The Natural Thyroid Diet

Thyroid Factor

Thyroid Factor is a program that was created by Dawn Sylvester to help women deal with thyroid issues. Dawn Sylvester is a 57 years old lady that has worked with 1,000's of real women. She has over the time tried to investigate the underlying reason why majority of women lose energy and also struggle with belly fat and fatigue as they age. It is a comprehensive program thatcomprises of Thyro pause, 11 kinds of thyroid saving foods that will work to help you boost fat burning Free T3. The program also teaches you all the hidden causes of thyroid which are making you fat and later a highly reliable Thyroid reboot plan which is an excellent plan you need to tackle your weight. Additionally, there are tips to reduce bulging fat fast and eventually obtain a healthy body. You also get several bonuses all aimed at helping you solve all the problems that comes with being overweight. The three bonuses you get are 21 Day Thyroid weight loss system, 101 Thyroid boosting foods and Thyroid Jumpstart Guide. More here...

Thyroid Factor Summary


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Vitamin D3 and Thyroid Receptors

Thyroid hormone receptors (TRa and TRjS) exhibit multiple modes of DNA binding, including both homodimerization and RXR het-erodimerization on a number of diverse response elements, where they can both activate and silence transcription, depending on the promoter context. The TRs are activated by triiodothyro-nine (T3), and physiological roles for these receptors include regulation of thyroid and pituitary tropic hormone production, affecting a variety of CNS and metabolic functions. Dominant human mutations within the TRfi gene (but not TRa) have been characterized, and individuals carrying these mutations display clinical symptoms of generalized resistance to thyroid hormone.362 The mutations interfere with ligand binding but not dimerization or DNA binding and likely represent dominant negative mutations.

Thyroid Stimulating Hormone Receptor

The growth and function of the thyroid are controlled by thyrotropin through activation of the thyroid-stimulating hormone (TSH) receptor.36 Mutations in TSH receptors are found in approximately 30 of all human thyroid adenomas.37 In recent years, various constitutively active mutations within the TSH receptor were identified and shown to be associated with continuous stimulation of the cAMP pathway, causing hyperthyroidism and thyroid hyperplasia. Similarly, in Graves' disease, autoantibodies mimic the action of thyrotropin,38 leading to activation of this receptor. Thyroid carcinogenesis, however, is associated with constitutively activating receptor mutants and an activating mutation within the Ras gene, suggesting that both the Ras and TSH mutations act synergistically to cause the tumor phenotype in some differentiated thyroid carcinomas.39

Thyroid Hormone Binding Site

FIGURE 6-11 Model of thyroxine-binding prealbumin (TBPA). The schematic model is derived from X-ray crystallographic studies of prealbumin, illustrating the interaction of four identical subunits forming a channel through the interior of the molecule, thereby forming two identical thyroid hormone-binding sites. The channel narrows at the center of the molecule. Although the binding sites are identical, T4 binds cooperatively occupation of T4 at one site presumably alters the conformation of the second site, which results in a lower affinity for the second T4-binding interaction. Depicted on the upper and lower sides of the molecule is a symmetric 3-pleated sheet structure that is relatively rich in amino acids with ionic side chains and that also contains tryptophan molecules. On the basic of computer graphic modeling studies, this site has been proposed to be a DNA-binding site. Reproduced with permission from Eberhardt, N. L., Apriletti, J. W., and Baxter, J. D. (1980). The...

Thyroid and other endocrine disorders

Thyroid disorders can be a diagnostic trap in family practice and early diagnosis is a real challenge. A family practice of 2500 patients can expect one new case of thyroid disorder each year and ten 'cases' in the practice with a slight preponderance of hyperthyroid patients compared with hypothyroid patients. 1 The diagnosis of an overactive or underactive thyroid can be difficult as the early clinical deviations from normality can be subtle. The clinical diagnosis of classical Graves' disease is usually obvious with the features of exophthalmos, hyperkinesis and a large goitre but if the eye and neck signs are absent it can be misdiagnosed as an anxiety state. Elderly patients may present with only cardiovascular signs such as atrial fibrillation and tachycardia or with unexplained weight loss. The hypothyroid patient can be very difficult to diagnose in the early stages, especially if the patient is being seen frequently. Hypothyroidism often has a gradual onset with general...

Thyroidstimulating hormone free thyroxine triiodothyronine

Thyroid autoantibodies Raised autoantibodies (antimicrosomal or antithyroid peroxidase) are suggestive of Hashimoto's disease (autoimmune thyroiditis). This is the single most cost-effective investigation in the diagnosis of thyroid nodules. It is the best way to assess a nodule for malignancy. Care needs to be taken in the interpretation of the cytology results in conjunction with an experienced cytologist pathologist. Thyroid isotope scan The scan may help in the differential diagnosis of thyroid nodules. A functioning nodule is said to be less likely to be malignant than a nonfunctioning nodule (cyst, colloid nodule, haemorrhage and carcinoma are not functioning). Thyroid ultrasound A thyroid ultrasound is usually more sensitive in the detection of thyroid nodules. A multinodular goitre may be diagnosed on ultrasound while the clinical impression may be that of a solitary nodule (the other nodules not being palpable clinically). A multinodular goitre is said to be less likely to be...

Classification Thyroid Problem

The thyroid-problem is a real world problem. The individual's task is to classify humans thyroid function. The dataset was obtained from the UCI-repository (Blake and Merz, 1998). It contains 3772 training and 3428 testing samples, each measured from one patient. A fitness case consists of a measurement vector containing 15 binary and 6 real valued entries of one human being and the appropriate thyroid function (class). There are three different classes for the function of the thyroid gland, named hyper function, hypo function and normal function. As Gathercole (Gathercole, 1998) already showed, two out of these three classes, the hyper function and the hypo function, are linearly separable. Given the measurement vector as input, an individual of the ACGP system should decide whether the thyroid gland is normal functioning (class 1), or should be characterized as hyper or hypo function (class 2).

