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Biomedical subjects

A Pinchera

Publications and source records attributed to A Pinchera.

At least 91 records · Page 5Linked to original sources
PubMed2000

Effects of hormonal replacement treatment on bone mineral density and metabolism in hypogonadal patients.

We investigated 22 male patients affected by prepubertal hypogonadism with a mean age of 34.3+/-5.2. A significant reduction of bone mineral density (BMD) at both the lumbar spine (L2-L4, -14%, 1.039+/-0.11 vs. 1.217+/-0.16 g/cm(2), P=0.005) and femoral neck (-11%; 0.927+/-0.09 vs. 1.034+/-0.16 g/cm(2), P=0.01) was found in patients compared to age-matched controls. The mean Z score was -1. 55 for vertebrae and -1.33 for femur. Eleven and nine patients, respectively, had a lumbar and femoral BMD at least 1 S.D. below the normal mean; 8 and 4, respectively, 2 S.D. below. There was a strong positive correlation between BMD and duration of hormone replacement treatment (HRT) for both sites: respectively, r=0.71, P<0.005 for the vertebrae, and r=0.60, P<0.01 for the femur. A weak correlation was also present between onset of HRT and BMD: r=0.6, P<0.01 at the lumbar level, and r=0.47, P<0.05 at the femoral neck.

Adult↗
PubMed2000

Role of megalin (gp330) in transcytosis of thyroglobulin by thyroid cells. A novel function in the control of thyroid hormone release.

When thyroglobulin (Tg) is endocytosed by thyrocytes and transported to lysosomes, thyroid hormones (T4 and T3) are released. However, some internalized Tg is transcytosed intact into the bloodstream, thereby avoiding proteolytic cleavage. Here we show that megalin (gp330), a Tg receptor on thyroid cells, plays a role in Tg transcytosis. Following incubation with exogenous rat Tg at 37 degrees C, Fisher rat thyroid (FRTL-5) cells, a differentiated thyroid cell line, released T3 into the medium. However, when cells were incubated with Tg plus either of two megalin competitors, T3 release was increased, suggesting that Tg internalized by megalin bypassed the lysosomal pathway, possibly with release of undegraded Tg from cells. To assess this possibility, we performed experiments in which FRTL-5 cells were incubated with either unlabeled or (125)I-labeled Tg at 37 degrees C to allow internalization, treated with heparin to remove cell surface-bound Tg, and further incubated at 37 degrees C to allow Tg release. Intact 330-kDa Tg was released into the medium, and the amount released was markedly reduced by megalin competitors. To investigate whether Tg release resulted from transcytosis, we studied FRTL-5 cells cultured as polarized layers with tight junctions on permeable filters in the upper chamber of dual chambered devices. Following the addition of Tg to the upper chamber and incubation at 37 degrees C, intact 330-kDa Tg was found in fluids collected from the lower chamber. The amount recovered was markedly reduced by megalin competitors, indicating that megalin mediates Tg transcytosis. We also studied Tg transcytosis in vivo, using a rat model of goiter induced by aminotriazole, in which increased release of thyrotropin induces massive colloid endocytosis. This was associated with increased megalin expression on thyrocytes and increased serum Tg levels, with reduced serum T3 levels, supporting the conclusion that megalin mediates Tg transcytosis. Tg transcytosis is a novel function of megalin, which usually transports ligands to lysosomes. Megalin-mediated transcytosis may regulate the extent of thyroid hormone release.

Amitrole↗
PubMed2000

Six novel MEN1 gene mutations in sporadic parathyroid tumors.

We report nine mutations of the multiple endocrine neoplasia type 1 (MEN1) gene in sporadic parathyroid adenomas. Six of them have not previously been described: E60X, P32R, 261delA, 934+2T-->G, S443P, and 1593insC. The tissue samples were initially submitted to LOH analysis at 11q13 followed by SSCP screening of LOH-positive samples. Mutations were identified by direct sequencing and subcloning. Three (E60X, P32R, and 261delA) were in exon 2, one (934+2bp) in the splice junction of exon 5, one (S443P) in exon 9, and one (1593insC) in exon 10. The 3 mutations in exon 2 were associated with loss and/or creation of a restriction site. The corresponding germline sequence of the MEN1 gene was normal. Most mutations would likely result in a nonfunctional menin protein, and therefore in the loss of a tumor suppressor protein.

