The effect of routine radiological reporting of thyroid incidentalomas on rates of thyroid needle biopsy, thyroid surgery and detection of thyroid malignancy.

OBJECTIVE: This study looked at the effect of a changing radiology reporting policy to routinely review the thyroid gland where visible and report on any thyroid lesion, recommending further investigation as appropriate. CONTEXT: Incidentaloma is a term used to describe a lesion found on imaging unrelated to the clinical issue under investigation. There is variability in the radiological reporting of thyroid incidentalomas and conflicting recommendations as to how these lesions should be managed. DESIGN: Data were collected retrospectively during a two-year period, including 12 months before and 12 months after the change in reporting policy and categorized according to whether the lesion under investigation was a thyroid incidentaloma or a symptomatic thyroid lesion. PATIENTS: All patients undergoing ultrasound-guided fine-needle aspiration cytology or core biopsy were included. MEASUREMENTS: The effects of the change in policy were analysed including rates of needle biopsy, rates of malignancy and subsequent surgical intervention. RESULTS: There was a 122% increase in thyroid incidentalomas undergoing needle biopsy, the majority of these were detected on computed tomography. The number of malignancies increased from 1 to 4 from year 1 to year 2. All patients were >35 years old. One patient had a positron emission tomography (PET)-detected cancer, two of four of the non-PET-detected malignancies were <1.5 cm. CONCLUSION: This study posits that routine radiological reporting of thyroid incidentalomas, with further investigation when clinically appropriate, is warranted. The results suggest that lesion size and CT characteristics are not reliable criteria to triage patients for investigation/biopsy.

Synthesis and spectroscopic characterization of a fluorescent pyrrole derivative containing electron acceptor and donor groups.

The synthesis and fluorescence characterization of a new pyrrole derivative (PyPDG) containing the electron donor-acceptor dansyl substituent is reported. The effects of temperature and solvent polarity on the steady-state fluorescence of this compound are investigated. Our results show that PyPDG exhibits desirable fluorescent properties which makes it a promising candidate to be used as the photoactive material in optical thermometry and thermography applications. Further, the electrochemical and emission properties of polymeric films obtained from the oxidation polymerization of PyPDG are also analyzed.

Bacterially mediated removal of phosphorus and cycling of nitrate and sulfate in the waste stream of a "zero-discharge" recirculating mariculture system.

Simultaneous removal of nitrogen and phosphorus by microbial biofilters has been used in a variety of water treatment systems including treatment systems in aquaculture. In this study, phosphorus, nitrate and sulfate cycling in the anaerobic loop of a zero-discharge, recirculating mariculture system was investigated using detailed geochemical measurements in the sludge layer of the digestion basin. High concentrations of nitrate and sulfate, circulating in the overlying water (∼15 mM), were removed by microbial respiration in the sludge resulting in a sulfide accumulation of up to 3 mM. Modelling of the observed S and O isotopic ratios in the surface sludge suggested that, with time, major respiration processes shifted from heterotrophic nitrate and sulfate reduction to autotrophic nitrate reduction. The much higher inorganic P content of the sludge relative to the fish feces is attributed to conversion of organic P to authigenic apatite. This conclusion is supported by: (a) X-ray diffraction analyses, which pointed to an accumulation of a calcium phosphate mineral phase that was different from P phases found in the feces, (b) the calculation that the pore waters of the sludge were highly oversaturated with respect to hydroxyapatite (saturation index = 4.87) and (c) there was a decrease in phosphate (and in the Ca/Na molar ratio) in the pore waters simultaneous with an increase in ammonia showing there had to be an additional P removal process at the same time as the heterotrophic breakdown of organic matter.

Transthyretin-thyroid hormone internalization by trophoblasts.

Normal fetal neurological development depends on a regulated supply of maternal thyroid hormone (TH). We have previously demonstrated that transthyretin (TTR) a TH binding protein, is synthesized, secreted and internalized by trophoblast cells and may provide a route for the transfer of TH from mother to fetus. Our objective was to determine if a member of the low-density lipoprotein receptor family mediates TTR or TTR-TH internalization. TTR-TH internalization by JEG-3 cells is reduced in the presence of receptor associated protein (RAP) or albumin suggesting that TTR-TH is internalized through an LDL-receptor dependent endocytic process.

