Concentrations of remifentanil, propofol, fentanyl, and midazolam during rewarming from therapeutic hypothermia.

BACKGROUND: The clearance of sedatives and analgesics may be reduced by therapeutic hypothermia. However, little is known about the concentrations of such drugs during rewarming. The aim of this study was to describe the serum concentrations of sedatives and analgesics during rewarming from therapeutic hypothermia. METHODS: Blood samples were collected for quantification of drug concentrations in 22 patients given analgesia/sedation with either remifentanil/propofol or fentanyl/midazolam during rewarming from therapeutic hypothermia (33-34°C) after cardiac arrest. Samples for were drawn before (-2 h) and during rewarming (0-8 h). Linear mixed effects models were used to describe serum concentrations and adjust for rates of infusion during rewarming from therapeutic hypothermia. RESULTS: Subjects with samples analyzed were remifentanil (n = 8), propofol (n = 14), fentanyl (n = 8), and midazolam (n = 8). Age, body mass index, and simplified acute physiology score II [mean (standard deviation)] were 64 (14.2) years, 27.3 (3.7) kg/m(2), and 69 (13.2), respectively. While the concentration of fentanyl was not significantly affected by temperature, concentrations of remifentanil, propofol, and midazolam decreased with core temperature by 16%, 12%, and 11% (mean values) from 33°C to 37°C after adjusting for rates of infusion, respectively. CONCLUSION: Concentrations of remifentanil, propofol, and midazolam decreased during rewarming from therapeutic hypothermia when adjusting for rates of infusion. No changes were demonstrated for fentanyl.

New avenues for residual stress analysis in ultrathin atomic layer deposited free-standing membranes through release of micro-cantilevers.

The fabrication of thinnest, yet undeformed membrane structures with nanometer resolution is a prerequisite for a variety of Microelectromechanical systems (MEMS). However, functionally relevant thin films are susceptible to growth-generated stress. To tune the performance and reach large aspect ratios, knowledge of the intrinsic material properties is indispensable. Here, we present a new method for stress evaluation through releasing defined micro-cantilever segments by focused ion beam (FIB) milling from a predefined free-standing membrane structure. Thereby, the cantilever segment is allowed to equilibrate to a stress-released state through measurable strain in the form of a resulting radius of curvature. This radius can be back-calculated to the residual stress state. The method was tested on a 20 nm and 50 nm thick tunnel-like ALD Image 1 membrane structure, revealing a significant amount of residual stress with 866 MPa and 6104 MPa, respectively. Complementary finite element analysis to estimate the stress distribution in the structure showed a 97% and 90% agreement in out-of-plane deflection for the 20 nm and 50 nm membranes, respectively. This work reveals the possibilities of releasing entire membrane segments from thin film membranes with a significant amount of residual stress and to use the resulting bending behavior for evaluating stress and strain by measuring their deformation.

Clinical Validation of a Predictive Model for the Presence of Cervical Lymph Node Metastasis in Papillary Thyroid Cancer.

BACKGROUND AND PURPOSE: Ultrasound is a standard technique to detect lymph node metastasis in papillary thyroid cancer. Cystic changes and microcalcifications are the most specific features of metastasis, but with low sensitivity. This prospective study compared the diagnostic accuracy of a predictive model for sonographic evaluation of lymph nodes relative to the radiologist's standard assessment in detecting papillary thyroid cancer metastasis in patients after thyroidectomy. MATERIALS AND METHODS: Cervical lymph node sonographic images were reported by a radiologist (R method) per standard practice. The same images were independently evaluated by another radiologist using a sonographic predictive model (M method). A test was considered positive for metastasis if the R or M method suggested lymph node biopsy. The result of lymph node biopsy or surgical pathology was used as the reference standard. We estimated relative true-positive fraction and relative false-positive fraction using log-linear models for correlated binary data for the M method compared with the R method. RESULTS: A total of 237 lymph nodes in 103 patients were evaluated. Our analysis of relative true-positive fraction and relative false-positive fraction included 54 nodes with pathologic results in which at least 1 method (R or M) was positive. The M method had a higher relative true-positive fraction of 1.46 (95% CI, 1.12-1.91; P = .006) and a lower relative false-positive fraction of 0.58 (95% CI, 0.36-0.92; P = .02) compared with the R method. CONCLUSIONS: The sonographic predictive model outperformed the standard assessment to detect lymph node metastasis in patients with papillary thyroid cancer and may reduce unnecessary biopsies.