Adenoma↗
PubMed2000

RET proto-oncogene mutations in thyroid carcinomas: clinical relevance.

Different forms of RET mutations are found in papillary and medullary thyroid carcinomas. Rearrangements with other genes (RET/PTC oncogene) play a causative role in a significant proportion of papillary thyroid carcinomas. In this case, several factors influence the frequency and the type of RET/PTC, such as exposure to radiation, age and histological variant of the papillary tumor. On the other hand, the presence of the mutation does not seem to influence the biological behavior of the tumor or its response to conventional treatment modalities. In the setting of medullary thyroid cancer, germline RET point-mutations are implicated in the pathogenesis of virtually all hereditary forms and somatic point-mutations in nearly half of the sporadic forms. The clinical impact of this finding is that family members at-risk of hereditary MTC may be screened by genetic analysis, to distinguish those carrying or not-carrying the mutation. The last can be reassured on their status and relieved from further follow-up. Those with the mutation may be treated at a pre-clinical stage of the disease or even before the disease is started. The present review is focused on the clinical implication of RET gene mutations in thyroid cancer patients.

Carcinoma, Medullary↗
PubMed2000

Thyroid and lipid metabolism.

Thyroid hormones influence all major metabolic pathways. Their most obvious and well-known action is an increase in basal energy expenditure obtained acting on protein, carbohydrate and lipid metabolism. With specific regard to lipid metabolism, thyroid hormones affect synthesis, mobilization and degradation of lipids, although degradation is influenced more than synthesis. The main and best-known effects on lipid metabolism include: (a) enhanced utilization of lipid substrates; (b) increase in the synthesis and mobilization of triglycerides stored in adipose tissue; (c) increase in the concentration of non-esterified fatty acids (NEFA); and (d) increase of lipoprotein-lipase activity. While severe hypothyroidism is usually associated with an increased serum concentration of total cholesterol and atherogenic lipoproteins, the occurrence of acute myocardial infarction (AMI) in hypothyroid patients is not frequent. However, hypothyroid patients appear to have an increased incidence of residual myocardial ischemia following AMI. Even in subclinical hypothyroidism, which is characterized by raised serum TSH levels with normal serum thyroid hormone concentrations, mild hyperlipidemia is present and may contribute to an increased risk of atherogenesis. Prudent substitution therapy with L-thyroxine is indicated in patients with both overt and subclinical hypothyroidism, with or without angina, to counteract the cardiovascular risk resulting from hyper-dyslipidemia.

Adipose Tissue↗
PubMed2000

Soluble interleukin-1 receptor antagonist concentration in patients with Graves' ophthalmopathy is neither related to cigarette smoking nor predictive of subsequent response to glucocorticoids.

OBJECTIVE: The aim of the present study was to evaluate serum soluble interleukin-1 receptor antagonist (sIL-1RA) concentration and its relationship with the degree of cigarette smoking in patients with Graves' ophthalmopathy (GO). DESIGN AND SUBJECTS: Twenty-two consecutive GO patients (20 women, two men; age range 25-68 years, mean 48 years; 12 smokers, 10 non-smokers) submitted to IV glucocorticoid pulses over a 3-month period. MEASUREMENTS: sIL-1RA levels were measured by an immunoenzymatic assay (sensitivity, 4 ng/l; normal range, 50-290 ng/l) before glucocorticoid treatment, after two months of therapy, and 3 months after drug withdrawal. RESULTS: Thirteen patients responded to treatment (59%; five smokers and eight non-smokers), nine were non-responders (41%; seven smokers and two non-smokers). Baseline median sIL-1RA concentration did not differ in smokers and non-smokers (222 and 173 ng/l, respectively; P = 0.69). Likewise, no significant differences were found between the two groups during treatment (537 and 389 ng/l, respectively; P = 0.28); sIL-1RA concentration after treatment was higher in smokers (258 vs. 94 ng/l; P = 0.02). There was no correlation between basal sIL-1RA levels and the degree of cigarette smoking. Likewise, there was no difference in sIL-1RA levels in responders and non-responders, either at baseline (186 vs. 216 ng/l; P = 0.83), during or after treatment. CONCLUSION: Our study suggests that circulating soluble interleukin-1 receptor antagonist levels, both at baseline and during glucocorticoid treatment, are neither influenced by cigarette smoking nor predictive of subsequent response to glucocorticoid treatment.