Transthyretin and the human placenta.

Since its discovery, transthyretin (TTR) has been regarded as an important hepatically derived protein carrier of thyroid hormones and retinol in blood. However, in more recent years it has been shown that TTR has other important functions. TTR is abundant in cerebrospinal fluid, where it may be involved in transport of thyroid hormones into the brain. TTR derived amyloid is associated with diseases such as senile systemic amyloidosis, familial amyloid polyneuropathy and familial amyloid cardiomyopathy. Recently, synthesis, secretion and uptake of TTR by human placenta have been reported. TTR appears to play an important role in the delivery of maternal thyroid hormone to the developing fetus. This review explores the various proposed roles of TTR and more recent findings on TTR synthesis and expression in the placenta.

Ontogenic changes in human placental sodium iodide symporter expression.

The human fetus requires a maternal supply of iodide to synthesize thyroid hormone from 16 weeks gestation. Placental iodide transport is regulated by the sodium iodide symporter (NIS). We studied the ontogeny of NIS in placentas from surgically terminated pregnancies and from normal term pregnancies. NIS mRNA was low at 6 weeks gestation and peaked at 12 weeks gestation. Placental NIS protein levels are significantly correlated with gestational age during early pregnancy and increase with increased placental vascularization. This would lead to increased iodide supply to meet increased fetal requirements for thyroid hormone synthesis as the pregnancy progresses.

Branchiobdellidan infestation on endangered white-clawed crayfish (Austropotamobius pallipes) in the UK.

Branchiobdellidans or crayfish worms are clitellate annelids and ectosymbionts of freshwater crayfish. An investigation of branchiobdellidan infestation was undertaken in a population of endangered white-clawed crayfish (Austropotamobius pallipes) in the river Aire, UK. Thirty two percent of animals were infested either by the adult parasite or their cocoons (n=107). Parasite burden increased with host size, but did not differ with sex. Observations of crayfish gill tissue revealed a strong positive relationship between melanization of filaments and parasite prevalence and burden. Taxonomic identification revealed that 1 species of branchiobdellidan was present, Branchiobdella astaci. The first sequences were generated for this species and phylogenetically analysed alongside published sequences for 5 other branchiobdellidan species in Europe. The position of B. astaci within the genus Branchiobdella was confirmed, and it was found to cluster as a sister group to B. parasita.

Secretion and transfer of the thyroid hormone binding protein transthyretin by human placenta.

CONTEXT: The thyroid hormone and retinol binding protein transthyretin (TTR) is synthesised by human trophoblasts. Polarised JEG-3 choriocarcinoma cells grown in bicameral chambers secrete TTR predominantly apically but also basally and these cells and human trophoblasts also take up TTR suggesting that there may be a placental TTR shuttle that participates in materno-fetal transfer of thyroid hormones and retinol. OBJECTIVES AND METHODS: Our objective was to investigate TTR secretion into the maternal and fetal circuits of the ex vivo dually perfused placental lobule to confirm that placenta secretes TTR into the fetal circulation. We also investigated translocation of Alexa Fluor-594 labelled TTR from incubation medium into the fetal placental capillaries in early (14-15 weeks) and term placental villus explants. RESULTS: The perfused placental lobule secretes TTR into the maternal and fetal circuits. Secretion in both circuits is linear with time and is predominantly into the maternal circuit (mean maternal/fetal ratio 99.4 ± 25.6). The mean data fitted well to a three compartment mathematical model (maternal circuit, placenta and fetal circuit, constant secretion of TTR and return of maternal circuit TTR to the placental compartment). Explants from early (14-15 weeks) and late (38-40 weeks) placentas translocated fluorescently labelled TTR from medium to villus (fetal) capillaries. CONCLUSIONS: Our results confirm that human placenta secretes TTR into maternal and fetal circulations and supports the hypothesis that placental TTR secreted into the maternal placental circulation can be taken up by trophoblasts and translocated to the fetal circulation, forming a TTR shuttle system. This may have important implications for materno-fetal transfer of thyroid hormones, retinol/retinol binding protein and xenobiotics (such as polychlorinated biphenyls) all of which bind to TTR.