Novel high-affinity PPARgamma agonist alone and in combination with paclitaxel inhibits human anaplastic thyroid carcinoma tumor growth via p21WAF1/CIP1.

Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists demonstrate antitumor activity likely through transactivating genes that regulate cell proliferation, apoptosis, and differentiation. The PAX8/PPARgamma fusion oncogene, which is common in human follicular thyroid carcinomas appears to act via dominant negative suppression of wild-type PPARgamma, suggesting that it may be a tumor suppressor gene in thyroid cells. We have identified a novel high-affinity PPARgamma agonist (RS5444) that is dependent upon PPARgamma for its biological activity. This is the first report of this molecule and its antitumor activity. In vitro, the IC50 for growth inhibition is approximately 0.8 nM while anaplastic thyroid carcinoma (ATC) tumor growth was inhibited three- to fourfold in nude mice. siRNA against PPARgamma and a pharmacological antagonist demonstrated that functional PPARgamma was required for growth inhibitory activity of RS5444. RS5444 upregulated the cell cycle kinase inhibitor, p21WAF1/CIP1. Silencing p21WAF1/CIP1 rendered cells insensitive to RS5444. RS5444 plus paclitaxel demonstrated additive antiproliferative activity in cell culture and minimal ATC tumor growth in vivo. RS5444 did not induce apoptosis but combined with paclitaxel, doubled the apoptotic index compared to that of paclitaxel. Our data indicate that functional PPARgamma is a molecular target for therapy in ATC. We demonstrated that RS5444, a thiazolidinedione (Tzd) derivative, alone or in combination with paclitaxel, may provide therapeutic benefit to patients diagnosed with ATC.

Thyroid hormone resistance and increased metabolic rate in the RXR-gamma-deficient mouse.

Vitamin A and retinoids affect pituitary-thyroid function through suppression of serum thyroid-stimulating hormone (TSH) levels and TSH-beta subunit gene expression. We have previously shown that retinoid X receptor-selective (RXR-selective) ligands can suppress serum TSH levels in vivo and TSH-beta promoter activity in vitro. The RXR-gamma isotype has limited tissue distribution that includes the thyrotrope cells of the anterior pituitary gland. In this study, we have performed a detailed analysis of the pituitary-thyroid function of mice lacking the gene for the RXR-gamma isotype. These mice had significantly higher serum T4 levels and TSH levels than did wild-type (WT) controls. Treatment of RXR-gamma-deficient and WT mice with T3 suppressed serum TSH and T4 levels in both groups, but RXR-gamma-deficient mice were relatively resistant to exogenous T3. RXR-gamma-deficient mice had significantly higher metabolic rates than did WT controls, suggesting that these animals have a pattern of central resistance to thyroid hormone. RXR-gamma, which is also expressed in skeletal muscle and the hypothalamus, may have a direct effect on muscle metabolism, regulation of food intake, or thyrotropin-releasing hormone levels in the hypothalamus. In conclusion, the RXR-gamma isotype appears to contribute to the regulation of serum TSH and T4 levels and to affect peripheral metabolism through regulation of the hypothalamic-pituitary-thyroid axis or through direct effects on skeletal muscle.

Radioiodine ablation of thyroid remnants after preparation with recombinant human thyrotropin in differentiated thyroid carcinoma: results of an international, randomized, controlled study.

