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.

Pendred's syndrome: identification of the genetic defect a century after its recognition.

Pendred's syndrome is an autosomal recessive disease characterized by goiter and congenital sensorineural deafness. Most patients with Pendred's syndrome are euthyroid, but the perchlorate test is positive indicating an impaired iodide organification. The sensorineural deafness is typically associated with a malformation of the inner ear, referred to as Mondini cochlea.

Phenocopies for deafness and goiter development in a large inbred Brazilian kindred with Pendred's syndrome associated with a novel mutation in the PDS gene.

Pendred's syndrome is an autosomal recessive disease characterized by goiter, impaired iodide organification, and congenital sensorineural deafness. The gene mutated in Pendred's syndrome, PDS (Pendred's syndrome gene), was cloned very recently and encodes the putative sulfate transporter pendrin. Pendred's syndrome may account for up to 10% of the cases with hereditary hearing loss, and pendrin mutations have also been found in a kindred with non-syndromic deafness.

A novel aminoterminal mutation in the KAL-1 gene in a large pedigree with X-linked Kallmann syndrome.

Kallmann syndrome is characterized by hypogonadotropic hypogonadism and anosmia. Autosomal dominant, autosomal recessive, and X-linked patterns of transmission have been described. The X-linked form of Kallmann syndrome (XLKS) is the least common of the three modes of inheritance and is caused by mutations in the putative cell adhesion protein, KAL-1.

Autosomal recessive deficiency of combined pituitary hormones (except ACTH) in a consanguineous Brazilian kindred.

Familial hypopituitarism represents a clinically and genetically heterogeneous disorder. In a subset of these families, defects in Pit-I, a transcription factor essential for proper pituitary development have been identified as underlying molecular cause. These patients present extreme short stature, GH, PRL and TSH deficiency but intact ACTH, LH and FSH secretion.

The thyroid hormone receptor variant alpha2 is a weak antagonist because it is deficient in interactions with nuclear receptor corepressors.

The thyroid hormone receptor splice variant, alpha2, is unable to bind thyroid hormone (T3) and has been proposed to function as an endogenous inhibitor of T3 action. In this report, we examined further the DNA sequence requirements for alpha2 binding to thyroid hormone response elements (TREs) in an attempt to identify response elements that mediate potent inhibition by alpha2. Heterodimers of alpha2 and retinoid X receptor were found to bind to a subset of TREs (DR4, direct repeats spaced by 4 bp) in which selected flanking and spacer sequences enhanced interactions with the AGGTCA core binding sequence.

Congenital nonautoimmune hyperthyroidism in a nonidentical twin caused by a sporadic germline mutation in the thyrotropin receptor gene.

Congenital hyperthyroidism is usually caused by maternal-to-fetal transfer of thyroid-stimulating antibodies from a mother with autoimmune thyroid disease. Very recently, activating thyrotropin (TSH) receptor germline mutations were detected in a few patients with sporadic nonautoimmune congenital hyperthyroidism, as well as in familial forms of nonautoimmune hyperthyroidism defining a new pathophysiological entity of hyperthyroidism. In this report, we describe a nonidentical twin girl with severe congenital hyperthyroidism.

Autosomal recessive deficiency of combined pituitary hormones (except ACTH) in a consanguineous Brazilian kindred.

Familial hypopituitarism represents a clinically and genetically heterogeneous disorder. In a subset of these families, defects in Pit-I, a transcription factor essential for proper pituitary development have been identified as underlying molecular cause. These patients present extreme short stature, GH, PRL and TSH deficiency but intact ACTH, LH and FSH secretion.

Congenital hyperthyroidism caused by a solitary toxic adenoma harboring a novel somatic mutation (serine281-->isoleucine) in the extracellular domain of the thyrotropin receptor.

Activating somatic mutations in the thyrotropin (TSH) receptor have been identified as a cause of hyperfunctioning thyroid adenomas, and germline mutations have been found in familial nonautoimmune hyperthyroidism and sporadic congenital hyperthyroidism. All mutations reported to date have been located in the transmembrane domain. We now report an example of an activating mutation in the extracellular, TSH-binding domain, found in a male infant with congenital hyperthyroidism due to a toxic adenoma.

Clonal X-inactivation analysis of human tumours using the human androgen receptor gene (HUMARA) polymorphism: a non-radioactive and semiquantitative strategy applicable to fresh and archival tissue.

Assessment of clonality of cellular proliferations is important in experimental and clinical cancer research. X-chromosome inactivation studies are widely used to assess clonality, but most assays require relatively large amounts of high molecular weight DNA. Two PCR-based strategies, the phosphoglycerate kinase (PGK) and the human androgen receptor (HUMARA) clonality assays allow studies of small tissue samples.