Expression and uptake of the thyroxine-binding protein transthyretin is regulated by oxygen in primary trophoblast placental cells.

Transplacental delivery of maternal thyroid hormones to the fetus, in particular thyroxine (T4), is critical in ensuring normal fetal neurological development. The fetus relies on maternal T4 till around 16 weeks gestation, but mechanisms of placental T4 transport are not yet fully elucidated. Placenta produces, secretes and takes up the thyroid hormone-binding protein transthyretin (TTR). Many placental genes are regulated by oxygen levels, which are relatively low (1%) in the early first trimester, rising to 3% in the mid first trimester and 8% in the early second trimester and thereafter. We examined the expression and uptake of TTR in isolated primary human placental cytotrophoblast cells cultured under different oxygen concentrations (1, 3, 8, 21% O2 and 200 µM desferrioxamine (DFO)) for 24 h. We observed sevenfold higher expression of TTR mRNA and protein levels at 1% O2 than at 8 and 21% O2. Significant increases were observed after culture at 3% O2 and following DFO treatment. We observed significantly higher uptake of ¹²5I-TTR and Alexa-594-TTR when cells were cultured at 1 and 3% O2 and in the presence of 200 µM DFO than at 8 and 21% O2. When JEG-3 choriocarcinoma cells were transfected with TTR promoter reporter constructs, increased luciferase activity was measured in cells cultured at 1 and 3% O2 in comparison to 8 and 21% O2. We conclude that placental TTR expression and uptake is increased by the relative hypoxia observed in the first trimester of pregnancy, a time when materno-fetal T4 transfer is the sole source of fetal T4.

Ontogenic changes in placental transthyretin.

OBJECTIVES: Before secretion of fetal thyroid hormone at around 16 weeks gestation normal fetal development depends on a constant supply of maternal thyroid hormone (TH), particularly thyroxine (T(4)). The detailed mechanisms of transplacental delivery of TH are still uncertain. The TH binding protein, transthyretin (TTR), is produced and secreted by placenta and may play a role in this process. The ontogeny of placental TTR is unknown. Our aim was to study changes in placental TTR in early and late pregnancy. STUDY DESIGN: We collected placentas from surgically terminated pregnancies between 6 and 17 weeks gestation (n = 44) and from normal term (38-39 weeks) pregnancies following caesarean section (n = 5). Real time-PCR, western blotting and immunohistochemistry were used to determine TTR mRNA and protein levels. RESULTS: There were highly significant correlations between gestational age and TTR mRNA (r = 0.974; p < 0.0001) and between gestational age and TTR protein (r = 0.901; p < 0.001) levels between weeks 6 and 13 of gestation. TTR expression did not increase between 13 and 17 weeks and was not different at term. Good correlation was observed between TTR mRNA and TTR protein between individual placental samples (r = 0.916; p < 0.0001). A similar trend was observed using immunohistochemical staining of placental paraffin sections. CONCLUSIONS: Our results demonstrate that TTR is expressed in the human placenta from at least 6 weeks gestation. Levels rise during the first trimester at a time when placental oxygen tensions are also rising. We hypothesise that TTR production and secretion by the placenta may facilitate transplacental delivery of TH to the fetus.

Thyroid hormones and fetal neurological development.