Endocrine Surgical Procedures Thyroid and Parathyroid Surgery

Thyroid and parathyroid procedures can be considered together as they involve surgery in the same area of the neck, and the haemostatic techniques are generally the same. For convenience, they may be divided into preoperative, intra-operative, and postoperative measures. All patients should stop aspirin, low molecular weight heparin, and similar medication likely to interfere with platelet function, at least one week beforehand. These simple measures will reduce the risk of postoperative ooze into the thyroid bed and prevent haematoma formation within the wound, which may take several weeks to resolve. After resolution of a haematoma, the scar may be tethered and unsightly and may need re-excision to improve the cosmetic appearance. A diamond shaped surgical field is created by mobilising the skin flaps superiorly as far as the thyroid cartilage and inferiorly to the suprasternal notch. It is maintained by a self-retaining Joll's retractor. The approach least likely to cause bleeding...

Autoimmune Thyroiditis

Selenium supplementation may improve inflammatory activity in chronic autoimmune thyroiditis patients, as evidenced by a significant reduction in the concentration of thyroid peroxidase antibodies (TPO-Ab) to 63.8 in selenium-supplemented subjects versus 88 (P 0.95) in placebo subjects (Gartner et al 2002). The randomised study of 70 females (mean age 47.5 years) compared 200 jg sodium selenium daily orally for 90 days to placebo. A follow-up crossover study of 47 patients from the initial 70 was conducted for a further 6 months (Gartner & Gasnier 2003). The group that continued to take sodium selenite (200 g day) experienced further significant decreases whereas the group that ceased selenium use experienced a significant increase. The patients who received 200 jg sodium selenite after placebo also experienced a significant decrease in levels of TPO-Ab.

Plate 79 Parathyroid And Thyroid Glands

The parathyroid glands are usually four in number. Each is surrounded by a capsule and lies on or is partially embedded in the thyroid gland. Connective tissue trabeculae extend from the capsule into the substance of the gland. The thyroid gland is located in the neck in close relation to the upper part of the trachea and the lower part of the larynx. It consists of two lateral lobes that are joined by a narrow isthmus. The follicle, which consists of a single layer of cuboidal or low columnar epithelium surrounding a colloid-filled space, is the functional unit of the thyroid gland. A rich capillary network is present in the connective tissue that separates the follicles. The connective tissue also contains lymphatic capillaries. Figure 2, thyroid gland, human, H& E x200. A histologic section of the thyroid gland is shown here. The follicles (F) vary somewhat in size and shape and appear closely packed. The homogeneous mass in the center of each follicle is the colloid. The...

Medullary thyroid cancer

Expression of carcinoembryonic antigen (CEA) by medullary thyroid carcinoma (MTC), a neoplasm that arises from the parafollicular cells of the thyroid, has been used as a target of radioimmunotherapy. More recently, cancer-testis antigens, in particular NY-ESO-1, have been detected in medullary thyroid cancer (10). Thus, vaccines targeting these antigens may be useful for treatment of this malignancy. Also, because medullary thyroid cancer frequently arises as a familial syndrome, one interesting approach would be to apply immunizations as a way to prevent development of the disease as has been demonstrated in an animal model of familial human MTC (11).

Hypothyroidism and Myxedema Coma

History of the Present Illness Fatigue, cold intolerance, constipation, weight gain or inability to lose weight, muscle weakness thyroid swelling or mass dyspnea on exertion mental slowing, dry hair and skin, deepening of voice carpal tunnel syndrome, amenorrhea. Somnolence, apathy, depression, paresthesias. Past Medical History Hyperthyroidism, thyroid testing, thyroid surgery.

Hyperthyroidism and Thyrotoxicosis

History of the Present Illness Tremor, nervousness, hyperkinesis (restlessness), fever, heat intolerance, palpitations, diaphoresis, irritability, insomnia thyroid enlargement, masses, thyroid pain, amenorrhea. Atrial fibrillation diplopia, reduced visual acuity, eye discomfort or pain, lacrimation recent upper respiratory infection. Previous thyroid function testing. Past Medical History Factors Precipitating Thyroid Storm Infection, surgery, diabetic ketoacidosis, pulmonary embolus, excess hormone medication, cerebral vascular accident, myocardial infarction, labor and delivery, iodine-131 or iodine therapy. Family History Thyroid disease.

The Importance Of Thyroid Hormone Sulfation During Fetal Development

Type Deiodinaseand Solfate

Thyroid hormone is essential for normal human development, and this is most evident in the central nervous system, where thyroid hormone deficiency in the fetal and neonatal periods can result in severe and prolonged neurodevelopmental deficit. A number of factors are involved in regulating the bioavailability of receptor active thyroid hormone (T3). Of particular importance are the deiodinase and sulfotrans-ferase enzyme systems governing the interconversion (and thus activation or deac-tivation) of the various iodothyronines. Deiodination constitutes one of the principal pathways of thyroid hormone metabolism. Under normal conditions, the prohormone thyroxine (T4) is the predominant secretory product of the thyroid gland. T4 is peripherally converted to receptor active T3 (3,3',5-triiodothyronine) by outer ring deiodination (ORD) or to receptor inactive reverse T3 (rT3) by inner ring deiodination (IRD). Both T3 and rT3 are further deiodinated, and therefore deactivated (via IRD and...

The Importance Of Sulfation In Thyroid Hormone Metabolism

The role of sulfation in thyroid hormone metabolism is intriguing. Sulfated iodo-thyronines do not bind to the thyroid hormone receptors nor are they substrates for D2 and D3, but their deiodination by D1 is strongly augmented. Figure 7.2 shows the effects of sulfation on the deiodination of different iodothyronines by D1 (Visser, 1996b). IRD (inactivation) of T4 sulfate (T4S) and T3 sulfate (T3S) is markedly facilitated, whereas outer ring deiodination (activation) of T4S is blocked (Visser, 1994, 1996b Visser et al., 1988). However, outer ring deiodination of other substrates is not inhibited by sulfation in fact, deiodination of rT3 sulfate (rT3S) is not affected and that of 3,3'-T2 sulfate (T2S) is even greatly stimulated (Visser, 1994 Visser et al., 1988). Under normal conditions, therefore, the main function of sulfation is to induce the irreversible degradation of thyroid hormone.