Expression of nitric oxide synthase III in human thyroid follicular cells: evidence for increased expression in hyperthyroidism.

Nitric oxide mediates a wide array of cellular functions in many tissues. It is generated by three known isoforms of nitric oxide synthases (NOS). Recently, the endothelial isoform, NOSIII, was shown to be abundantly expressed in the rat thyroid gland and its expression increased in goitrous glands.

Adherence of Borrelia burgdorferi to granulocytes of different animal species.

Adherence of 4 Borrelia (B.) burgdorferi strains (z7/22, z7/27, z7/41, PBi) to polymorphonuclear granulocytes from different domestic animals (horses, cattle, sheep, dogs) was investigated. All 4 strains adhered to the granulocytes.

Sexually dimorphic transcriptional responses to gonadotropin-releasing hormone require chronic in vivo exposure to estradiol.

GnRH regulates secretion of the gonadotropins, LH and FSH, in a sexually dimorphic manner. In the present study, we examined GnRH regulation of the gonadotropin alpha-subunit promoter to assess whether sex-dependent hormonal effects are manifest at the transcriptional level. Primary cultures of male or female rat pituitary cells were transfected with a reporter gene containing the alpha-promoter linked to luciferase (-420 alpha-LUC) and then subjected to treatment with GnRH for 24 h.

Second zinc finger mutants of thyroid hormone receptor selectively preserve DNA binding and heterodimerization but eliminate transcriptional activation.

Transcriptional regulation by thyroid hormone is mediated through its nuclear receptors (TRs), which bind to target responsive elements as homodimers or as heterodimers with 9-cis retinoic acid receptors (RXRs). We examined the dimerization and functional properties of TRs containing mutations in the first and second zinc finger regions of the DNA binding domain. Interestingly, a mutation (R158G) in the loop of second zinc finger, or a chimeric mutant in which the second zinc finger of the glucocorticoid receptor (GR) was substituted for that of the TR, did not form homodimer, but still bound as a heterodimer with RXR alpha.

Constitutive activation of the Gs alpha protein-adenylate cyclase pathway may not be sufficient to generate toxic thyroid adenomas.

In toxic thyroid adenomas, mutations in the TSH receptor (TSH-R) gene or the gene encoding the alpha-subunit of the stimulatory guanine nucleotide-binding protein (Gs alpha) have been demonstrated to constitutively activate the cAMP cascade, which subsequently stimulates the growth and function of these tumors. However, the widely varying thyroid phenotypes in patients with TSH-R germline mutations, ranging from only slightly enlarged diffuse to multinodular goiters, suggest that additional mechanisms may be effective in the pathogenesis of toxic adenomas. We have investigated the levels of stimulatory and inhibitory G protein alpha-subunits together with basal and TSH-stimulated adenylate cyclase (AC) activity in toxic adenomas with or without activating mutations and in nodular and extranodular tissues of a toxic goiter due to a germline mutation in the TSH-R gene.

Syndrome of resistance to thyroid hormone: insights into thyroid hormone action.

Thyroid hormones (T3, T4) exert multiple cellular effects through nuclear thyroid hormone receptors (TR alpha, TR beta). Thyroid hormone receptors are transcription factors that act by altering patterns of gene expression. Resistance to thyroid hormone (RTH) is a rare disorder caused by mutations in the TR beta gene.

Thyroid hormone (T3) inhibits ciprofibrate-induced transcription of genes encoding beta-oxidation enzymes: cross talk between peroxisome proliferator and T3 signaling pathways.

Peroxisome proliferators cause rapid and coordinated transcriptional activation of genes encoding peroxisomal beta-oxidation system enzymes by activating peroxisome proliferator-activated receptor (PPAR) isoform(s). Since the thyroid hormone (T3; 3,3',5-triiodothyronine) receptor (TR), another member of the nuclear hormone receptor superfamily, regulates a subset of fatty acid metabolism genes shared with PPAR, we examined the possibility of interplay between peroxisome proliferator and T3 signaling pathways. T3 inhibited ciprofibrate-induced luciferase activity as well as the endogenous peroxisomal beta-oxidation enzymes in transgenic mice carrying a 3.

Isolation and characterization of fibronectin-binding sites of Borrelia garinii N34.

Adherence of bacteria to host cell membranes is one of the initial steps of microbial pathogenicity. Numerous studies have suggested that fibronectin promotes this interaction in some bacterial species. In this study, we have examined the ability of Borrelia garinii to bind fibronectin.