Genes of detoxification are important modulators of hereditary medullary thyroid carcinoma risk.

CONTEXT: Different inherited profiles of genes involved in cellular mechanisms of activation and detoxification of carcinogenic products can provide specific protection or determine the risk for cancer. Low-penetrance polymorphic genes related to the biotransformation of environmental toxins have been associated with susceptibility to and the phenotype of, human tumours. OBJECTIVE: To investigate the role of germline inheritance of polymorphisms in CYP1A2*F, CYP1A1 m1, GSTP1, NAT2 and TP53 genes in hereditary medullary thyroid carcinoma (HMTC) patients. DESIGN: This study was developed in University of Campinas (Unicamp). PATIENTS: We studied 132 patients with HMTC, 88 first-degree relatives of HMTC patients and 575 control individuals. MEASUREMENTS: All patients with MTC and their relatives were sequenced for the RET gene and five genes were genotyped using TaqMan(®) system. RESULTS: We observed that the inheritance of CYP1A2*F (OR = 2·10; 95% CI = 1·11-3·97; P = 0·022), GSTP1 (OR = 4·41; 95% CI = 2·47-7·88; P < 0·001) and NAT2 (OR = 2·54; 95% CI = 1·16-5·58; P = 0·020) variants increased the risk for HMTC. In addition, multiple regression analysis showed that the inheritance of GSTP1 polymorphisms was associated with the diagnosis in older patients (B = 8·0229; 95% IC = ± 5·5735; P = 0·0054). Concerning the group of HTMC relatives, CYP1A2*F (OR = 2:40; 95% CI = 1·19-4·86; P = 0·015), CYP1A1 m1 (OR = 2·79; 95% CI = 1:04-7·51; P = 0·042), GSTP1 (OR = 2·86; 95% IC = 1·53-5·32; P < 0·001) and NAT2 (OR = 2·25; 95% IC = 1·20-4·22; P = 0·012) were associated with HMTC risk. CONCLUSIONS: We have demonstrated that the inheritance of specific genes determining the individual response to environmental toxins may contribute to the risk and phenotypic variability that exists in patients with HMTC. Moreover, we identified a group at risk in relatives of HMTC patients.

Comprehensive analysis of RET gene should be performed in patients with multiple endocrine neoplasia type 2 (MEN 2) syndrome and no apparent genotype-phenotype correlation: an appraisal of p.Y791F and p.C634Y RET mutations in five unrelated Brazilian families.

BACKGROUND: We previously identified a four-generation family with medullary thyroid cancer (MTC) and a germline p.Y791F RET mutation whose cancer lacked a strong genotype-phenotype correlation. The entire gene coding region of the RET gene should be sequenced when genotype-phenotype discrepancies are observed in patients with multiple endocrine neoplasia type 2 (MEN 2), even if a RET hotspot mutation has been identified. METHODS: A new genetic test was performed in the index case of this family with the p.Y791F RET germline mutation. The entire coding region of the RET gene was investigated by direct sequencing of PCR products. Once a mutation was identified, the target exon was sequenced in all at-risk relatives. RESULTS: An additional p.C634Y germline mutation in the RET gene was identified in the reported family. The double mutation occurred in cis and segregated with the phenotype. Through the Brazilian Genetic Screening Program developed at our institution, we additionally report the combination of these two mutations (p.C634Y/p.Y791F) in the RET gene in four other unrelated families. The overall penetrance of MTC and pheochromocytoma in patients with the p.C634Y/p.Y791F mutations was 79% and 13%, respectively. CONCLUSION: Our data emphasises that a comprehensive analysis of the RET gene may reveal multiple germline mutations in MEN 2 patients who exhibit an atypical clinical course of the disease.

Seizure suppression by asynchronous non-periodic electrical stimulation of the amygdala is partially mediated by indirect desynchronization from nucleus accumbens.