CONTEXT: After surgery for differentiated thyroid carcinoma, many patients are treated with radioiodine to ablate remnant thyroid tissue. This procedure has been performed with the patient in the hypothyroid state to promote endogenous TSH stimulation and is often associated with hypothyroid symptoms and impaired quality of life. OBJECTIVE AND INTERVENTION: This international, randomized, controlled, multicenter trial aimed to compare the efficacy and safety of recombinant human TSH (rhTSH) to prepare euthyroid patients on L-thyroxine therapy (euthyroid group) to ablate remnant thyroid tissue with 3.7 GBq (100 mCi) 131I, compared with that with conventional remnant ablation performed in the hypothyroid state (hypothyroid group). Quality of life was determined at the time of randomization and ablation. After the administration of the 131-I dose, the rate of radiation clearance from blood, thyroid remnant, and whole body was measured. RESULTS: The predefined primary criterion for successful ablation was "no visible uptake in the thyroid bed, or if visible, fractional uptake less than 0.1%" on neck scans performed 8 months after therapy and was satisfied in 100% of patients in both groups. A secondary criterion for ablation, an rhTSH-stimulated serum thyroglobulin concentration less than 2 ng/ml, was fulfilled by 23 of 24 (96%) euthyroid patients and 18 of 21 (86%) hypothyroid patients (P = 0.2341). Quality of life was well preserved in the euthyroid group, compared with the hypothyroid group, as demonstrated by their lower pretreatment scores on the Billewicz scale for hypothyroid signs and symptoms, 27 +/- 7 vs. 18 +/- 4 (P < 0.0001) and their significantly higher Short Form-36 Health Assessment Scale scores in five of eight categories. Euthyroid patients had a statistically significant one third lower radiation dose to the blood, compared with patients in the hypothyroid group. CONCLUSIONS: This study demonstrates comparable remnant ablation rates in patients prepared for 131I remnant ablation with 3.7 GBq by either administering rhTSH or withholding thyroid hormone. rhTSH-prepared patients maintained a higher quality of life and received less radiation exposure to the blood.

The combination of Pit-1 and Pit-1T have a synergistic stimulatory effect on the thyrotropin beta-subunit promoter but not the growth hormone or prolactin promoters.

Pit-1 is a pituitary-specific transcription factor with protein expression limited to thyrotrope, somatotrope, and lactotrope cells of the anterior pituitary gland. We have recently described a thyrotrope-specific variant isoform of Pit-1, called Pit-1T, which contains an additional 14 amino acids in the activation domain generated by an alternate 3'-splicing choice. Pit-1T, in the presence of Pit-1, stimulates the thyrotropin beta-subunit (TSH beta) promoter in a thyrotrope-derived cell that lacks all Pit-1 isoform proteins. Three laboratories have identified another Pit-1 splice variant, called Pit-1 beta, which contains an additional 26 amino acids in the activation domain that is generated by a similar 3'-alternate splice choice. Pit-1 beta has been shown to stimulate the GH promoter, but not the PRL or TSH beta promoters. In this report, we evaluate the effect of the three Pit-1 isoforms (Pit-1, Pit-1T, and Pit-1 beta) on the GH, PRL, and TSH beta promoters when introduced into different cell types. The combination of Pit-1 and Pit-1T had a synergistic stimulatory effect on the TSH beta promoter, but not on the PRL or GH promoters in a thyrotrope-derived cell line that lacks all Pit-1 protein isoforms (alpha TSH cells). When added to GH3 cells, which lack only the Pit-1T isoform, Pit-1T selectively stimulated the TSH beta promoter and not the GH or PRL promoters, suggesting that the thyrotrope-specific Pit-1T exhibits a promoter-specific effect.(ABSTRACT TRUNCATED AT 250 WORDS)

N-terminal variants of thyroid hormone receptor beta: differential function and potential contribution to syndrome of resistance to thyroid hormone.

