New Therapeutic Horizons for Graves' Hyperthyroidism.

Graves' hyperthyroidism is characterized by the presence of autoantibodies that stimulate the thyroid-stimulating hormone receptor (TSHR), resulting in uncontrolled secretion of excessive thyroid hormone. Conventional treatments, including antithyroid medication, radioiodine, or surgery have remained largely unchanged for the past 70 years and either lack efficacy for many patients, or result in lifelong thyroid hormone replacement therapy, in the case of the latter 2 options. The demand for new therapeutic options, combined with greater insight into basic immunobiology, has led to the emergence of novel approaches to treat Graves' hyperthyroidism. The current therapies under investigation include biologics, small molecules, and peptide immunomodulation. There is a growing focus on TSHR-specific treatment modalities, which carry the advantage of eliciting a specific, targeted approach, with the aim of avoiding disruption of the functioning immune system. These therapies present a new opportunity to supersede the inadequate treatments currently available for some Graves' patients, offering hope of successful restoration of euthyroidism without the need for ongoing therapy. Several of these therapeutic options have the potential to translate into clinical practice in the near future. This review provides a comprehensive summary of the recent advances and various stages of development of the novel therapeutic approaches to treat Graves' hyperthyroidism.

RiceAntherNet: a gene co-expression network for identifying anther and pollen development genes.

In plants, normal anther and pollen development involves many important biological events and complex molecular regulatory coordination. Understanding gene regulatory relationships during male reproductive development is essential for fundamental biology and crop breeding. In this work, we developed a rice gene co-expression network for anther development (RiceAntherNet) that allows prediction of gene regulatory relationships during pollen development. RiceAntherNet was generated from 57 rice anther tissue microarrays across all developmental stages. The microarray datasets from nine rice male sterile mutants, including msp1-4, ostdl1a, gamyb-2, tip2, udt1-1, tdr, eat1-1, ptc1 and mads3-4, were used to explore and test the network. Among the changed genes, three clades showing differential expression patterns were constructed to identify genes associated with pollen formation. Many of these have known roles in pollen development, for example, seven genes in Clade 1 (OsABCG15, OsLAP5, OsLAP6, DPW, CYP703A3, OsNP1 and OsCP1) are involved in rice pollen wall formation. Furthermore, Clade 1 contained 12 genes whose predicted orthologs in Arabidopsis have been reported as key during pollen development and may play similar roles in rice. Genes in Clade 2 are expressed earlier than Clade 1 (anther stages 2-9), while genes in Clade 3 are expressed later (stages 10-12). RiceAntherNet serves as a valuable tool for identifying novel genes during plant anther and pollen development. A website is provided (https://www.cpib.ac.uk/anther/riceindex.html) to present the expression profiles for gene characterization. This will assist in determining the key relationships between genes, thus enabling characterization of critical genes associated with anther and pollen regulatory networks.

Biphasic regulation of the transcription factor ABORTED MICROSPORES (AMS) is essential for tapetum and pollen development in Arabidopsis.

Viable pollen is essential for plant reproduction and crop yield. Its production requires coordinated expression at specific stages during anther development, involving early meiosis-associated events and late pollen wall formation. The ABORTED MICROSPORES (AMS) transcription factor is a master regulator of sporopollenin biosynthesis, secretion and pollen wall formation in Arabidopsis. Here we show that it has complex regulation and additional essential roles earlier in pollen formation. An inducible-AMS reporter was created for functional rescue, protein expression pattern analysis, and to distinguish between direct and indirect targets. Mathematical modelling was used to create regulatory networks based on wild-type RNA and protein expression. Dual activity of AMS was defined by biphasic protein expression in anther tapetal cells, with an initial peak around pollen meiosis and then later during pollen wall development. Direct AMS-regulated targets exhibit temporal regulation, indicating that additional factors are associated with their regulation. We demonstrate that AMS biphasic expression is essential for pollen development, and defines distinct functional activities during early and late pollen development. Mathematical modelling suggests that AMS may competitively form a protein complex with other tapetum-expressed transcription factors, and that biphasic regulation is due to repression of upstream regulators and promotion of AMS protein degradation.

PREGO (presentation of Graves' orbitopathy) study: changes in referral patterns to European Group On Graves' Orbitopathy (EUGOGO) centres over the period from 2000 to 2012.

BACKGROUND/AIMS: The epidemiology of Graves' orbitopathy (GO) may be changing. The aim of the study was to identify trends in presentation of GO to tertiary centres and initial management over time. METHODS: Prospective observational study of European Group On Graves' Orbitopathy (EUGOGO) centres. All new referrals with a diagnosis of GO over a 4-month period in 2012 were included. Clinical and demographic characteristics, referral timelines and initial decisions about management were recorded. The data were compared with a similar EUGOGO survey performed in 2000. RESULTS: The demographic characteristics of 269 patients studied in 2012 were similar to those collected in the year 2000, including smoking rates (40.0% vs 40.2%). Mild (60.5% vs 41.2%, p<0.01) and inactive GO (63.2% vs 39.9%, p<0.01) were more prevalent in 2012. The times from diagnosis of thyroid disease to being seen in EUGOGO centres (6 vs 16 months) and from first symptoms of GO (9 vs 16 months) or from diagnosis of GO (6 vs 12 months) to first consultation in EUGOGO centres were shorter in 2012 (p<0.01). The initial management plans for GO were no different except surgical treatments for patients with mild inactive disease were more frequently offered in the 2012 cohort than in 2000 (27.3% vs 17%, p<0.05), and selenium supplements were offered only in the 2012 cohort (21.2% vs 0%, p<0.01). CONCLUSIONS: These findings suggest that the clinical manifestations of patients with GO may be changing over time in Europe.