Electrical stimulation (ES) of the nervous system is a promising alternative for the treatment of refractory epilepsy. Based on the understanding that seizures are the expression of neural hypersynchronism, our group developed and tested a non-standard form of low-energy temporally unstructured ES termed NPS (Non-periodic stimulation), with pseudo-randomized inter-pulse intervals. Previous investigation demonstrated that NPS applied to the amygdala has a robust anticonvulsant effect against both acute and chronic seizures, and suggested that its therapeutic effect is based on direct desynchronization of ictogenic neural circuits. Further mechanistic investigation using functional magnetic resonance imaging has shown that NPS also activates nucleus accumbens (NAc) in seizure-free rats, raising the hypothesis of an alternative therapeutic mechanism: NPS-enhanced indirect inhibition / desynchronization of ictogenic circuits by NAc. In order to investigate this idea, here we evaluated behavior and cortical electrographic activity from animals submitted to pentylenetetrazole (PTZ) induced seizures, treated with NPS and with or without bilateral electrolytic lesion of NAc. NPS-treated animals with bilateral lesion of NAc expressed unexpected straub tail in addition to other stereotypical convulsive behavior, displayed increased susceptibility to PTZ (lower drug threshold), and had a much longer electrographic seizure, with a greater number of spikes, firing at a higher rate. Moreover, analysis of spike morphology showed an increase in amplitude and slope in these animals, suggesting that ablation of NAc results in disinhibition and/or increase of neural synchronism within ictogenic circuits. NPS had no therapeutic effect whatsoever in lesioned animals, while it displayed a mild anticonvulsant effect in those with intact brains. Results corroborate the notion that NAc has a key role in controlling aberrant epileptiform activity in ictogenic circuits through indirect polysynaptic connections that may enroll the ventral pallidum and ventral tegmental area. They also point to the possibility that NPS may enhance this effect, putatively by benefiting from the structure's property of detecting saliences.

Asynchronous, bilateral, and biphasic temporally unstructured electrical stimulation of amygdalae enhances the suppression of pentylenetetrazole-induced seizures in rats.

A promising alternative for the treatment of refractory epilepsy is electrical stimulation (ES) of the central nervous system. Based on the premise that epilepsy is a result of neural hypersynchronization, we have previously demonstrated that a novel non-standard form of electrical stimulation with randomized inter-pulse intervals, termed non-periodic stimulation (NPS), applied to the amygdala is robustly anticonvulsant. This investigation also suggested that NPS attains its therapeutic effect by desynchronization of epileptiform activity. Here, we further explored the desynchronization hypothesis by testing how the efficacy of NPS in the suppression of convulsive behaviors depends on morphological, spatial, and temporal parameters of stimulus. For this purpose, we varied the number of pulse phases (monopolar versus bipolar square pulses), side of stimulation (right versus left), number of application hemispheres (unilateral versus bilateral), and interhemispheric temporal synchronicity (synchronous versus asynchronous), while measuring the impact on the anticonvulsant action of NPS. Wistar rats received a controlled infusion of the convulsant agent pentylenetetrazole (PTZ, 10 mg/min), together with one of six variations of NPS applied to the amygdala. A stimulated PTZ-free group of animals was also performed as a positive control. Latency to convulsive behavior was used to measure seizure threshold. Animals receiving NPS displayed significant higher threshold for forelimb clonus and generalized tonic-clonic seizures for all patterns. Thresholds seemed to increase gradually from mono to biphasic, unilateral to bilateral, and synchronous to asynchronous stimuli. Thus, combined biphasic, bilateral, and asynchronous stimulation resulted in the greatest seizure threshold. PTZ free animals did not develop any observable convulsive behavior or other uncommon motor activity. These results confirm that NPS has anticonvulsant properties and that biphasic, bilateral, and asynchronous stimulation enhances its efficacy. The fact that lack of synchronism between stimuli of each hemisphere maximizes NPS anticonvulsant power is evidence to desynchronization as tool for suppression of seizures.

Demonstration of the production and physiological role of insulin-like growth factor II in rat thyroid follicular cells in culture.

