identified being the most promising hit compound with good inhibitory activity (IC50 = 3.06 ± 0.40 µ M) and acceptable cytotoxicity profile comparable to the parent compound of frentizole. The satisfactory physical-chemical properties suggesting its capability to permeate through BBB make compound 12 a novel lead structure for further development and biological assessment.

ABSTRACTIntroduction: Graves’ disease (GD) and thyroid-associated ophthalmopathy (TAO) are thought to result from actions of pathogenic antibodies mediated through the thyrotropin receptor (TSHR). This leads to the unregulated consequences of the antibody-mediated receptor activity in the thyroid and connective tissues of the orbit. Recent studies reveal antibodies that appear to be directed against the insulin-like growth factor-I receptor (IGF-IR).Areas covered: In this brief article, I attempt to review the fundamental characteristics of the TSHR, its role in GD and TAO, and its relationship to IGF-IR. Strong evidence supports the concept that the two receptors form a physical and functional complex and that IGF-IR activity is required for some of the down-stream signaling initiated through TSHR. Recently developed small molecules and monoclonal antibodies that block TSHR and IGF-IR signaling are also reviewed in the narrow context of their potential utility as therapeutics in GD and TAO. The Pubmed database was searched from its inception for relevant publications.Expert opinion: Those agents that can interrupt the TSHR and IGF-IR pathways possess the potential for offering more specific and better tolerated treatments of both hyperthyroidism and TAO. This would spare patients exposure to toxic drugs, ionizing radiation and potentially hazardous surgeries.

The sources and biological impact of 3,3',5,5' tetraiodothyroacetic acid (TA4) are uncertain. CD34+ fibrocytes express several proteins involved in the production of thyroid hormones. They infiltrate the orbit in Graves disease (GD), an autoimmune process known as thyroid-associated ophthalmopathy. It appears that the thyrotropin receptor plays an important role in the pathogenesis of thyroid-associated ophthalmopathy.

Published in the September 1974 issue of Artforum, my article “The Provincialism Problem” argued that a world art system, centered on the New York artworld, condemned artists elsewhere to misleadingly perceive their situation as necessarily subservient, and their art as lesser, secondary, and dependent. In fact, this system condemned all involved, including New York based artists, to a vicious cycle of mutual inequity. The article called for artists, critics, and curators to radically reimagine these relationships. Often cited in the decades since then, in recent years it is frequently used as a foil to demonstrate how, within the international artworld, the situation has improved significantly. In this essay, I review the acute awareness of these issues in the Australian artworld during the 1960s and 1970s, and the situation in New York in the early and mid-1970s that lead me to write the article in concert with other members of the Art & Language group. I note some of the critical responses to the article since its publication, explore key aspects of center-periphery theory, and conclude by arguing that the provincialism problem has not been solved—it has, rather, been globalized then neoliberalized, and thus remains problematic.

AimsSomatic insertions/deletions in exon 9 of the calreticulin gene have been identified in patients with essential thrombocythemia and primary myelofibrosis. Over 55 mutations have been discovered, 80% of which consist of either type 1 52-bp deletion or type 2 5-bp insertion. Other mutations (types 3–5) in conjunction with types 1 and 2 account for >87% of identified mutations. The aim of this study was development of a rapid PCR-based assay using LightCycler Hybridisation Probes for the detection of type 1–5 CALRmutations.MethodA real-time PCR assay using a novel HybProbe set was developed for use on the LightCycler 480 Instrument II. The acceptor probe was labelled with LC640 and Faststart DNA Master HybProbe kit was used for PCR reactions.ResultsAssay limit of detection was determined to be seven target copies with a probability of 95%. The specificity of the assay was determined by using synthetic constructs of CALRwild-type and CALRmutation types 1–5 with no non-specific detection observed. Samples from 21 patients with essential thrombocythemia (ET) and 12 patients with primary myelofibrosis (PMF), together with 29 control samples from patients diagnosed with various conditions, were screened using the assay. Of these, 24 were found to have mutations in CALRexon 9, with the assay detecting 8 type 1 mutations, 12 type 2 mutations, 2 type 24 mutations, 1 type 20 mutation and 1 31-bp deletion.ConclusionsThe novel assay described has potential for application as a rapid, sensitive, high-throughput screening method in the clinical diagnostics setting.