Adult↗
PubMed2000

New breakpoints in both the H4 and RET genes create a variant of PTC-1 in a post-Chernobyl papillary thyroid carcinoma.

Two main types of RET/PTC oncogene, named RET/PTC-1 and 3, occur in papillary thyroid carcinomas especially in those from Belarus children after the Chernobyl nuclear accident. Several variants of RET/PTC-3 have also been found, having different break points with respect to the classical RET/PTC-3. To our knowledge, no variant of RET/PTC-1 has been described up to now. We found a post-Chernobyl papillary thyroid carcinoma with an RET/PTC-1 rearrangement characterized by a transcript longer than expected. Sequence analysis of the PCR product obtained after RT-PCR revealed new fusion points between H4 and RET genes. The genomic sequence showed new breakpoints in both H4 intronic and in RET exonic regions. The RET gene breakpoint occurred within exon 11, at variance with the classical form of RET/PTC-1, in which it is in intron 11. As a consequence of this new fusion point, the transcript included 132 nucleotides of exon 11, coding for 44 amino acids of RET protein. Regarding the H4 gene, the classical breakpoint is in the first intron and the cDNA contains a fragment of 339 nucleotides. In our case the cDNA had a longer fragment of H4 involving a total of 1266 nucleotides. Sequencing of genomic DNA revealed a rearrangement breakpoint at position 886 of a new H4 intron located downstream of the 1266 coding region. Furthermore, as a consequence of the activation of a cryptic splicing site, 132 nucleotides of this intron were spliced between the H4 and RET genes. Sequence analysis of the new chimera showed that the original frames of H4 and RET were joint with the intronic sequence without disruption of the open reading frame (ORF). Moreover, the genomic DNA of this case showed transforming activity in the DNA-mediated transfection assay using NIH-3T3 cells. In conclusion, we describe here the first variant of RET/PTC-1 oncogene, which we have termed 'long'-PTC-1, characterized by new breakpoints of both genes involved in the rearrangement and having transforming activity. Similar to previously reported PTC-3 variants, long-PTC-1 has been found in a post-Chernobyl papillary thyroid carcinoma confirming that RET/PTC rearrangements other than the classical forms (RET/PTC-1 and -3) are specifically associated with radiation-induced papillary thyroid cancer.

Carcinoma, Papillary↗
PubMed2000

Contrast-enhanced color Doppler ultrasonography in suspected parathyroid lesions.

PURPOSE: To assess the usefulness of US contrast media in the evaluation of patients with primary hyperparathyroidism, with a nodule showing US features of a primary parathyroid lesion but lacking the color Doppler US appearance of a parathyroid mass. MATERIAL AND METHODS: Thirteen patients (7 female, 6 male; age range 51-79 years) were examined with US before and after administration of a stabilized galactose-based microbubble contrast agent. Ten patients underwent surgery and the final histological examination demonstrated parathyroid adenoma in 9 cases and a mesenchymal benign nodule in 1 case. Three nodules were proved to be of thyroid origin at fine-needle aspiration biopsy. RESULTS AND CONCLUSION: The use of a US contrast agent resulted in a diagnostic gain compared to unenhanced studies in 12/13 cases. Color Doppler findings characteristic of parathyroid lesions were observed in 7/13 cases, of thyroid nodules in 4/13 cases, and nonspecific patterns in 2/13 cases. Contrast-enhanced color Doppler US can be proposed in selected patients in whom unenhanced color Doppler provides uncertain findings. Its ideal application should be the evaluation of cervical lesions without detectable intranodular flow at unenhanced Doppler studies. In these cases, the contrast agent helps in visualizing typical color Doppler signals of the parathyroid lesions ("vascular pole" and "mixed pattern").

Adenoma↗
PubMed2000

Neuropsychological follow-up in early-treated congenital hypothyroidism: a problem-oriented approach.