FlowerNet: a gene expression correlation network for anther and pollen development.

Floral formation, in particular anther and pollen development, is a complex biological process with critical importance for seed set and for targeted plant breeding. Many key transcription factors regulating this process have been identified; however, their direct role remains largely unknown. Using publicly available gene expression data from Arabidopsis (Arabidopsis thaliana), focusing on those studies that analyze stamen-, pollen-, or flower-specific expression, we generated a network model of the global transcriptional interactions (FlowerNet). FlowerNet highlights clusters of genes that are transcriptionally coregulated and therefore likely to have interacting roles. Focusing on four clusters, and using a number of data sets not included in the generation of FlowerNet, we show that there is a close correlation in how the genes are expressed across a variety of conditions, including male-sterile mutants. This highlights the important role that FlowerNet can play in identifying new players in anther and pollen development. However, due to the use of general floral expression data in FlowerNet, it also has broad application in the characterization of genes associated with all aspects of floral development and reproduction. To aid the dissection of genes of interest, we have made FlowerNet available as a community resource (http://www.cpib.ac.uk/anther). For this resource, we also have generated plots showing anther/flower expression from a variety of experiments: These are normalized together where possible to allow further dissection of the resource.

Prevention and treatment of vitamin D deficiency.

Vitamin D insufficiency and deficiency are widespread in many countries. We review the evidence pertaining to its prevention and treatment. Deficiency may be adequately treated with many different therapeutic regimens of either cholecalciferol or ergocalciferol, owing to the high therapeutic index of both compounds. Nevertheless, the current evidence suggests that regular dosing with oral cholecalciferol (e.g., 60,000 IU weekly) may have slight advantages over other regimens when replenishing vitamin D stores following deficiency. For long-term supplementation, smaller regular doses, such as cholecalciferol 1,000 IU daily, or 10,000 IU weekly, are suitable. Giving reliable and specific advice about appropriate sunlight exposure remains difficult because of differing interindividual skin pigmentation and variable sunlight UVB content at different latitudes, at different times of year, and in different terrestrial environments.

Radioiodine treatment for benign thyroid disorders: results of a nationwide survey of UK endocrinologists.

BACKGROUND: A survey of physicians' practice relating to radioiodine administration for hyperthyroidism was carried out in the UK over 15 years ago and showed wide variations in patient management. This led to the development of national guidelines for the use of radioiodine in hyperthyroidism. As there have been significant advances in the field since that survey, we carried out another survey to study the prevalent practices relating to radioiodine therapy for benign thyroid disorders across the UK. SUBJECTS AND METHODS: We mailed 698 UK consultant endocrinologists a questionnaire on radioiodine treatment based on three patient scenarios: hyperthyroid Graves' disease, subclinical hyperthyroidism and nontoxic goitre. RESULTS: The response rate was 40%. For the scenario of an initial presentation of Graves' disease, 80%, 19% and 0.4% of respondents preferred thionamide, radioiodine or thyroidectomy, respectively. There were inconsistencies in respondents' recommendations on radioiodine dose, the use of pre- and post-radioiodine supplementary treatments, timing of a repeat dose, and the use of radioiodine in thyroid eye disease. For the case of subclinical hyperthyroidism, one-third of respondents would generally initiate treatment. The majority were more likely to treat subclinical hyperthyroidism in the presence of paroxysmal atrial fibrillation or osteoporosis. If a decision were made to treat subclinical hyperthyroidism, 63%, 35%, 1% and 0.4% would recommend radioiodine, thionamide, beta-blocker and thyroidectomy, respectively. For the scenario of nontoxic goitre, 62%, 21%, 13% and 5% favoured observation, thyroidectomy, radioiodine and thyroxine, respectively. CONCLUSIONS: There remain significant differences in several aspects of clinical practice relating to the use of radioiodine treatment for benign thyroid disorders in the UK.

Comparison of the retrobulbar and Peterson nerve block techniques via magnetic resonance imaging in bovine cadavers.

OBJECTIVE: To use magnetic resonance (MR) imaging to describe and compare the anatomic distribution of a lipid contrast medium injected via the retrobulbar and Peterson nerve block techniques in heads of bovine cadavers. DESIGN: Original study. SAMPLE: 5 grossly normal heads obtained from cattle at necropsy. PROCEDURE: Standardized techniques for the modified retrobulbar and Peterson nerve blocks were established. Each cadaver had 1 treatment performed on a randomly selected side of the head; the second treatment was performed on the alternate side of the head. Injections were performed with canola oil, which is an MR-positive contrast medium. Images of heads in the transverse and dorsal planes were obtained with a 3.0 Tesla short-bore MR system. RESULTS: The retrobulbar technique was characterized by widespread distribution of the contrast medium around the periorbital structures; further distribution of the medium was detected along the optic nerve and in the ethmoid turbinates and nasopharynx. After the Peterson nerve block technique, contrast medium was repeatedly located in the pterygopalatine fossa, but distribution to surrounding structures was minimal. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicate that the retrobulbar injection technique results in a greater distribution of contrast medium to the target nerves and surrounding structures, compared with that achieved via the Peterson nerve block technique. This may explain the previously reported clinical impression that the retrobulbar block is more reliable than the Peterson nerve block but is associated with a greater risk of complications.