The human syndrome of resistance to thyroid hormone (RTH) is associated with dominant mutations in the thyroid hormone receptor beta (TR beta) gene that generate mutant receptors with impaired binding for T3. Although the TR beta gene differentially expresses two N-terminal variant receptors, TR beta 1 and TR beta 2, functional analyses of RTH mutants have focused exclusively on TR beta 1. Since TR beta 2 is expressed in tissues that are malfunctional in RTH, the role of mutations in the context of TR beta 2 was examined. We compared the functional properties of corresponding RTH mutations in the common C-terminal domain of both TR beta 1 and TR beta 2. Wild type TR beta 1 and TR beta 2 bound similarly as homodimers and as heterodimers with retinoid X receptors to T3-responsive elements consisting of a direct repeat with 4-base pair spacing or an everted repeat. Homodimers, but not monomers or heterodimers, of both receptor subtypes were dissociated by the addition of T3. However, TR beta 2 formed at least 10-fold more stable homodimers than TR beta 1 on a palindromic repeat element, indicating that the N termini of TR beta 1 and TR beta 2 differentially influence dimerization on DNA. The RTH-like mutants of both TR beta 1 and TR beta 2 were equally insensitive to T3. They were defective in T3 binding but still bound DNA like their wild type counterparts except that the T3-dependent dissociation of homodimers from DNA was severely reduced. Wild type TR beta 1 and TR beta 2 mediated T3-inducible transactivation in cotransfection assays; this, however, was abolished in both mutants. TR beta 1 mediated more sensitive T3-dependent transcriptional suppression than TR beta 2 through the negative T3 response region of the TSH beta gene. Again, the mutation abolished T3-dependent suppression by both mutants. Furthermore, both mutants inhibited T3-inducible transcriptional activation by different wild type TR alpha and beta variants. These results indicate that both mutants have the potential to contribute to the pathogenesis of RTH and suggest that a reassessment of previous models of RTH is required to take into account the inhibitory activity of both TR beta 2 and TR beta 1 mutants.

The thyrotrope-restricted isoform of the retinoid-X receptor-gamma1 mediates 9-cis-retinoic acid suppression of thyrotropin-beta promoter activity.

TSHbeta is a subunit of TSH that is uniquely expressed and regulated in the thyrotrope cells of the anterior pituitary gland. Thyroid hormone receptors (TR) are known to mediate T3 suppression of TSHbeta gene expression at the level of promoter activity. The role of other nuclear receptors in regulation of this gene is less clearly defined. Retinoid X receptors (RXR) are a family of nuclear transcription factors that function both as 9-cis-retinoic acid (RA) ligand-dependent receptors and heterodimeric partners with TR and other nuclear receptors. Recently, the RXR isoform, RXRgamma, has been identified in the anterior pituitary gland and found to be restricted to thyrotrope cells within the pitutiary. In this report, we have further characterized the distribution of RXRgamma1, the thyrotrope-restricted isoform of RXRgamma, in murine tissues and different cell types. We have found that RXRgamma1 mRNA and protein are expressed in the TtT-97 thyrotropic tumor, but not the thyrotrope-variant alphaTSH cells or somatotrope-derived GH3 cells. Furthermore, we have studied the effects of RXRgamma1 on TSHbeta promoter activity and hormone regulation in these pituitary-derived cell types. Both T3 and 9-cis-RA independently suppressed promoter activity in the TtT-97 thyrotropes. Interestingly, the combination of ligands suppressed promoter activity more than either alone, indicating that these hormones may act cooperatively to regulate TSHbeta gene expression in thyrotropes. The RXRgamma1 isoform was necessary for the 9-cis-RA-mediated suppression of TSHbeta promoter activity in alphaTSH and GH3 cells, both of which lack this isoform. RXRbeta, a more widely distributed isoform, did not mediate these effects. Finally, we showed that the murine TSHbeta promoter region between -200 and -149 mediated a majority of the 9-cis-RA suppression of promoter activity in thyrotropes. This region is distinct from the T3-mediated response region near the transcription start site. These data suggest that retinoids can mediate TSHbeta gene regulation in thyrotropes and the thyrotrope-restricted isoform, RXRgamma1, is required for this effect.