The development of fetal thyroid function is dependent on the embryogenesis, differentiation, and maturation of the thyroid gland. This is coupled with evolution of the hypothalamic-pituitary-thyroid axis and thyroid hormone metabolism, resulting in the regulation of thyroid hormone action, production, and secretion. Throughout gestation there is a steady supply of maternal thyroxine (T(4)) which has been observed in embryonic circulation as early as 4 weeks post-implantation. This is essential for normal early fetal neurogenesis. Triiodothyronine concentrations remain very low during gestation due to metabolism via placental and fetal deiodinase type 3. T(4) concentrations are highly regulated to maintain low concentrations, essential for protecting the fetus and reaching key neurological sites such as the cerebral cortex at specific developmental stages. There are many known cell membrane thyroid hormone transporters in fetal brain that play an essential role in regulating thyroid hormone concentrations in key structures. They also provide the route for intracellular thyroid hormone interaction with associated thyroid hormone receptors, which activate their action. There is a growing body of experimental evidence from rats and humans to suggest that even mild maternal hypothyroxinemia may lead to abnormalities in fetal neurological development. Our review will focus on the ontogeny of thyroid hormone in fetal development, with a focus on cell membrane transporters and TR action in the brain.

Oxygen concentration regulates expression and uptake of transthyretin, a thyroxine binding protein, in JEG-3 choriocarcinoma cells.

Maternal thyroid hormone is provided to the fetus before the onset of fetal thyroid function (at about 16 weeks) and is essential for normal neurologic development. Mechanisms of transport are uncertain but transthyretin (TTR), a thyroxine binding protein produced by the placenta may be involved. Placental oxygen concentrations in early pregnancy are low, about 1% early in the first trimester and rising to 8% over the next 12 weeks. This study investigated the regulation of TTR expression, secretion and uptake in JEG-3 placental cells cultured at different oxygen concentrations. TTR mRNA and protein expression and (125)I-TTR and Alexa-Fluor594-TTR uptake were significantly higher in cells cultured at 1% and 3% O(2), than at 8% O(2). This suggests that increased carrier mediated T(4) transport by placental TTR may be induced by the low oxygen environment of early pregnancy, a time when the fetus has its highest requirement for transport of maternal T(4).

Regulation of hypoxia inducible factors (HIF) in hypoxia and normoxia during placental development.

During the first trimester of pregnancy the human placenta develops in an hypoxic environment caused by the occlusion of uterine spiral arterioles by extravillous trophoblasts (EVT). This period of low oxygen tension is crucial for successful pregnancy. In low oxygen environments, Hypoxia Inducible Factors (HIF) are the main regulators in the transcription of a number of genes. Target genes can induce anaerobic processes, reducing oxygen consumption, or promote angiogenesis, which establishes and enhances the vascular environment. The HIFs can function throughout all stages of placental differentiation and growth both in normal and pathological pregnancies (compromised by hypoxia/ischemia). Interestingly, HIFs respond to a multitude of changes during pregnancy, including 1) low oxygen, 2) renin-angiotensin system (RAS), 3) cytokines, and 4) growth factors, all of which regulate placental function. This review explores oxygen-dependent and oxygen-independent regulation and the role of HIF in placental development and differentiation.

The synthesis, full characterisation and utilisation of template-free silica sodalite, a novel polymorph of silica.

Empty glass: Subjecting ethylene glycol silica sodalite to heat (680 degrees C) under a nitrogen atmosphere (i) successfully removes the templating agent to give cubic silica sodalite, which, upon consequent heating under an oxygen atmosphere (ii), transforms into a rhombohedral form of the empty sodalite, in effect a novel polymorph of silica.

Evaluation of random plasma cortisol and the low dose corticotropin test as indicators of adrenal secretory capacity in critically ill patients: a prospective study.