Insulin-like growth factors (IGFs) are potent mitogens for FRTL5 rat thyroid follicular cells. IGFs also synergize the independent mitogenic effects of thyrotropin-stimulating hormone (TSH) and other agents that increase intracellular AMP concentration. We examined whether FRTL5 cells and M12 cells, a TSH-independent mutant cell line derived therefrom, secrete IGF that regulates the growth of rat thyroid follicular cells. Immunoreactive IGF-II, but not IGF-I, was found in media conditioned by FRTL5 cells; media from M12 cells contained four- to fivefold higher concentrations. Medium conditioned by FRTL5 and M12 both stimulated [3H]thymidine incorporation in FRTL5 and amplified the mitogenic effects of TSH. M12-conditioned medium was more potent than FRTL5-conditioned medium. Sm-1.2, a monoclonal antibody that recognizes IGF-I and IGF-II but not insulin, inhibited basal DNA synthesis in FRTL5 and M12 cells and the mitogenic effects in FRTL5 of agents that are synergized by IGF, such as TSH, forskolin, Bt2cAMP, and Graves'-IgG. Sm-1.2 did not inhibit the mitogenic response to insulin. Thus, rat insulin-like growth factor II (rIGF-II) is an autocrine growth factor that regulates FRTL5 growth, in part by amplifying the mitogenic response to TSH. Results with M12 cells raise the possibility that endogenous rIGF-II may partially mediate the TSH-independent growth of these cells.

Role of the adjunctive antimicrobial photodynamic therapy to periodontal treatment at plasmatic oxidative stress and vascular behavior.

BACKGROUND: To evaluate for the first time in vivo the effects of methylene blue (MB) photosensitizer dissolved in ethanol in antimicrobial photodynamic therapy (aPDT) as adjuvant periodontal treatment, at plasmatic oxidative stress and vascular behavior in rat model. METHODS: Wistar rats were divided into negative control (NC, no periodontitis) and positive control (PC, with periodontitis, without any treatment). The other groups had periodontitis and were treated with scaling and root planing (SRP); SRP+aPDT+MB dissolved in water (aPDT I); SRP+aPDT+MB dissolved in ethanol (aPDT II). The periodontitis was induced by ligature at the mandibular right first molar. At 7/15/30days, rats were euthanized, the plasma was used to determine oxidative stress parameters and gingival tissue for histomorphometric analysis. RESULTS: PC showed higher thiobarbituric acid reactive substances levels in 7/15/30days. aPDT II was able to block the lipid peroxidation, especially between 15th and 30th days. Glutathione reduced levels were consumed in PC, aPDT I and II groups throughout the experiment. aPDT II increased the vitamin C levels which were restored in this group in the 30th day. aPDT II group showed the highest number of blood vessels. CONCLUSION: In summary, the aPDT with MB dissolved in ethanol provides better therapeutic responses in periodontitis treatment.

The Ala45Thr polymorphism of NEUROD1 is associated with type 1 diabetes in Brazilian women.

BACKGROUND: NEUROD1 encodes a transcription factor expressed in the endocrine pancreas, and involved in beta-cell development, function and mechanisms of apoptosis. In this study, we investigated the association of a frequent polymorphism in exon 2 of NEUROD1 (G > A; Ala45Thr) with Type 1 diabetes in Brazilian subjects. METHODS: A population/association study comprising 246 unrelated Type 1 diabetic and 275 nondiabetic white Brazilian subjects. The Ala45Thr variant was genotyped by a PCR-RFLP method. RESULTS: The frequency of the Thr allele was significantly higher in patients with Type 1 diabetes than in controls (42.3% vs 35.3%, P=0.02). Stratification by gender showed that homozygosity for the Thr allele was associated with Type 1 diabetes in women with odds ratio of 3.66 (95% C.I. 1.43-10.11, P=0.009) as compared to homozygosity for the Ala allele. This effect was not observed in men. CONCLUSIONS: We found a gender-specific association of the Ala45Thr variant of NEUROD1 with Type 1 diabetes in Brazilian women. Our results suggest that gender as well as ethnicity might modulate the association of NEUROD1 with Type 1 diabetes.