Considering that this condition is associated with reduced body stores of carnitine and that l-carnitine is a peripheral antagonist of thyroid hormone action in some tissues according to in vivo studies, carnitine treatment has been investigated in hyperthyroidism. One 6-month, randomised, double-blind placebo-controlled trial involving 50 women with induced suppression of thyroid-stimulating hormone showed that doses 2007 Elsevier Australia


Myxedema coma results from extreme hypothyroidism and is characterized by impaired mentation, hypoventilation, hypothermia, hyponatremia, and CHF. Treatment is with iV thyroid hormones (300-500 mcg of levothyroxine sodium in patients without heart disease). Cortisol should also be given.

Thyroid Gland

FIGURE 6-1 Location and structure of thyroid gland in humans. main structural and functional units of the thyroid parenchyma. In the human thyroid gland there are 20-30 million follicles. The thyroid gland has a rich blood supply, with each lobe being serviced by three arteries. The blood flow to the thyroid gland is 5 ml g min. The thyroid tissues comprise two principal cell types the follicle cell (see the following paragraph) and parafollicular cells or C cells. The C cells are found in the follicular wall or the interfollicular spaces and are responsible for the production of the polypeptide hormone, calcitonin (see Chapter 9). A follicle consists of a single layer of epithelial cells enclosing a cavity termed the follicle lumen. This lumen is filled with a viscous proteinaceous solution, the colloid. Each follicle is encased by a thin basement membrane (see Figures 6-2 and 6-7). The fresh colloid is clear in appearance and composed of homogeneous granules that are secretory...

Thyroid Hormone

Spontaneous and stimulated GH secretion is markedly attenuated in clinical and biochemical hypothyroidism in humans this abnormality corrects during thyroid hormone replacement (7,57,58). Thyroid hormone deficiency is associated with reduced hypothalamic GHRH production, leading to GH deficiency and down-regulation of GHRH receptor numbers on pituitary somatotropes (7,59). Thyroid hormone facilitates binding of GHRH to its receptor. GH secretion is reduced in hypothyroid subjects following Hyperthyroid subjects have significant increases in 24-h GH pulse frequency, augmented GH pulse amplitude, and 3.7-fold higher GH production rates, similar to the effects of sex steroids on GH secretion (63). These observations of enhanced GH secretion in hyperthyroidism suggest some alteration in GH neuroregulatory control including increased somatotrope responsiveness to GHRH or a reduction in somatostatin tone, and is independent of IGF concentration (63). On the other hand, other investigators...

Ithyroid Follicles

Thyroid follicles are hounded by follicular cells and parafollicular cells. A. Contain thyroid-stimulating hormone (TSH) receptors E. Oxidize iodide (2I + H207 > I7) using the enzyme thyroid peroxidase and iodinate tyrosine residues in thyroglobulin, thereby forming monoiodotyrosine (MIT) and di-iodotyrosine (DIT), which are then coupled to form triiodothyronine (T5) and thyroxine (T4) H. Deiodinatc MIT and DIT using the enzyme deiodinase to recycle iodide (I ) and secrete Tj and T.( into the bloodstream, which then circulate bound to thyroid-binding globulin (TBG). T4, which is converted by the liver and kidney into the functionally more potent T5, accounts for 90 of the thyroid output T, accounts for 10 of the thyroid output.

Thyroid Tumors

Thyroid tumors are the second tumor type for which the U.S. EPA has developed generic guidance for risk assessment (55). The agency efforts have been directed specifically at tumors of the thyroid follicular cells, but some of the information gained from analysis of these tumors will likely be applicable to other endocrine tumor sites in the future. Clinical manifestation of thyroid cancer in humans in the United States is uncommon and largely nonfatal. The only known human thyroid carcinogen is X-radiation, which causes an increase in papillary tumors. Human thyroid follicular cell cancer is most often diagnosed histologically as a papillary tumor. The rodent thyroid neoplasms rarely metastasize, whereas the human cancers frequently metastasize. The molecular events that lead to thyroid follicular cell tumors are not fully known. In rodents, these tumors arise from mutation, perturbation of thyroid and pituitary hormone status with increased stimulation of thyroid cell growth by...

Parathyroid glands

The parathyroid glands are small endocrine glands closely associated with the thyroid. They are ovoid, a few millimeters in diameter, and arranged in two pairs, constituting the superior and inferior parathyroid glands. They are usually located in the connective tissue on the posterior surface of the lateral lobes of the thyroid gland. However, the number and location may vary. In 2 to 10 of individuals, additional glands are associated with the thymus. Structurally, each parathyroid gland is surrounded by a thin connective tissue capsule that separates it from the thyroid. Septa extend from the capsule into the gland to divide it into poorly defined lobules and to separate the densely packed cords of cells. The connective tissue is more evident in the adult, with the development of fat cells that increase with age and ultimately constitute as much as 60 to 70 of the glandular mass. The glands receive their blood supply from the inferior thyroid arteries or from anastomoses between...

Tissue Distribution Of The Human Sult1a Subfamily

One interesting observation made by Richard et al. (2001) was the developmental expression difference apparent between SULT1A1 and SULT1A3 in lung and liver tissues. Assessing the dopamine and thyroid hormone sulfonation ability of fetal tissues, it was found that high liver SULT1A1 activity was generally retained into adulthood however, lung activity reduced approximately 10-fold toward 3,3'-T2 (Gilissen et al., 1994 Richard et al., 2001). Sulfonation activity of dopamine was high in the fetal liver and lung but reduced significantly in the postnatal tissues (Pacifici et al., 1993 Richard et al., 2001). Protein levels confirmed these results, suggesting that SULT1A1 and 1A3 are abundantly expressed in the fetal liver and that the SULT 1 A3 enzyme almost disappears in the adult tissue (Richard et al., 2001). This same pattern has also been observed for SULT1A3 in the kidney (Cap-piello et al., 1991). These data suggest an important role for these two SULTs in

Ontogeny And Tissue Distribution Of Iodothyronine Sulfotransferases

HSULT1E1 is expressed in the liver, mammary gland, uterus, placenta, and in a wide range of fetal tissues, such as lung, liver, adrenal, kidney, small bowel, thyroid, heart, and brain (Rubin et al., 1999 Stanley, 2001 Stanley et al., 2001 Strott, 1996). It is possible that the hSULT1E1 in the endometrium contributes to the high iodo-thyronine sulfate levels in the fetal serum and amniotic fluid (see Discussion).