Structural and functional characterization of the genomic locus encoding the murine beta 2 thyroid hormone receptor.

beta 1 and beta 2 are functional thyroid hormone receptors (TRs) that are generated from the same genomic locus by splicing of a different amino terminus onto a common carboxyl region containing the DNA and hormone binding domains. TR beta 1 is widely expressed whereas TR beta 2 is found primarily in the pituitary gland although low levels of expression have been described in other tissues. To gain insight into the mechanisms governing expression of this complex transcriptional unit, we cloned mouse genomic fragments containing the common carboxyl terminus as well as the unique TR beta 2 amino-terminal sequence that was located at least 25 kilobases upstream. The DNA and ligand binding exons are identical in size and location of their boundaries to those of the human TR beta 1 gene. To determine whether the region 5' of the TR beta 2 amino terminus represented the promoter region, we examined it for sites of transcriptional initiation and for its ability to function as a promoter in TR beta 2-expressing thyrotrope cells. Multiple transcriptional start sites extending over 400 base pairs (bp) were identified with those more proximal showing inhibition by T3. Transcription was not detected more than 400 bp upstream from the putative AUG codon, although initiation downstream of this AUG was demonstrated indicating alternative AUG usage. A fragment containing 500 bp of the TR beta 2 5'-region exhibited preferential promoter activity when transfected into thyrotrope cells that express endogenous TR beta 2. Deletion studies demonstrated that removal of consensus binding sites for the transcription factor Pit-1 resulted in loss of this cell specificity. We therefore conclude that the promoter region responsible for expression of the TR beta 2 isoform in pituitary thyrotropes is distinct from that described for TR beta 1 and is located many kilobases upstream from their common exons.

Susceptibility of Snails to Infection with Schistosomes is influenced by Temperature and Expression of Heat Shock Proteins.

The freshwater snail, Biomphalaria glabrata is the obligate intermediate host for the transmission of the parasitic trematode, Schistosoma mansoni the causative agent of the chronic debilitating neglected tropical disease, schistosomiasis. We showed previously that in juvenile snails, early and significant induction of stress manifested by the expression of stress proteins, Hsp 70, Hsp 90 and reverse transcriptase (RT) of the non- LTR retrotransposon, nimbus, is a characteristic feature of juvenile susceptible NMRI but not resistant BS-90 snails. These latter, however, could be rendered susceptible after mild heat shock at 32°C, revealing that resistance in the BS-90 resistant snail to schistosomes is a temperature dependent trait. Here we tested the hypothesis that maintenance of BS-90 resistant snails at the permissive temperature for several generations affects the resistance phenotype displayed at the non-permissive temperature of 25°C. The progeny of BS-90 snails bred and maintained through several generations (F1 to F4) at 32°C were susceptible to the schistosome infection when returned to room temperature, shedding cercariae at four weeks post-infection. Moreover, the study of expression levels of the heat shock protein (Hsp) 70 protein by ELISA and western blot analysis, showed that this protein is also differentially expressed between susceptible and resistant snails, with susceptible snails expressing more protein than their resistant counterparts after early exposure to wild-type but not to radiation-attenuated miracidia. These data suggested that in the face of global warming, the ability to sustain a reduction in schistosomiasis by using refractory snails as a strategy to block transmission of the disease might prove challenging since non-lethal elevation in temperature, affects snail susceptibility to S. mansoni.

A consensus report of the role of serum thyroglobulin as a monitoring method for low-risk patients with papillary thyroid carcinoma.