Gene expression profiles reveal that DCN, DIO1, and DIO2 are underexpressed in benign and malignant thyroid tumors.

To investigate the molecular events involved in the pathogenesis and/or progression of thyroid tumors, we compared the gene expression profiles of three thyroid carcinoma cell lines, which represent major tumor subtypes of thyroid cancer and normal thyroid tissue. Using cDNA array methodology, we investigated the expression of 1807 open reading frame expressed sequence tags (ORESTES), selected from head and neck tumor libraries generated through the Brazilian Human Cancer Project-LICR/FAPESP. We found that 505 transcripts were differentially expressed in the thyroid carcinoma cell lines. Using a more stringent criterion, transcripts underexpressed or overexpressed more than fivefold in 1 of 3 or 3 of 3 carcinoma cell lines, a list of 55 ESTs were detected. Five candidate genes were further validated by quantitative polymerase chain reaction (qPCR) in an independent set of 52 thyroid tumors and 22 matched normal thyroid tissues. DCN was found underexpressed in a high percentage of the follicular thyroid adenomas, follicular thyroid carcinomas, and follicular variant of papillary thyroid carcinomas. DIO1 and DIO2 were underexpressed in nearly all papillary thyroid carcinomas. These genes not only could help to better define a tumor signature for thyroid tumors, but may, in part, also become useful as potential targets for thyroid tumor treatment.

Subcellular localization of thyroxine and reverse triiodothyronine outer ring monodeiodinating activities.

In order to examine the subcellular localization of outer ring T4- and rT3-monodeiodinating activities, nuclear, mitochondrial, microsomal, cytosol, and plasma membrane fractions of rat liver homogenate were incubated with either T4 or rT3 in phosphate buffer (pH 7.35) in the presence of 2 mM dithiothreitol for 15 min at 37 C, and the amount of product (T3 in the case of T4 and 3,3'-diiodothyronine in the case of rT3) was measured by specific RIA. The various tissue fractions were also examined for the relative concentration of various marker enzymes. T4 and rT3 monodeiodinating activities correlated better with enzyme markers of plasma membranes than of any other subcellular fraction in most tissue fractions. A fraction could be isolated, however, in which the monodeiodinating activities correlated better with the enzyme markers of microsomes than of plasma membranes. The various data suggest that plasma membranes and microsomes are two main sites of T4- and rT3-monodeiodinating activities. The location of T4 to T3 converting activity in the plasma membranes may serve to modulate the delivery of the more potent thyroid hormone, i.e. T3, into the cells.

The role of glucocorticoids in the stress-induced reduction of extrathyroidal 3,5,3'-triiodothyronine generation in rats.

Serum concentrations of T4, T3, and rT3 as well as liver and kidney 5'-deiodinase activity, have been examined in rats stressed by restraint. After immobilization, serum concentrations of T3 decreased significantly (6 hr, -33 +/- 1%; 8 h, -42 +/- 3%), while serum rT3 increased (6 h, +55 +/- 3%; 8 h, +75 +/- 5%). In the same or similarly treated animals, there was a time-dependent reduction in T4 5'-deiodinase activity in both liver (4 h, -23 +/- 2%; 8 h, -43 +/- 3%) and kidney (4 h, -18 +/- 1%; 8 h, -42 +/- 3%) homogenates. The reduction in hepatic and renal T3 production was due to reduced enzyme activity and not to reduced substrate availability. In spite of reductions in serum TSH (4 h, -9 +/- 1%; 8 h, -51 +/- 5%), the serum T4 concentration did not fall. The serum concentration of corticosterone reached 30 times the basal level after 8 h of restraint. Either adrenalectomy or metyrapone treatment, followed by replacement with nonstress doses of B, completely prevented the alterations of iodothyronine metabolism induced by restraint. These results indicate that the stress-induced elevation of plasma glucocorticoids plays a key role in the pathogenesis of the low T3 syndrome in this model. The reduction in serum T3 may be accounted for by a reduction in T3 production by liver and kidney, adding support to the concept that these organs are an important source of plasma T3 in the rat.