SULT1C2 (originally referred to as SULT1C1) was identified on the basis of sequence homology of its cDNA to those of other SULTs (Her et al., 1997). In adults, this enzyme is most highly expressed in the stomach, thyroid, and kidney, and it is also expressed in the fetal liver (Her et al., 1997). Cloning and characterization of the human SULT1C2 gene (Freimuth et al., 2000) made it possible to perform a genotype-to-phenotype resequencing study of this gene. That experiment utilized DNA extracted from blood samples obtained from 89 randomly selected Caucasian blood donors (Freimuth et al., 2001) and resulted in the identification of 19 polymorphisms, including 4 nonsynonymous cSNPs and 5 insertions deletions


SULT1B1 was initially referred to as a thyroid hormone-sulfating SULT due to its ability to sulfate a number of thyroid hormones, including T3 and T4 (Fujita et al., 1997 Wang et al., 1998). The highest levels of activity were observed with 3,3'-T2, which is consistent with the role of sulfation in increasing the rate of thyroid hormone deiodination (Visser, 1994, 1996). Thyroid hormones are also substrates for several other human SULTs. SULT1E1 efficiently sulfates thyroid hormones, and SULT1A1 has thyroid hormone sulfation activity as well (Kester et al., 1999a, b Young et al., 1988). Expressed SULT1B1 also efficiently conjugates several prototypical phenolic substrates such as 1-naphthol and PNP. Most steroids are not readily sulfated by expressed human SULT1B1 (Fujita et al., 1999 Wang et al., 1998).

Sult1c1 And Sult1c2

In a human fetal liver-spleen cDNA library. The clone was obtained from the American Type Culture Collection and encoded a 296 amino acid protein that was 62 identical in sequence to a rat SULT1C1 sequence (Nagata et al., 1993). SULT1C1 displays approximately 50 amino acid sequence identity with the human SULT1 proteins, resulting in its inclusion in the SULT1 subfamily. SULT1C1 message expression was reported in human adult stomach, kidney, and thyroid as well as in fetal kidney and liver (Her et al., 1997). The structural SULT1C1 gene was localized to chromosome 2q11.1-11.2 (Her et al., 1997). Resequencing of the SULT1C1 gene of 89 Caucasians detected 4 nonsynonymous SNPs and 5 insertion deletions, indicating that SULT1C1 is polymorphic in humans (Freimuth et al., 2001).


Thyroid hormone metabolism is an important process in the regulation of thyroid hormone homeostasis. The prohormone T4 can be activated by outer ring deiodina-tion to T3 or inactivated by IRD to rT3. T3 and rT3 are further metabolized to 3,3'-T2. In addition, iodothyronines are also metabolized by sulfotransferase-catalyzed conjugation of the phenolic hydroxyl group (Visser, 1996b). Still, the tissue-specific expression of the sulfotransferases makes the understanding of the physiological importance of the different sulfotransferases rather complex. We showed a strong correlation between substrate specificities of hSULTlAl and those of native iodothyronine sulfotransferase activities in human liver and kidney, which suggests an important role for hSULTlAl in thyroid hormone sulfation in these tissues (Figure 7.5 Kester et al., 1999a). Richard et al. (2001) studied hSULTlAl and hSULT1A3 expression and 3,3'-T2 sulfation in the hSULT1E1 may be especially important for iodothyronine...


Until recently, SULT1A1 was predominantly seen as an enzyme that was primarily involved in xenobiotic metabolism. This observation was based on it having the widest tissue distribution of any SULT, including liver and intestine, and its broad substrate range (Eisenhofer et al., 1999 Falany, 1997). The recent elucidation of the crystal structure of SULT1A1, which shows the active site of this enzyme to be more versatile than first expected, provides a rational explanation for its substrate diversity. More recent data suggest that SULT1A1 plays a significant role in the metabolism of the iodothyronines, especially 3,3'-T2 (Li et al., 2001 Richard et al., 2001), which we have recently shown binds effectively to the active site of this isozyme (Gamage et al., 2003). 3,3'-T2 is thought to act through nonnuclear pathways to enhance mitochondrial respiration and thus resting metabolism (Li et al., 2001). SULT1A1 is also capable of sulfonating T3 and thyroxine (T4) and may play a more...


As with SULT2A1, reports on the expression of the SULT2B1 isoforms in human tissues vary considerably depending on the reporting laboratory and the methodology employed. Northern analysis performed using a probe that would detect both SULT2B1 isoforms revealed strong expression in the placenta, prostate, and trachea with faint expression in the small intestine and lung, whereas there was no expression in the heart, brain, spinal cord, liver, skeletal muscle, kidney, pancreas, ovary, testis, stomach, colon, adrenal, thyroid, and bone marrow (Her et al., 1998). RT-PCR revealed that SULT2B1a is expressed in the colon, kidney, ovary, and skin in addition to those tissues detected by northern analysis (Javitt et al., 2001). RT-PCR further revealed that the SULT2B1b isoform is more widely and vigorously expressed than SULT2B1a (Javitt et al., 2001). Another RT-PCR analysis of adult human tissues revealed SULT2B1a and SULT2B1b expression in skin, esophagus, stomach, duodenum, colon, lung,...

Sult1 Family

SULT1B1 thyroid hormones, 2-naphthol, dopamine The SULT1B subfamily has been identified recently and may be involved in the sulfation of thyroid hormones (Fujita et al., 1997, 1999 Saeki et al., 1998 Sakakibara et al., 1995 Tamura et al., 1999 Wang et al., 1998). This family also catalyzes the sulfation of prototypic phenolic substrates, such as 2-naphthol and dopamine, but not steroid hormones. (HUMAN)SULT1B1 mRNA has been detected in liver, colon, small intestine, and blood leukocytes. The SULT1C subfamily is also a recently identified gene family that encodes at least four isoforms (Hehonah et al., 1999 Her et al., 1997 Nagata et al., 1993 Sakakibara et al., 1998a Tamura et al., 1998 Xiangrong et al., 2000 Yoshinari et al., 1998b). The function of these enzymes is not yet fully understood but (RAT)SULT1C1 and (HUMAN)SULT1C4 catalyze the sulfation of the procarcinogen N-OH-2-acety-laminoflorene as well as p-nitrophenol, the prototypic phenolic SULT substrate. (RAT)SULT1C1 is liver...