Screening programs for congenital hypothyroidism (CH) dramatically improved the neuropsychological prognosis in affected children. However, mild impairments in cognitive performances, poorer motor skills, defective language abilities, and learning problems have been reported in some studies of early-treated CH children. The occurrence of these defects makes neuropsychological follow-up mandatory. The aim of the present study was to identify those neuropsychological functions that are more frequently affected in early-treated CH children and that might require prompt rehabilitation treatment to prevent permanent defects. The study group involved 24 CH children. Levothyroxine (LT4) treatment (initial dose 8-10 microg/kg per day) was started at mean age of 28 days (range 15-45) and was then adjusted with the goal to keep thyrotropin (TSH) and free thyroid hormone levels in the normal range. Cognitive evaluation was performed at 3, 5, and 7 years of age and did not significantly differ from that of controls. Mean neurological scores were lower in children 5 years of age than in controls. Children with severe neonatal hypothyroidism (serum thyroxine [T4] < 2 microg/dL) had significantly lower neurological scores compared to less affected CH children and normal controls. The most affected functions were balance, extremity coordination, fine motricity, quality of movements, associated movements, and head movements. Language disorders were observed in half of CH children at 3 and 5 years of age, but moderately severe defects were restricted to those with severe neonatal hypothyroidism. In conclusion, a problem-oriented, simplified neuropsychological follow-up of early-treated children with CH should not systematically include the frequent repetition of time-consuming and expensive psychometric tests because individual IQ scores are in the normal range of tests in almost all CH children and can be differentiated from those of normal controls only on a population-statistic basis. Selected tests of motor proficiency are indicated at 3 and 5 years of age to detect those defects in motor skills that appear to be more specifically affected in CH children. Language performances are at particular risk in CH children, and should be always checked at 3 and 5 years of age. Children with even mild language disorders or delayed language achievements should be regularly reevaluated at 6-month intervals and, if no spontaneous improvement is observed, they should receive specific rehabilitation treatment. No further motor and language evaluation is warranted in CH children with normal tests at age 5 years.

Child↗
PubMed2000

Cyclin D1 overexpression in thyroid carcinomas: relation with clinico-pathological parameters, retinoblastoma gene product, and Ki67 labeling index.

Cyclin D1 is a G1 cyclin participating in the control of cell cycle progression through interaction with the retinoblastoma gene product (pRB). The overexpression of positive regulators (such as cyclin D1) has been reported in a variety of neoplasms, but their role in thyroid tumorigenesis is yet to be established. In our series of 54 thyroid carcinomas, cyclin D1 overexpression (detected by both immunohistochemistry and by Northern blotting) was correlated with prognostic variables, proliferative activity and pRB. Cyclin D1 overexpression was observed in 35% of thyroid carcinomas with a significantly higher expression of this cyclin in neoplastic tissues than in matched normal parenchyma. In well-differentiated carcinomas, the cyclin D1 mRNA overexpression was inversely correlated with nodal status (p = 0.03), while the protein product was higher in tumors from patients less than 40 than patients over 40 years of age. Inversely, there was no significant correlation with gender and tumor status, pRB and with proliferative activity.

Adenocarcinoma, Follicular↗
PubMed2000

Increased frequency of euthyroid ophthalmopathy in patients with Graves' disease associated with myasthenia gravis.

We previously showed that myasthenia gravis (MG) has a mild clinical expression when associated with autoimmune thyroid diseases (AITD). In the present study we have investigated the frequency of thyroid-associated ophthalmopathy (TAO) in patients with Graves' disease (GD) associated with MG as compared with GD patients without MG. A total of 418 patients with GD were studied, 31 with MG and 387 without MG. TAO was evaluated by physical examination, exophthalmometry, computerized tomography, and computerized visual fields assessment. The overall prevalence of TAO was similar in GD patients with MG (61.2%) and in those without MG (56.4%). When the analysis was restricted to GD patients with ocular MG, a greater frequency of TAO was found (84.6%), compared with GD patients without MG or with GD patients with generalized MG, although the differences did not reach the statistical significance. GD patients with MG had a significantly greater prevalence (12.9%) of euthyroid ophthalmopathy (clinically overt ophthalmopathy without previous and/or current hyperthyroidism) than those without MG (3.1%; p = 0.003). The results suggest a preferential association between the ocular manifestations of GD and MG, which may be due to immunological cross-reactivity against common autoimmune targets in the eye muscle as well as to a common genetic background.

Adult↗
PubMed2000

Sporadic nonautoimmune congenital hyperthyroidism due to a strong activating mutation of the thyrotropin receptor gene.