3'-5'-Diiodothyronine in health and disease: studies by a radioimmunoassay.

A simple, reproducible, and highly specific RIA has been developed for measurement of 3',5'-diiodothyronine ((3',5'-T2) in unextracted serum. Interference in binding of radioactive 3',5'-T2 to anti-3',5'-T2 by serum proteins was minimized by using 0.4 M phosphate buffer (pH 6.2) and merthiolate. The detection threshold of the RIA was 2.5 ng/100 ml. Recovery of nonradioactive 3',5'-T2 added to serum averaged 99%. T4, T3, and rT3 cross-reacted with 3',5'-T2-binding sites on anti-3',5'-T2 antibody only to the extent of 0.0025, less than 0.0004, and 0.22%, respectively. 3'-Monoiodothyronine cross-reacted 1.7%. Serum 3',5'-T2 concentrations were (mean +/- SD) 6.4 +/- 2.4 ng/100 ml in 53 normal subjects, 4.2 +/- 3.5 ng/100 ml in 7 hypothyroid patients, 14.9 +/- 7.7 ng/ml in 25 patients with hepatic cirrhosis, and 14.3 +/- 5.3 ng/100 ml in 31 newborns' cord blood sera. The values in each of the latter four groups were significantly different from normal. The mean serum 3',5'-T2 concentration of 7.7 +/- 2.5 ng/ml in eight subjects in the third trimester of pregnancy did not differ significantly from normal at a time when serum T4 and T3 were clearly elevated. Oral administration of 300 microgram rT3 to 9 normal subjects led to a mean maximal increase in serum 3',5'-T2 concentration of 45% at 1 h. Total fasting in 3 obese subjects was associated with a significant increase in serum 3',5'-T2 from 8.6 to 16.3 ng/100 ml at 6-8 days; serum rT3 increased similarly, while serum T3 decreased and T4 did not change. Administration of dexamethasone (2 mg also associated with nearly parallel increases in serum 3',5'-T2 and rT3 and a decrease in serum T3. 3',5'-T2 concentrations were also measured in amniotic fluids at different stages of gestation; the mean value of 15.2 ng/100 ml at 15-20 weeks gestation was significantly higher than that of 5.8 ng/ml at 33-40 weeks gestation. Pronase hydrolysates of 9 autopsy specimens of normal thyroid glands contained (mean +/- SD) 350 +/- 144 microgram T4 and 0.24 +/- 0.15 microgram 3',5'-T2/g wet wt. On the basis of these data and those available for MCRs of 3',5'-T2 and T4, it was estimated that thyroidal secretion contributes less than 1% of 3',5'-T2 measured in serum of normal man. The various data suggest that: 1) 3',5'-T2 is a normal component of human serum; 2) almost all 3',5'-T2 in human serum derives from extrathyroidal sources; and 3) changes in serum 3',5'-2 generally parallel those in rT3.

Detection of recurrent thyroid cancer by sensitive nested reverse transcription-polymerase chain reaction of thyroglobulin and sodium/iodide symporter messenger ribonucleic acid transcripts in peripheral blood.