Contraindications And Precautions

A case study of depression of thyroid hormones in a woman taking Aloe vera juice has been reported (Pigatto & Guzzi 2005). The patient consumed 10 mL daily for 11 months and laboratory testing showed reduced levels of thyroxine and triiodothyonine. Levels returned to normal progressively after discontinuing the aloe juice and the patient achieved full clinical remission after 16 months. Reduced serum levels of the thyroid hormones T3 and T4 have been reported for Aloe vera in vivo (Kar etal 2002).

Pacemaker Cells Control Heart Rate

This process occurs about 60 to 100 times each minute, resulting in the spontaneous heart beat. Cells in the AV node also have pacemaker potentials, but they are slower to reach threshold (only about 40 beats min) and thus the SA node dominates with its faster rhythm. Purkinje fibers also have intrinsic pacemaker activity. An isolated strip of Purkinje fibers will spontaneously generate action potentials with a frequency of about 25 to 40 action potentials min, a rate slower than that of either SA or AV nodal cells. The AV node and Purkinje fibers are called latent pacemakers because they will assume the pacemaker role should the signals from the more proximate and dominant pacemaker be interrupted. Thus the AV node takes over when there is SA nodal arrest, and the pacemaker moves to Purkinje fibers when conduction below the AV node is interrupted, blocking transmission of the impulse generated by higher pacemakers. The firing rate of the SA node can be modulated by both sympathetic...

Biosynthesis Of Hormones

The biosynthesis of all hormones largely occurs in specialized cells usually present in endocrine glands, which have the genetic phenotype to permit the correct orderly production of the hormone in question. Chapter 2 describes the production of the steroid hormones, while Chapters 6,11, and 16 describe the biosynthesis of the thyroid hormones, epinephrine, and prostaglandins, respectively. The next section of this chapter will provide a general description of the biosynthesis of peptide and protein hormones.

Complications And Prognosis

Existing longitudinal studies of persons with SS show that the clinical course of SS is slowly progressive and is life altering, rather than life threatening, for most patients. One study found no overall increased mortality in a population of individuals with SS when compared to controls (12). Those with SS also do not have increased cardiovascular mortality, as do individuals with SLE, despite the apparent overlap in signs and symptoms. Salivary glands in SS begin with focal lymphocytic infiltrates but can progress to a lymphoepithelial lesion (lymphoepithelial sialadenitis). This is often associated with chronic clinical enlargement of major salivary glands, occurring in about one-third of patients. Rarely, it may progress to a MALT lymphoma, an indolent tumor progressing for years, or become a high-grade B-cell non-Hodgkin's lymphoma. Various studies have shown a significantly higher prevalence of lymphoma in SS patients than in the general population. Lymphomas occur most...

Physical investigations

The aim of physical investigation is to find a treatable lesion and or make an aetiological diagnosis. 'Routine' laboratory tests seldom yield abnormal results in young adult psychiatric patients, unless there are physical symptoms or signs, or a history of alcohol misuse. Therefore, screening of younger patients who appear to be in good physical health is clearly not cost-effective, although many units do carry out blood tests on all new admissions, and these reveal occasional cases of unsuspected organic disease, most commonly thyroid dysfunction in women. rocyte sedimentation rate (ESR) urea and electrolytes thyroid and liver function vitamin Bi2 and folate urine testing for glucose, protein, cells, and bacteria and chest radiography (but skull radiography very seldom yields useful information). Other tests such as the electroencephalogram (EEG), brain scan, analysis of blood or urine for drugs, syphilis serology, and HIV testing may be done if clinical indications exist. (Except...

Congestive Heart Failure

Past Medical History Past episodes of heart failure hypertension, excess salt or fluid intake noncompliance with diuretics, digoxin, antihypertensives alcoholism, drug use, diabetes, coronary artery disease, myocardial infarction, heart murmur, arrhythmias. Thyroid disease, anemia, pulmonary disease.

Evolution of the Nuclear Receptor Superfamily

Detailed comparative sequence analysis of receptors across species predicts that the DNA-binding function of these proteins evolved prior to ligand-binding capacity. All NRs from organisms that evolved prior to chordates, arthropods, and nematodes are more similar to orphan receptors that lack known ligands than to steroid or thyroid family members, suggesting that the prototypes of NRs were orphans.9,13,14 Steroid hormone receptors are apparently restricted to vertebrates, with the exception of the insect ecdysone receptor (EcR), representing the prototypical steroid receptor. The insect EcR, which most closely resembles the farnesoid X receptor (FXR) in primary sequence, is required for virtually every aspect of insect larval meta-morphosis.15 The primary function of EcR in this process is to induce expression of numerous orphan NRs (several of which have vertebrate homologs of unknown function) and establish a temporal regulatory hierarchy of NR activity.16 Interestingly, EcR...

Other Breast Cancer Genes High Risk Breast Cancer Genes

Breast cancer is involved in two other hereditary syndromes, for which causative genes have been identified. The Li-Fraumeni syndrome is characterized by childhood sarcoma and early-onset breast cancer, brain tumors, and a variety of other cancers. Most families with Li-Fraumeni syndrome appear to be due to germline mutations in the TP53 gene. TP53 mutations confer a very high risk of breast cancer (approaching 100 by age 50) but are much rarer than BRCA1 or BRCA2 mutations (45,46). Cowden's syndrome is a rare syndrome characterized by hamartomas, multiple hamartomas, thyroid cancer, and mucocutaneous lesions and is due to germline mutations in PTEN (61). The risk of breast cancer associated with Cowden's syndrome has not been well estimated, but it is of the order of 30 to 50 lifetime (47).