It is unclear whether a random plasma cortisol measurement and the corticotropin (ACTH) test adequately reflect glucocorticoid secretory capacity in critical illness. This study aimed to determine whether these tests provide information representative of the 24 hour period. Plasma cortisol was measured hourly for 24 hours in 21 critically ill septic patients followed by a corticotropin test with 1 microg dose administered intravenously. Serum and urine were analysed for ACTH and free cortisol respectively. Marked hourly variability in plasma cortisol was evident (coefficient of variation 8-30%) with no demonstrable circadian rhythm. The individual mean plasma cortisol concentrations ranged from 286 +/- 59 nmol/l to 796 +/- 83 nmol/l. The 24 hour mean plasma cortisol was strongly correlated with both random plasma cortisol (r2 0.9, P < 0.0001) and the cortisol response to corticotropin (r2 0.72, P < 0.001). Only nine percent of patients increased their plasma cortisol by 250 nmol/l after corticotropin (euadrenal response). However, 35% of non-responders had spontaneous hourly rises > 250 nmol/l thus highlighting the limitations of a single point corticotropin test. Urinary free cortisol was elevated (865 +/- 937 nmol) in both corticotropin responders and non-responders suggesting elevated plasma free cortisol. No significant relationship was demonstrable between plasma cortisol and ACTH. We conclude that although random cortisol measurements and the low dose corticotropin tests reliably reflect the 24 hour mean cortisol in critical illness, they do not take into account the pulsatile nature of cortisol secretion. Consequently, there is the potential for erroneous conclusions about adrenal function based on a single measurement. We suggest that caution be exercised when drawing conclusions on the adequacy of adrenal function based on a single random plasma cortisol or the corticotropin test.

Thyroid hormone export from cells: contribution of P-glycoprotein.

Verapamil inhibits tri-iodothyronine (T3) efflux from several cell types, suggesting the involvement of multidrug resistance-associated (MDR) proteins in T3 transport. The direct involvement of P-glycoprotein (P-gp) has not, however, been investigated. We compared the transport of 125I-T3 in MDCKII cells that had been transfected with mdr1 cDNA (MDCKII-MDR) versus wild-type MDCKII cells (MDCKII), and examined the effect of conventional (verapamil and nitrendipine) and specific MDR inhibitors (VX 853 and VX 710) on 125I-T3 efflux. We confirmed by Western blotting the enhanced expression of P-gp in MDCKII-MDR cells. The calculated rate of 125I-T3 efflux from MDCKII-MDR cells (around 0.30/min) was increased twofold compared with MDCKII cells (around 0.15/min). Overall, cellular accumulation of 125I-T3 was reduced by 26% in MDCKII-MDR cells compared with MDCKII cells, probably reflecting enhanced export of T3 from MDCKII-MDR cells rather than reduced cellular uptake, as P-gp typically exports substances from cells. Verapamil lowered the rate of 125I-T3 efflux from both MDCKII and MDCKII-MDR cells by 42% and 66% respectively, while nitrendipine reduced 125I-T3 efflux rate by 36% and 48% respectively, suggesting that both substances inhibited other cellular T3 transporters in addition to P-gp. The specific MDR inhibitors VX 853 and VX 710 had no effect of 125I-T3 efflux rate from wild-type MDCKII cells but reduced 125I-T3 export in MDCKII-MDR cells by 50% and 53% respectively. These results have provided the first direct evidence that P-gp exports thyroid hormone from cells.

The BeWo choriocarcinoma cell line as a model of iodide transport by placenta.

Cultured human choriocarcinoma cells of the BeWo line exhibited saturable accumulation of radioiodide. Inhibition by competing anions followed the affinity series perchlorate >> iodide > or = thiocyanate, consistent with uptake through the thyroid iodide transporter, NIS, whose messenger RNA was found in BeWo cells, and whose protein was distributed towards the apical pole of the cells. Efflux obeyed first order kinetics and was inhibited by DIDS, an antagonist of anion exchangers including pendrin, whose messenger RNA was also present. In cultures where iodide uptake through NIS was blocked with excess perchlorate, radioiodide accumulation was stimulated by exposure to medium in which physiological anions were replaced by 2-morpholinoethanesulfonic acid (MES), consistent with the operation of an anion exchange mechanism taking up iodide. Chloride in the medium was more effective than sulfate at inhibiting this uptake, matching the ionic specificity of pendrin. These studies provide evidence that the trophoblast accumulates iodide through NIS and releases it to the fetal compartment through pendrin.

Effect of copper, zinc, and manganese supplementation and source on reproduction, mineral status, and performance in grazing beef cattle over a two-year period.