To investigate whether circulating thyroglobulin (Tg) messenger ribonucleic acid (mRNA) and sodium/iodide symporter (NIS) mRNA transcripts in peripheral blood are valuable in the follow-up of patients with thyroid cancer, we developed highly sensitive nested Tg and NIS mRNA detection assays and compared their accuracy with serum thyroglobulin (sTg) and whole body scan with 131I during the monitoring of 34 patients with well differentiated thyroid carcinoma who had undergone total thyroidectomy (17 of 34 also submitted to thyroid ablation with radioiodine) and were taking T4. Circulating Tg mRNA was found in 13 of 34 patients, 5 of 13 with detectable and 8 of 13 with undetectable sTg. From these 8 patients with undetectable Tg, 6 showed no cervical radioiodine uptake, and 3 presented proven metastatic disease (2 of them positive for antithyroglobulin antibodies). NIS mRNA was detected in 11 of 34 patients, but its measurement did not improve the ability to detect patients with metastases. Overall, identification of metastatic thyroid cancer was better associated with Tg mRNA than with NIS mRNA, sTg, or whole body scan (83% vs. 16.6% vs. 50% vs. 50%; P < 0.001). These data showed that circulating Tg mRNA is not only a more sensitive marker of residual thyroid tissue or thyroid cancer than sTg, particularly in patients during T4 therapy and with positive antithyroglobulin antibodies, but also was more sensitive than NIS mRNA in all patients.

Peripheral blood T and B lymphocytes, in vitro stimulation with phytohemagglutinin, and sensitization with 2,4-dinitrochlorobenzene in Grave's disease.

The percentage and absolute numbers of thymos-dependent (T) and thymos-independent (B) peripheral blood lymphocytes, the in vitro response of lymphocytes to phytohemagglutinin (PHA), and the sensitization with 2,4dinitrochlorobenzene (DNCB) was studied in 26 patients with hyperthyroidism due to Graves' disease. The results showed a normal percentage of both T and B cells and increased absoluted numbers of total lymphocytes in patients compared with 30 healthy controls. The in vitro response to PHA was normal in most patients with the exception of 5 of them who showed an impaired response. All patients developed a reaction of delayed hypersensitivity to DNCB. Our study indicated that there is no general abnormality in cell-mediated immunity in Graves' disease.

Supranormal stimulation of deoxyribonucleic acid synthesis in FRTL5 cells by serum from patients with untreated acromegaly.

Insulin-like growth factor I (IGF-I) is one of a number of mitogenic factors in the serum of animals and humans. We demonstrated previously that IGF-I is a potent mitogen for FRTL5 cells, a line of rat thyroid follicular cells. In this study, we assessed the relevance of this finding with respect to the levels of IGF-I found in human serum by comparing the effects of normal serum and serum from patients with untreated acromegaly or hypopituitarism on DNA synthesis in quiescent FRTL5 cells. As expected, when added to cells maintained in Coon's modified Ham's F-12 medium containing 0.1% BSA, but devoid of insulin, transferrin, TSH, or calf serum, normal serum produced a dose-dependent stimulation of [3H]thymidine incorporation into DNA. A similar, but more marked, effect was produced by the addition of serum from patients with untreated acromegaly. In multiple experiments, a standard concentration (0.5%) of acromegaly serum was more stimulatory to DNA synthesis than was normal serum. In a single experiment designed to eliminate interassay variation and define the relationship between the ability of serum to stimulate DNA synthesis and its IGF-I concentration, studies were performed with 0.5% concentrations of serum from 9 normal subjects, 15 patients with untreated acromegaly, and 3 patients with panhypopituitarism. On the average, [3H]thymidine incorporation in the presence of serum from patients with acromegaly was approximately 3 times, and that in the presence of serum from patients with hypopituitarism only one fourth, that in the presence of serum from normal subjects; there was no overlap of individual values in the three groups. For the entire study group, we found a highly significant correlation (r = 0.86) between the serum IGF-I concentration and the ability of that serum to stimulate thymidine incorporation into the DNA of FRTL5 cells. The stimulatory effects of serum from both normal and acromegalic subjects were decreased or abolished by the addition of a monoclonal antibody against IGF-I. In hypophysectomized rats, GH increases the thyroid to body weight ratio and enhances the effect of TSH to promote thyroid growth. Further, an inordinate frequency of nontoxic goiter in patients with acromegaly has been reported. Taken together with these observations, our findings suggest that the effect of IGF-I to promote thyroid cell growth in vitro has a counterpart in the living animal or patient.