Management of anesthesia

Preoperative all elective surgery should be postponed until the patient is rendered euthyroid with medical treatment. Preoperative assessment should include normal thyroid function tests, and a resting heart rate < 85 beats min. The combination of beta antagonists and potassium iodide is effective in rendering most patients euthyroid in 10 days. Consider esmolol when surgery cannot be delayed. Antithyroid medications and beta-blockers should be continued through the morning of surgery. C. Postoperative most serious postoperative problem is thyroid storm, which is characterized by hyperpyrexia, tachycardia, altered consciousness, and hypotension. Most commonly occurs 6-24 hours postoperatively. Treatment includes hydration and cooling, propranolol (0.5 mg increments until heart rate is below 100 beats min) or esmolol. Consider cortisol (100-200 mg IV every 8 hours), propylthiouracil (250 mg every 6 hours orally) followed by sodium iodide (1 gm IV over 12 hours), and correction of...

Hormone Response Elements and the DNABinding Domain

Figure 3.3 The nuclear receptor DNA-binding domain and the hormone response element (HRE). A The HREs are composed of either direct repeats (DRs), inverted repeats (IRs), or everted repeats (ERs). The preferred half-site sequence for class I receptors is 5'-AGAACA-3', while the preferred halfsite sequence for class II, III, and IV is 5'-AGGTCA-3'. B The nuclear receptor DNA-binding domain (DBD) is distinguished by two zinc fingers. The zinc fingers of human thyroid receptor beta (TR 8) are depicted. Residues contributing to the P box and D box are indicated as open squares. C A list of individual

The Real World of Health Policy

WHEREAS The term dioxin refers to a group of chemicals that includes furans and biphenyl compounds (the most well-known dioxin being 2,3.7.8-TCDD), and dioxin is a potent human carcinogen and an endocrine-disrupting chemical affecting thyroid and steroid hormones, scientifically linked to endometriosis, immune system impairment, diabetes, neurotoxicity, birth defects, testicular atrophy and reproductive dysfunction and

Hdac3 Interacting Proteins

One of the biggest challenges in the study of HDAC3, as in the study of other HDACs, is to understand the exact mechanisms by which HDAC3 changes gene expression and how it affects the functions of the transcriptional machinery. Early in the studies of HDACs, the identification and characterization of HDAC1 2 binding proteins were tremendously useful in elucidating the mechanisms of action and functions of these two HDACs. Following similar strategies, Wen et al. isolated a large HDAC3-containing multisubunit complex using anti-HDAC3 immunoaffinity chromatography (Table 2) (34,46). The purified endogenous HDAC3 complex from HeLa cells contained nuclear receptor corepressor (NCoR) and silencing mediator for retinoid and thyroid receptors (SMRT) proteins. In parallel, NCoR and SMRT were identified in an anti-Flag affinity-purified complex from nuclear extracts of a cell line expressing Flag-tagged HDAC3 (47). Further evidence that HDAC3 stably associates with SMRT and NCoR came from the...

Nuclear Receptor Coactivators

The p160 family of coactivators consists of three members, designated steroid receptor coactivator 1-3 (SRC-1-3).149,150 SRC-2 represents the molecules known variously as activating cofactor of thyroid and retinoid receptors (ACTR), receptor-associated coactivator 3 (RAC3), amplified in breast cancer 1 (AIB1), thyroid receptor activator molecule 1 (TRAM1), and CBP cointegrator protein (p CIP). SRC-3 is also known as the glucocorticoid receptor interacting protein (GRIP1) and transcription intermediary factor 2 (TIF2). In general, these proteins interact with NRs in an AF-2- and lig-and-dependent manner. Several NRs appear to activate transcription constitutively, independent of apparent ligand availability. The class IV receptors ERR1, ERR2 and ERR3, for example, seem to activate transcription by recruiting p160 family coactivators through the LBD.151,152 Class I and class II receptors, however, bind p160 family proteins in a ligand-dependent manner.

Cellular and tissue host range in vivo

Endothelial cells seem to represent another important target for infection in vivo as suggested by endothelial cell activation and or damage secondary to HHV-6 reactivation, which may predispose to the development of thrombotic micro-angiopathy (Matsuda et al., 1999 Takatsuka et al., 2003). Finally, in healthy subjects, HHV-6 DNA has been demonstrated ex vivo in several tissues including tonsils, salivary glands, thyroid, brain, liver, myocardium, kidney, and thyroid (Fox et al., 1990 Corbellino et al., 1993 Luppi et al., 1994a Chan et al., 2001 Grivel et al., 2001 Ozaki et al., 2001 Roush et al., 2001 Ishikawa et al., 2002 Donati et al., 2003 Harma et al., 2003). Nevertheless, it is unclear to what extent the detection of viral DNA reflects the ability of HHV-6 to infect tissue-specific resident cells or, alternatively, infiltrating lymphoid and monocytic cells.

Human Chorionic Gonadotropin

Luteinizing hormone (LH), follicle-stimulating hormone (FSH), and thyroid-stimulating hormone (TSH). The P subunit is biologically active and structurally and antigenically distinct, allowing for the production of specific antibodies used in immunoassays.9 However, at times, these antibodies may cross-react with the P subunit of LH, which is 70 homologous to that of hCG. In addition, hCG, at high levels, may clinically mimic these pituitary hormones. Hyperthyroidism has been reported,10 and the 5 of GCT patients who develop gynecomastia are believed to do so secondary to a testosterone estrogen imbalance caused by the effect of hCG on the Leydig's cells.

Nuclear Receptor Corepressors

ErbA.167 It potentiates transcriptional repression by TR and Rev-ErbA and represses transcription when fused to a heterologous DBD. Interestingly, SUN-CoR also interacts with N-CoR. Alien interacts with TR, DAX-1, and COUP-TFI but not with RXR, RARa, or GR.168 Addition of thyroid hormone leads to dissociation of Alien from TR. Alien is a highly conserved protein showing 90 identity between the human and Drosophila homologs. Drosophila Alien shows similar activities in that it interacts in a hormone-sensitive manner with TR and harbors an autonomous silencing function. The mechanism underlying its repression activity, however, has not been demostrated. The nuclear protein SMRT and its isoform thyroid receptor associated cofactor 2 (TRAC2) were isolated by a yeast two-hybrid assay using RXR as bait.105,169-171 It contains four autonomous repression domains and two receptor interaction domains,170 and can interact with a panel of receptors, including unliganded RAR, TR, PPARa, PPARy,...