The de novo occurrence of germline-activating thyrotropin receptor (TSHR) gene mutations has been reported as the cause of sporadic nonautoimmune neonatal hyperthyroidism in eight children. We report the case of an Italian infant girl who presented at birth with severe hyperthyroidism and goiter. Ultrasonografic examination of the infant's thyroid showed a diffuse goiter with a normal echogenic pattern. Serum antithyroglobulin, antithyroperoxidase, and antithyrotropin receptor antibodies were undetectable. Treatment with propylthiouracyl, propranolol, and saturated potassium iodide solution started at 44 days of life with the resolution of thyrotoxic symptoms. Once euthyroidism was achieved, the dose of propylthiouracyl was tapered, but hyperthyroidism recurred. Auxological parameters showed an acceleration of linear growth and bone age. DNA was extracted from peripheral white blood cells of the patient, the sister, and the two parents. All of exon 10 of the TSHR gene was amplified by polymerase chain reaction (PCR) and subjected to direct sequencing. In the thyrotoxic infant girl, a substitution of cytosine to thymine was detected, changing isoleucine 568 into a threonine (1568T), located in the second extracellular loop. The normal sequence could also be detected, indicating heterozygosis of the mutated allele. This mutation was previously described as a somatic mutation in a patient with toxic thyroid adenoma. The sister and the parents of the propositus, all euthyroid, showed the wild-type TSHR gene. In conclusion, we describe a case of a de novo germinal mutation of the TSHR causing severe congenital hyperthyroidism.

Adenoma↗
PubMed2000

Management of Graves' ophthalmopathy: reality and perspectives.

Graves' ophthalmopathy is an debilitating disease impairing the quality of life of affected individuals. Despite recent progress in the understanding of its pathogenesis, treatment is often not satisfactory. In mild cases, local therapeutic measures (artificial tears and ointments, sunglasses, nocturnal taping of the eyes, prisms) can control symptoms and signs. In severe forms of the disease (3-5%), aggressive measures are required. If the disease is active, high-dose glucocorticoids and/or orbital radiotherapy, or orbital decompression represent the mainstay of treatment. If the disease is severe but inactive, orbital decompression is preferred. Novel treatments such as somatostatin analogs or intravenous immunoglobulins are under evaluation. Rehabilitative (extraocular muscle or eyelid) surgery is often needed after treatment and inactivation of eye disease. Correction of both hyper- and hypothyroidism is crucial for the ophthalmopathy. Antithyroid drugs and thyroidectomy do not influence the course of the ophthalmopathy, whereas radioiodine treatment may cause the progression of preexisting ophthalmopathy, especially in smokers. The exacerbation, however, is prevented by glucocorticoids. In addition, thyroid ablation may prove beneficial for the ophthalmopathy in view of the pathogenetic model relating eye disease to autoimmune reactions directed against antigens shared by the thyroid and the orbit.

Animals↗
PubMed2000

Parathyroid expression of calcium-sensing receptor protein and in vivo parathyroid hormone-Ca(2+) set-point in patients with primary hyperparathyroidism.

A reduced expression of calcium-sensing receptor (CaR) messenger ribonucleic acid and protein accompanied by abnormalities in parathyroid cell proliferation and PTH secretion are present in primary hyperparathyroidism. We studied the expression of CaR protein by immunohistochemistry in 36 sporadic parathyroid adenomas and investigated the relationship between CaR expression and several preoperative clinical parameters, including the set-point of Ca(2+)-regulated PTH secretion (measured in vivo). The adenomas were classified in 4 categories according to the intensity of immunohistochemical staining: 5 (14%) showed a CaR staining intensity similar to that of normal parathyroid ( ), 10 (27%) showed moderate staining (++), 16 (45%) showed weak staining (+), and 5 (14%) were negative (-). The intensity of CaR staining was not related to preoperative serum Ca(2+), PTH levels or adenoma volume. Twenty-nine patients underwent preoperatively the calcium infusion test to evaluate the PTH-Ca(2+) set-point. Individual values of PTH-Ca(2+) set-point ranged from 1.38-1.93 mmol/L and were significantly correlated with basal Ca(2+) levels (r = 0.96; P: = 0. 0001) and adenoma volume (r = 0.5; P: = 0.01). The mean PTH-Ca(2+) set-point values were significantly different in the 4 groups of patients classified according to immunohistochemical staining intensity of their adenoma (P: = 0.025; F = 3.78); the mean PTH-Ca(2+) set-point was significantly higher in the groups classified as negative than in those classified as weak or moderate. No correlation was observed between the PTH-Ca(2+) set-point and basal PTH levels or between the percent maximal PTH inhibition and adenoma volume and basal PTH or Ca(2+) levels. In summary, our data suggest that there is a relationship between apparent CaR protein expression and PTH-Ca(2+) set-point abnormality, suggesting that a reduced receptor content might have an important role in the pathogenesis of primary hyperparathyroidism.