Assessment of the efficacy and safety of nimesulide vs naproxen in paediatric patients with respiratory tract infections. A comparative single-blind study.

A total of 99 paediatric patients (57 male, 42 female) aged 1 to 12 years, weighing 10 to 40kg and with acute pharyngo-amygdalitis were enrolled in a single-blind study to assess the efficacy and tolerability of nimesulide in comparison with naproxen when both drugs were administered over an 8-day treatment period. Among the 2 treatment groups comprising 99 evaluable patients, demographic analysis of age, weight and height did not reveal statistically significant differences. Evaluation of fever, pain, inflammation and nasal obstruction over the 8-day treatment period showed a significant improvement in these parameters for those patients treated with nimesulide when compared with naproxen from day 1, with remission of symptoms starting from day 3. These findings were complemented by a superior tolerability profile reported for nimesulide-treated patients. In conclusion, nimesulide appears to be a safe and effective treatment for paediatric patients with pharyngo-amygdalitis and it has shown superior efficacy and tolerability when compared with naproxen.

Outcome of thyroid function in newborns from mothers treated with amiodarone.

Amiodarone, a drug extensively used as an antiarrhythmic agent, contains 37% iodine and causes several thyroid abnormalities. The transplacental passage of amiodarone occurs with chronic therapy; we describe in this report the outcome of 9 pregnant women who used amiodarone (200 mg/day) for treatment of resistant tachycardia and the follow-up of their newborns. All women were clinically euthyroid at the 3rd trimester and showed expected values of thyroid hormones (mean +/- SD: total T4, 228 +/- 45 nmol/L; total T3, 4.0 +/- 0.65 nmol/L; TSH, 4.0 +/- 1.8 mU/L; negative thyroid antibodies). At birth all newborns were normal on routine examination with no goiter or corneal changes. T4 and TSH, measured on dried umbilical blood spots were normal or borderline-normal in 8 of 9 babies. Only 1 neonate presented clearly abnormal values of T4 and TSH (96 mU/L); on clinical grounds the baby was normal, without signs of hypothyroidism. At 1 month of life, T4 and TSH were normal. Follow-ups at 3, 6, and 12 months were normal. We conclude that is not necessary to discontinue treatment with amiodarone in pregnant women with resistant tachycardia, but it is imperative to evaluate the thyroid function of the newborn, since transient hypothyroidism may occur.

Prospective and controlled study of ophthalmopathy after radioiodine therapy for Graves' hyperthyroidism.

The effects of radioiodine (131I) therapy for hyperthyroidism on the ocular process of Graves' disease is controversial. In order to evaluate the outcome of ophthalmopathy after radioiodine therapy for thyrotoxicosis we studied prospectively 30 Graves' hyperthyroid patients, 22 submitted to radioiodine (131I) treatment (group A) and 8 treated with antithyroid drugs (group B). All patients were evaluated by clinical ophthalmologic examination, and ocular proptosis (OP) was measured with both a Hertel exophthalmometer (HE) and computed tomography (CT) before and 4 to 7 months after therapy. No statistical difference was obtained between pre- and post-treatment OP measurements in each eye in either group, and we did not observe worsening in the ophthalmopathy of patients treated with drugs or radioiodine. After therapy, there was an improvement in the clinical signs of ophthalmopathy in 59% of group A and in 37.5% of group B patients. We found a significant correlation between OP measured by HE and by CT. CT findings showed an increase in orbital fat and/or muscle thickening in all patients at baseline, proving to be a useful procedure for ophthalmologic diagnosis in doubtful cases. No patient in either group developed hypothyroidism or elevated TSH levels during the study period; this may explain our good results in the evolution of Graves' ophthalmopathy after treatment with 131I and antithyroid drugs. Euthyroidism seems to be an important factor in the outcome of ophthalmopathy after therapy, whatever the mode of treatment chosen to achieve it.