Recent studies have provided new information regarding the optimal surveillance protocols for low-risk patients with differentiated thyroid cancer (DTC). This article summarizes the main issues brought out in a consensus conference of thyroid cancer specialists who analyzed and discussed this new data. There is growing recognition of the value of serum thyroglobulin (Tg) as part of routine surveillance. An undetectable serum Tg measured during thyroid hormone suppression of TSH (THST) is often misleading. Eight studies show that 21% of 784 patients who had no clinical evidence of tumor with baseline serum Tg levels usually below 1 micro g/liter during THST had, in response to recombinant human TSH (rhTSH), a rise in serum Tg to more than 2 micro g/liter. When this happened, 36% of the patients were found to have metastases (36% at distant sites) that were identified in 91% by an rhTSH-stimulated Tg above 2 micro g/liter. Diagnostic whole body scanning, after either rhTSH or thyroid hormone withdrawal, identified only 19% of the cases of metastases. Ten studies comprising 1599 patients demonstrate that a TSH-stimulated Tg test using a Tg cutoff of 2 micro g/liter (either after thyroid hormone withdrawal or 72 h after rhTSH) is sufficiently sensitive to be used as the principal test in the follow-up management of low-risk patients with DTC and that the routine use of diagnostic whole body scanning in follow-up should be discouraged. On the basis of the foregoing, we propose a surveillance guideline using TSH-stimulated Tg levels for patients who have undergone total or near-total thyroidectomy and (131)I ablation for DTC and have no clinical evidence of residual tumor with a serum Tg below 1 micro g/liter during THST.

A comparison of recombinant human thyrotropin and thyroid hormone withdrawal for the detection of thyroid remnant or cancer.

Recombinant human TSH has been developed to facilitate monitoring for thyroid carcinoma recurrence or persistence without the attendant morbidity of hypothyroidism seen after thyroid hormone withdrawal. The objectives of this study were to compare the effect of administered recombinant human TSH with thyroid hormone withdrawal on the results of radioiodine whole body scanning (WBS) and serum thyroglobulin (Tg) levels. Two hundred and twenty-nine adult patients with differentiated thyroid cancer requiring radioiodine WBS were studied. Radioiodine WBS and serum Tg measurements were performed after administration of recombinant human TSH and again after thyroid hormone withdrawal in each patient. Radioiodine whole body scans were concordant between the recombinant TSH-stimulated and thyroid hormone withdrawal phases in 195 of 220 (89%) patients. Of the discordant scans, 8 (4%) had superior scans after recombinant human TSH administration, and 17 (8%) had superior scans after thyroid hormone withdrawal (P = 0.108). Based on a serum Tg level of 2 ng/mL or more, thyroid tissue or cancer was detected during thyroid hormone therapy in 22%, after recombinant human TSH stimulation in 52%, and after thyroid hormone withdrawal in 56% of patients with disease or tissue limited to the thyroid bed and in 80%, 100%, and 100% of patients, respectively, with metastatic disease. A combination of radioiodine WBS and serum Tg after recombinant human TSH stimulation detected thyroid tissue or cancer in 93% of patients with disease or tissue limited to the thyroid bed and 100% of patients with metastatic disease. In conclusion, recombinant human TSH administration is a safe and effective means of stimulating radioiodine uptake and serum Tg levels in patients undergoing evaluation for thyroid cancer persistence and recurrence.

Effect of dietary macronutrient composition on tissue-specific lipoprotein lipase activity and insulin action in normal-weight subjects.

The effects of macronutrient composition on fasting and postprandial activities of adipose tissue lipoprotein lipase (ATLPL) and skeletal muscle LPL (SMLPL) and on insulin sensitivity (S(I)) were studied in 25 normal-weight subjects. Each subject was fed a high-carbohydrate (HC) diet for 16 d and a high-fat (HF) diet for 16 d, in randomized order. On day 15 of each diet, biopsies for ATLPL and SMLPL were done in the fasted state and 6 h postprandially. On day 16 of each diet, a euglycemic clamp was used to measure S(I). There was no effect of diet composition on fasting ATLPL or SMLPL. With both diets and in both tissues, LPL increased significantly from fasting to 6 h postprandially. In adipose tissue only there was a significant difference between the 2 diets in LPL meal response (HC >HF, P = 0.024). There was no effect of diet composition on S(I). After the HC diet only, there were significant correlations between fasting SMLPL and S(I), but not ATLPL. After the HF diet, associations between insulin action and LPL were evident only in the postprandial state. In summary, 16 d of HC compared with HF feeding in normal-weight subjects increased the responsiveness of ATLPL to an HC compared with an HF meal. However, the same diets had no effect on fasting ATLPL or SMLPL, the responsiveness of SMLPL to a meal, or S(I). These data suggest that in normal-weight subjects habitual dietary carbohydrate intake may have a stronger effect on subcutaneous fat storage than does dietary fat intake.