Adenoma↗
PubMed2000

Congenital hypothyroidism with impaired thyroid response to thyrotropin (TSH) and absent circulating thyroglobulin: evidence for a new inactivating mutation of the TSH receptor gene.

Congenital hypothyroidism due to impaired thyroid response to TSH was originally described by Stanbury. A diagnosis of congenital hypothyroidism with thyroid unresponsiveness to TSH is accepted if the patient has congenital hypothyroidism, the thyroid gland is in the normal position in the neck, the size of the thyroid is either normal or atrophic, the serum TSH level is increased, the bioactivity of TSH is intact, and the response of the thyroid gland to TSH stimulation is decreased. In all originally described cases serum thyroglobulin was undetectable. We describe a 22-yr-old female patient who was severely hypothyroid and mentally retarded. Serum T4 and T3 concentrations were below the sensitivity of the methods, with elevated serum TSH levels. Serum thyroglobulin was undetectable. A normally shaped hypoplastic gland located in the appropriate anatomical position in the neck was found at scintiscan. The gland did not respond after administration of bovine TSH in terms of 131I uptake, serum thyroid hormones, and thyroglobulin secretion. A diagnosis of congenital hypothyroidism due to TSH unresponsiveness was formulated. Genetic analysis in the propositus showed a homozygous inactivating mutation of the TSH receptor that had not been previously described. The mutation consisted of the substitution of an isoleucine in place of a highly conserved threonine at position 477 in the first extracellular loop of the receptor (T477I). The brother, one sister of the father (whose DNA was not available), the mother of the propositus, one sister, and the brother were heterozygous for T477I. All the heterozygous persons were unaffected. After transfection in COS-7 cells, the mutant receptor displayed an extremely low expression at cell surface. At variance with cells transfected with the wild-type TSH receptor, cells transfected with the mutant T477I did not show constitutive activity for the adenylyl cyclase pathway. A dramatic reduction in the amount of cAMP accumulation after bovine TSH challenge was observed in cells transfected with the mutant T477I receptor. A structural defect in the mutant TSH receptor protein was probably responsible for the poor routing of the receptor to the cell membrane. This is the first time that a loss of function mutation of the TSH receptor is described in a patient with severe congenital hypothyroidism and absent circulating thyroglobulin due to TSH unresponsiveness and the first time that an inactivating mutation of the TSH receptor is described in the first extracellular loop.

Adult↗
PubMed2000

Activating thyrotropin receptor mutations are present in nonadenomatous hyperfunctioning nodules of toxic or autonomous multinodular goiter.

Toxic multinodular goiter, a heterogeneous disease producing hyperthyroidism, is frequently found in iodine-deficient areas. The pathogenesis of this common clinical entity is still unclear. The aim of the present study was to search for activating TSH receptor (TSHr) or Gs alpha mutations in areas of toxic or functionally autonomous multinodular goiters that appeared hyperfunctioning at thyroid scintiscan but did not clearly correspond to definite nodules at physical or ultrasonographic examination. Surgical tissue specimens from nine patients were carefully dissected, matching thyroid scintiscan and thyroid ultrasonography, to isolate hyperfunctioning and nonfunctioning areas even if they did not correspond to well-defined nodules. TSHr and Gs alpha mutations were searched for by direct sequencing after PCR amplification of genomic DNA. Only 2 adenomas were identified at microscopic examination, whereas the remaining 18 hyperfunctioning areas corresponded to hyperplastic nodules containing multiple aggregates of micromacrofollicules not surrounded by a capsule. Activating TSHr mutations were detected in 14 of these 20 hyperfunctioning areas, whereas no mutation was identified in nonfunctioning nodules or areas contained in the same gland. No Gs alpha mutation was found. In conclusion, activating TSHr mutations are present in the majority of nonadenomatous hyperfunctioning nodules scattered throughout the gland in patients with toxic or functionally autonomous multinodular goiter.

Adenoma↗