Only LAmino Acids Occur in Proteins

With the sole exception of glycine, the a-carbon of amino acids is chiral. Although some protein amino acids are dextrorotatory and some levorotatory, all share the absolute configuration of L-glyceraldehyde and thus are L-a-amino acids. Several free L-a-amino acids fulfill important roles in metabolic processes. Examples include ornithine, citrulline, and argininosuccinate that participate in urea synthesis tyrosine in formation of thyroid hormones and glutamate in neurotransmitter biosynthesis. D-Amino acids that occur naturally include free D-serine and D-aspartate in brain tissue, D-alanine and D-glutamate in the cell walls of grampositive bacteria, and D-amino acids in some nonmam-malian peptides and certain antibiotics.

Crosstalk Between Nuclear Receptors and Other Transcription Factors

Figure 3.8 Chemical structures of steroid and thyroid hormone receptor ligands. Natural hormones and examples of high-affinity synthetic agonists and antagonists are presented for each of the steroid and thyroid classes of receptor. Agonist activity is defined as the ability to induce receptor-dependent transcription of natural or synthetic response element reporters in cotransfection experiments and, in most cases, is supported by in vitro ligand-receptor binding studies. ER, estrogen receptor PR, progesterone receptor AR, androgen receptor GR, glucocorticoid receptor MR, mineralocorticoid receptor VDR, vitamin D receptor TR, thyroid hormone receptor. Figure 3.11 Cross-talk between nuclear receptors and activator protein 1 (AP-1), nuclear factor kappa B (NF-kB), and signal transducer and activator of transcription 5 (STAT5) documenting how nuclear receptors may influence the activity of other transcription factors. The effects of nuclear receptor cross-talk are indicated as +,...

Expression of Heterologous Proteins to Get a Phenotype

Screens to find ligands for steroid hormone receptors such as the retinoid receptors have been designed in S. cerevisiae 32 . Steroid hormone receptors occur intracellularly. They have a ligand-binding domain, a dimerization domain, and a transactivation domain. When ligands induce these receptors to homo- or heterodimerize, their transactivation domain binds the specific response elements and activates specific promoters. The dimerization of the steroid hormone receptors followed by binding and transactivation of specific promoters can be studied in yeast. Homodimerization has been demonstrated using retinoic acid receptors, thyroid hormone receptors, and estrogen receptors 33,34 . Heterodimerization with the RXR retinoid receptor can also be demonstrated 35 . In this system, the RAR, retinoic acid receptors respond to a number of retinoids, but RXR responds only to the RXR-specific 9-cis isomer of retinoic acid 35 . Because all mammalian cells have many representatives of the...

Molecular Pathophysiology

Amino acid substitutions at each of 20 separate positions cause constitutive activation of TSH or LH CG receptors 9 . The TSH receptor has been particularly fertile in activating mutations because of the fact that somatic mutations leading to activation of the TSHr cause a readily detectable thyroid phenotype (i.e., autonomous toxic adenomas) 10 . Much less frequent are germline mutations with similar activating effects. When affecting the TSHr or LH CGr, they cause autosomal dominant hyperthyroidism or pseudo precocious puberty of the male, respectively 3,9 . Except for a single anecdotal case, no disease has been associated with activating mutations of the FSHr 4 .

The Genotoxic Mechanism

Growth Factor-Induced Cell Proliferation. Hormones. Rodent thyroid follicular cell tumor in contrast to human thyroid tumors that are mostly induced by ionizing radiation, thyroid follicular cell tumors in rodents are induced by genotoxic or nongenotoxic carcinogens. Several nongenotoxic chemicals (such as perchlorate, thiorueas, lithium, lupiditine) are known to perturb the balance of the thyroid stimulating hormone (TSH) in rodents. These chemicals are referred to as goitrogens and their modes of action are different. They may deplete iodine accumulation by inhibiting iodine trapping in the thyroid or by blocking binding of iodine and coupling of iodothyronine to form thyroxine and triiodothyronine. Alternately, they may inhibit thyroid hormone secretion by pro-teolysis or enhance metabolism of thyroxine by inducing liver metabolic enzymes (78). Disruption of thyroxine function activates the pituitary-thyroid feedback mechanism, which increases the production of TSH. An increase...

Conclusions and Perspectives

E., and Vassart G. (2001). Thyroid disorders, in Scriver, C., Ed., The Metabolic and Molecular Bases of Inherited Diseases, pp. 4029-4076. McGraw-Hill, New York. 10. Parma J., Duprez L., Van Sande J., Cochaux P., Gervy C., Mockel J., Dumont J. E., and Vassart G. (1993). Somatic mutations in the thy-rotropin receptor gene cause hyperfunctioning thyroid adenomas. Nature 365, 649-651. 28. Hauser, F., Nothacker, H. P., and Grimmelikhuijzen, C. J. (1997). Molecular cloning, genomic organization, and developmental regulation of a novel receptor from Drosophila melanogaster structurally related to members of the thyroid-stimulating hormone, follicle-stimulating hormone, luteinizing hormone choriogonadotropin receptor family from mammals. J. Biol. Chem. 272, 1002-1010. 38. Osuga, Y., Liang, S. G., Dallas, J. S., Wang, C., and Hsueh, A. J. (1998). Soluble ecto-domain mutant of thyrotropin (TSH). Receptor incapable of binding TSH neutralizes the action of thyroid-...

Beliefs Underlying Stigma

In addition to attributions of responsibility, research suggests that perceptions of causality and stability of obesity are also important factors contributing to stigmatizing attitudes. Obese people are more likely to be stigmatized if their overweight condition is perceived to be caused by controllable versus uncontrollable causes (e.g., overeating vs. a thyroid condition) and if the obesity is perceived to be personally changeable rather than an irreversible condition (51,52).