Isotope imaging for metastatic thyroid cancer.

Many isotopes are available for imaging patients with suspected thyroid cancer recurrence and metastases. TSH-stimulated low-dose 131I whole-body scanning with serum thyroglobulin either by standard LT4 withdrawal or rhTSH stimulation is the preferred test for monitoring patients without palpable disease or elevated serum thyroglobulin on LT4 therapy (Fig. 5). This approach has the advantage of finding disease that may be amenable to 131I therapy, although low-dose 131I scans are less sensitive than are scans with other imaging agents. 123I has better imaging characteristics than 131I and has been shown to be equivalent or superior to low-dose 131I in recent studies. As the availability of 123I increases and the cost decreases, this agent may replace 131I in imaging for recurrent or metastatic thyroid cancer. Patients who have an elevated serum thyroglobulin on LT4 therapy or after TSH stimulation but have a negative low-dose 131I scan require other imaging procedures to find the suspected disease. The authors currently perform a sensitive neck ultrasound to look for surgically remediable disease and consider a noncontrast CT scan of the chest to look for small pulmonary metastases that poorly concentrate low doses of 131I (Fig. 5). Fluoro-18-deoxyglucose PET, 99mTc MIBI, 201Tl, and 99mTc tetrofosmin are primarily useful in the setting of a negative whole-body 131I scan and elevated serum thyroglobulin. 18FDG-PET seems to have the highest sensitivity in this setting and would be the preferred imaging agent, but availability and cost are major issues (Fig. 5). Although some researchers have advocated these radiopharmaceuticals as first-line agents replacing 131I, there is little support for this position. This approach to imaging is not cost-effective because positive scans in these patients would most likely require 131I scintigraphy to determine whether the lesions are amenable to radioiodine therapy. 99mTc pertechnetate, 99mTc furifosmin, and somatostatin receptor scintigraphy have a limited role in imaging for recurrent or metastatic differentiated thyroid carcinoma. In choosing among 99mTc MIBI, 201Tl, and 99mTc tetrofosmin, the technetium label of sestamibi and tetrofosmin results in better image quality and faster imaging than 201Tl. Although 99mTc sestamibi and 99mTc tetrofosmin have not been compared in a large series, the higher tumor-to-background ratio and consistently high sensitivities of 99mTc tetrofosmin suggest that it could potentially have additional value over 99mTc sestamibi, but there is still limited experience with 99mTc tetrofosmin.

Analysis of Pit-1 in regulating mouse TSH beta promoter activity in thyrotropes.

TSH beta gene expression is restricted to pituitary thyrotropes. Since Pit-1 is present in these cells, we characterized Pit-1 RNA and protein in thyrotropes, and tested its function in regulating TSH beta promoter activity. We demonstrate that both TtT-97 thyrotropic tumors and pituitaries contain four Pit-1 transcripts of 3.2, 2.6, 2.4, and 1.9 kb, respectively. Only two transcripts of 2.7 and 2.1 kb were detected in alpha TSH cells, a thyrotrope derived cell that no longer expresses TSH beta. Western analysis revealed Pit-1 protein in TtT-97 cells but not in alpha TSH cells. DNase I protection assays localized Pit-1 binding to three areas of the mouse TSH beta promoter. However, basal TSH beta promoter activity was minimally stimulated when alpha TSH cells or TtT-97 thyrotropes were co-transfected with mouse Pit-1 and a mTSH beta luciferase construct. These studies suggest that Pit-1 is not limiting for cell-specific expression of the TSH beta gene in thyrotrope-derived cells and implies that additional thyrotropic factors are likely required.

Volumetric blood flow measurement with the use of dynamic 3-dimensional ultrasound color flow imaging.