Expression of transforming growth factor beta1, beta2, and beta3 in multinodular goiters and differentiated thyroid carcinomas: a comparative study.

The various isoforms of transforming growth factor-beta (TGFbeta) are growth-inhibiting cytokines for cells of epithelial origin. In malignant thyroid tumors, several studies documented a high expression of TGFbeta in the majority of thyroid follicular cells suggesting a possible role as an inhibitor of cell proliferation. In contrast to this uniform pattern of TGFbeta expression in thyroid cancer, scarce and controversial data have been reported on the expression of TGFbeta in benign multinodular goiter. In the present study, we therefore analyzed the expression of TGFbeta1, TGFbeta2, and TGFbeta3 in normal thyroid tissue, multinodular goiters and papillary thyroid carcinomas by immunohistochemistry. In normal thyroid tissue, expression of the 3 TGFbeta isoforms was barely detectable. However, in the carcinomas, almost all epithelial cells displayed immunoreactivity for the three TGFbeta isoforms. In the nodules from multinodular goiters, all 3 isoforms were found to be expressed although the immunolocalization of the 3 proteins was highly variable. TGFbeta-immunostaining was found in scattered clusters of variable size and, its expression pattern was heterogenous among individual cells within single follicles. TGFbeta-positivity was present in spite of immunostaining for proliferating cell nuclear antigen (PCNA), a marker for actively proliferating cells. In conclusion, this study shows that thyroid carcinomas and benign tumors express the TGFbeta1, TGFbeta2, and TGFbeta3 isoforms. In contrast to the abundant and homogeneous expression in differentiated thyroid carcinomas, TGFbeta expression displays a highly variable interfollicular and intrafollicular pattern in multinodular goiters, suggesting an important role of TGFbeta isoforms in tumorigenesis of thyroid cells.

Thyroid suppression test with a single oral dose of levothyroxine in the diagnosis of functional thyroid autonomy.

OBJECTIVE: To propose a modified form of thyroid suppression test with use of a single oral dose of levothyroxine (35 mg/kg). METHODS: After a baseline scintigram, 23 patients with nodular goiter suspected of autonomous function (warm or hot nodules, subnormal or undetectable thyrotropin levels, or both findings) and 14 normal subjects underwent a repeated scintigram 4 days after administration of levothyroxine. We evaluated triiodothyronine (T(3)), free thyroxine, and thyrotropin before and on the first, second, third, fourth, and seventh days after administration of the individualized dose of levothyroxine. RESULTS: The 99th percentile of postsuppression uptake in normal subjects was determined, and an uptake >12.4%, a 131 I concentration restricted to the nodule, or both factors were adopted as the criteria for diagnosis of an autonomously functioning thyroid nodule. Twelve patients were considered to have autonomously functioning nodules, and 11 patients were considered to have nonautonomous nodules. Baseline thyrotropin levels in patients with autonomous nodules did not differ significantly from those in patients with nonautonomous nodules. No signs or symptoms of toxicity were detected during the test, but all study subjects had increased free thyroxine values, and seven had high levels of T(3). CONCLUSION: The thyroid suppression test with 35 mg/kg of levothyroxine is an effective method for the diagnosis of an autonomously functioning thyroid nodule, is nontoxic, and avoids the inaccurate use of the medication occasionally observed with T(3). Even sensitive methods of thyrotropin determination cannot replace this test in the evaluation of autonomous thyroid function.

Immunohistochemical demonstration of insulin-like growth factor I (IGF-1) in normal and pathological human pituitary glands.

The authors have studied the presence and distribution of Insulin-Like-Growth-Factor-1 (IGF-1) in 5 autopsied normal and 20 surgically removed human pituitary adenomas, employing a peroxidase-anti-peroxidase method. IGF-1 could be demonstrated in all cases, with variation of cells immunostaining from 60% in normal pituitary gland to 100% in corticotroph cell adenoma.