Crossbred, multiparous beef cows (n = 178 in Year 1; n = 148 in Year 2) were used to evaluate the effects of Cu, Zn, and Mn supplementation and source on reproduction, mineral status, and performance in grazing cattle in eastern Colorado over a 2-yr period. Cows were stratified by expected calving date, age, BW, BCS, and liver mineral status and assigned to the following treatments: 1) control (no supplemental Cu, Zn, or Mn); 2) organic (ORG; 50% organic and 50% inorganic Cu, Zn, and Mn); and 3) inorganic (ING; 100% inorganic CuSO4, ZnSO4, and MnSO4). Free-choice mineral feeders were used to provide current NRC-recommended concentrations of Cu, Zn, and Mn from 82 d (Year 1) and 81 d (Year 2) before the average calving date of the herd through 110 d (Year 1) and 135 d (Year 2) after calving. At the end of Year 1, supplemented cows had greater liver Cu (P < 0.01), Zn (P < 0.05), and Mn (P < 0.01) concentrations compared with controls, whereas liver Cu concentration was greater (P < 0.01) in ORG vs. ING cows. At the end of Year 2, supplemented cows had greater (P < 0.01) liver Cu concentrations relative to controls, whereas control cows had greater (P < 0.02) liver Mn concentration than did supplemented cows. In Year 1, pregnancy rate to AI in control cows did not differ (P = 0.47) from supplemented cows, but there was a trend (P < 0.08) for pregnancy rate to be higher for ORG than ING cows. In Year 2, supplemented cows had a higher (P < 0.02) pregnancy rate to AI than controls. In both years, when cows were inseminated after an observed estrus, supplemented cows had a higher (P < 0.04) pregnancy rate than did controls. Also, for both years, overall 60-d pregnancy rate tended (P = 0.10) to be higher for supplemented cows than for controls. In Year 1, kilograms of calf weaned per cow exposed was greater (P < 0.02) in controls than in supplemented cows, and kilograms of calf weaned per cow exposed was greater (P < 0.01) in ING than ORG treatments. However, in Year 2, kilograms of calf weaned per cow exposed was greater (P < 0.02) in controls than in supplemented cows, and tended (P = 0.09) to be greater in ORG than ING treatments. Results indicate that supplementation and source of trace minerals affected mineral status and kilograms of calf weaned per cow exposed in grazing beef cows. Supplementation also improved pregnancy rate to AI compared with cows not supplemented with Cu, Zn, or Mn for more than 1 yr. Furthermore, mineral source may influence pregnancy rate to AI.

Assessing quality of life in Australian patients with Graves' ophthalmopathy.

AIMS: To determine quality of life and adequacy of education and counselling in Australian patients with Graves' ophthalmopathy during the course of their illness. METHODS: A cross sectional study was conducted at the orbital and endocrinology clinics of Royal Brisbane Hospital on 162 consecutive patients with Graves' ophthalmopathy who were managed between the 1992 and 2000. The Graves' ophthalmopathy quality of life (GO-QOL) survey modified for Australian conditions was distributed to study participants. Of the 19 questions asked, nine questions related to visual functioning, eight questions were about the psychosocial consequences of changed appearance, and two questions referred to education and counselling. Additionally, clinical data on the severity of illness were collected retrospectively from the medical notes of these patients. RESULTS: Completed questionnaires were received from 128 patients. The majority of patients reported limitations in daily activities such as hobbies, driving, watching television and reading, as well as impaired self confidence. The mean GO-QOL scores in this study were (100 representing maximum QOL): visual functioning 59.0 (SD 28.0), psychosocial consequences of changed appearance 54.5 (28.4), and education and counselling 59.1 (38.8). Only about a quarter of patients indicated that education and counselling were adequate and helpful. CONCLUSION: Graves' ophthalmopathy profoundly affects QOL and adequate education and counselling are essential for helping patients to cope with their illness. The GO-QOL survey is a simple, practical tool that can be used easily in a clinic to determine the QOL issues in subjects with Graves' ophthalmopathy.