We describe a new method for measuring blood volume flow with the use of freehand dynamic 3-dimensional echocardiography. During 10 to 20 cardiac cycles, the ultrasonographic probe was slowly tilted while its spatial position was continuously recorded with a magnetic position sensor system. The ultrasonographic data were acquired in color flow imaging mode, and the separate raw digital tissue and Doppler data were transferred to an external personal computer for postprocessing. From each time step in the reconstructed 3-dimensional data, one cross-sectional slice was extracted with the measured and recorded velocity vector components perpendicular to the slice. The volume flow rate through these slices was found by integrating the velocity vector components, and was independent of the angle between the actual flow direction and the measured velocity vector. Allowing the extracted surface to move according to the movement of anatomic structures, an estimate of the flow through the cardiac valves was achieved. The temporal resolution was preserved in the 3-dimensional reconstruction, and with a frame rate of up to 104 frames/s, the reconstruction jitter artifacts were reduced. Examples of in vivo blood volume flow measurement are given, showing the possibilities of measuring the cardiac output and analyzing blood flow velocity profiles.

A new method describing cross-sectional blood flow velocity profiles in the left ventricular outflow tract of patients with atrial fibrillation with the use of high-frame rate 2-dimensional color flow imaging.

A new Doppler method was developed to evaluate the instantaneous cross-sectional velocity profile variability in the left ventricular outlet tract in patients with atrial fibrillation. Blood flow velocities acquired at a high frame rate (>90 frames/s) from a single heart cycle were used to display the velocity profile. In 9 patients, 2 heart cycles with different R-R interval lengths were recorded in color flow mode in a transthoracic apical 5-chamber and long-axis view. Raw digital ultrasound data were analyzed with an external personal computer. The data indicated a variable skew in the profiles with the highest velocities and velocity-time integral (VTI) most often located in the center and toward the septum. The maximum VTI overestimated the mean VTI by approximately 40%. No significant difference existed between the two heartbeats. Thus the VTI can be averaged from heartbeats of different R-R lengths in atrial fibrillation.

Management practices among primary care physicians and thyroid specialists in the care of hypothyroid patients.

Prospective studies are not available to address various issues commonly encountered in the management of hypothyroid patients. We have conducted a case-based mail survey of American Thyroid Association (ATA) members and primary care providers (PCP) regarding hypothyroidism management issues. A majority of ATA members and a minority of PCPs used antithyroid antibody testing in the evaluation of hypothyroidism. Approximately 2/3 of all respondents indicated that they would treat patients with mild thyroid failure when antithyroid antibodies are negative; 77% of PCPs and 95% of ATA members recommended treatment when antibodies are positive. For a young patient with mild thyroid failure, 71% of ATA members would initiate a full levothyroxine (LT4) replacement dose of 1.6 microg/kg per day or slightly lower; PCPs were more likely to start with a low dose and titrate upwards. For a young patient with overt hypothyroidism, 42% of PCPs and 51% of ATA respondents recommended an initial full LT4 replacement dose. The majority of all respondents would start with a low LT4 dose and adjust the dose gradually in an elderly patient, regardless of the severity of thyroid hormone deficiency. More than 40% of ATA respondents chose a target thyrotropin (TSH) range of 0.5-2.0 microU/mL for a young patient while 39% favored a goal of 1.0-4.0 microU/mL for an elderly patient. PCPs more often chose a broader TSH goal of 0.5-5.0 microU/mL. In conclusion, the current practice patterns of PCPs and ATA members that were elicited in this survey differ significantly in regard to the evaluation and management of hypothyroidism.

Secondary malignancy of the thyroid gland: a case report and review of the literature.

Metastatic cancer to the thyroid gland is uncommon. In this report we describe a patient with a malignant fibrous histiocytoma that metastasized to the thyroid, possibly to a preexisting thyroid nodule. A review of the literature reveals that breast and lung carcinoma are the most frequently identified sources of secondary thyroid carcinoma found at autopsy, while renal carcinoma comprises over 50% of secondary thyroid malignancies discovered clinically. A number of authors suggest that preexisting thyroid disease (i.e., multinodular goiter and thyroid nodules) may provide a nidus for metastases to the thyroid gland.