Family Communication Issues And The Duty To Warn

In the public health sector, breaches of confidentiality may be permissible to curtail the spread of preventable communicable diseases (63). With respect to case law, the well-known Tarasoff ruling established a provider's obligation to breach confidentiality in order to warn a third party of imminent and preventable harm (64). In this 1976 case, a psychotherapist failed to warn a woman about his patient's intention to kill her, which he eventually did. Almost 20 years later, the duty to warn was tested in the courts as it applies to the threat of genetically transmissible diseases within families. Two cases in U.S. state appellate courts are relevant. In Pate v Threlkel, the Florida court ruled in 1995 that the physician's duty to warn relatives about a genetic condition (i.e., medullary thyroid cancer) is fulfilled by notifying the patient who is affected by the condition of the responsibility to inform relatives of their risk (65). In Safer v Estate of Pack, the New Jersey appeals...

Detection and Assessment

A physical examination and laboratory screening (e.g., complete blood count, liver function, serum testosterone level, serum vitamin B12, thyroid function) may be performed to exclude potential systemic causes of depressive symptomatology. Testosterone deficiency associated with depressive symptomatology (e.g., anhedo-nia, fatigue, and sexual dysfunction) has been described in males with PD and may possibly be managed with testosterone replacement therapy (120). Likewise, symptoms of hypothyroidism (e.g., anxiety, difficulty with concentration, dysphoria, fatigue, irritability, and motor retardation) resemble depressive symptomatology and are treatable with thyroid replacement. It is also important to ensure that patients are on optimal doses of antiparkinson drugs to minimize motor fluctuations that may contribute to mood fluctuations.

Cannabinoid Receptors

Activation of cannabinoid CB1 receptors has been shown to inhibit growth of xenograph tumors of thyroid origin via attenuation of p21ras activity.26 Stimulation of this receptor with the metabolically stable endocannabinoid analog (Met-F-AEA) resulted in inhibition of tumor angiogenesis and metastasis via suppression of VEGF and its receptor (Flt-1) and enhancement of p27kip1 levels in rat thyroid metastatic cells and in abrogation of formation of metastatic nodules in vivo.26 Effects could be counteracted with the selective CB1 receptor antagonist. These data suggest that the cannabinoid system may be targeted pharmacologically to block molecular and cellular processes to intervening cancer growth and spreading.

Biomedical Importance

Bioenergetics, or biochemical thermodynamics, is the study of the energy changes accompanying biochemical reactions. Biologic systems are essentially isothermic and use chemical energy to power living processes. How an animal obtains suitable fuel from its food to provide this energy is basic to the understanding of normal nutrition and metabolism. Death from starvation occurs when available energy reserves are depleted, and certain forms of malnutrition are associated with energy imbalance (marasmus). Thyroid hormones control the rate of energy release (metabolic rate), and disease results when they malfunction. Excess storage of surplus energy causes obesity, one of the most common diseases of Western society.

Laboratory Examination

Erectile dysfunction (ED) often occurs together with sexual disinterest and it may not be easy to establish which preceded the other. Under such circumstances, it is wise to investigate common causes of ED by ensuring that the patient does not have diabetes (obtaining a fasting blood sugar), or elevated lipids assessing his total cholesterol, high density lipoprotein (HDL), low density lipoprotein (LDL), and triglycerides , or abnormal thyroid function investigating his thyroid stimulating hormone (TSH) .

Cholecytostokinin2 Receptor

The cholecytostokinin-2 receptor (CCK2R) shows growth-promoting effects on normal and neoplastic gastrointestinal cells when stimulated by gastrin. It is highly expressed in many cancers of different origins including medullary thyroid carcinomas, small cell lung cancers, astrocytomas, and ovarian cancers but is not present in the corresponding tissues.40 A constitutively active CCK2R mutant in which the conserved glutamate (E) within the (E)-aspartate (D)-arginine (R)-tyrosine (Y)

Extent Of Local Tumour Spread

Lymphocytic reaction prominent sparse. Perineural space involvement. Solitary multifocal, one or two lobes. Involvement of lesion capsule, extracapsular spread. Involvement of thyroid capsule, extrathyroid spread. pT1 tumour < 2 cm in greatest dimension, limited to thyroid pT2 2 cm < tumour < 4 cm in greatest dimension, limited to thyroid pT3 tumour > 4 cm in greatest dimension, limited to thyroid or any tumour with minimal extrathyroid extension (e.g. to sternothy-roid muscles or perithyroid tissues) pT4 beyond thyroid capsule with invasion a subcutaneous soft tissues, larynx, trachea, oesophagus, recurrent laryngeal nerve, or, b prevertebral fascia, mediastinal vessels or encases carotid artery Figure 16.1. Thyroid carcinoma pT4 beyond thyroid capsule with invasion a subcutaneous soft tissues, larynx, trachea, oesophagus, recurrent laryngeal nerve, or, b prevertebral fascia, mediastinal vessels or encases carotid artery Figure 16.1. Thyroid...

Is achieving extreme old age worthwhile the centenarian phenotype

Independently functioning at age 92 (Hitt et al., 1999). Most subjects experienced a decline in their cognitive function only in the last three to five years of their lives (Perls, 1997 Silver et al., 1998). Upon further examination of the ages of onset for ten common age-associated diseases (hypertension, heart disease, diabetes, stroke, non-skin cancer, skin cancer, osteoporosis, thyroid condition, Parkinson's disease, chronic obstructive pulmonary disease and cataracts) among 424 centenarians (323 males and 101 females), the subjects were noted to fit into three morbidity profiles ''survivors,'' ''delayers'' and ''escapers'' (Evert et al., 2003). Survivors, individuals who were diagnosed with age-related illness prior to age 80, accounted for 24 of the male and 43 of the female centenarians (p 0.0009). Delayers, individuals who delayed the onset of age-related diseases until at least age 80, accounted for 44 of the male and 42 of female centenarians. Escapers, individuals who...

Intracellular Receptors

The nuclear receptor (NR) superfamily is composed of steroid receptors including androgen, estrogen, glucocorticoid, mineralcorticoid and progesterone receptor, nonsteroidal receptors like thyroid hormone, vitamin D and retinoic acid receptors, ecdysone receptors, which are found in insects, and orphan NR receptors (Table 3), which constitute the majority of the members of the NR superfamily 20 . The NRs are transcription factors that regulate the development and metabolism through control of gene expression. All nuclear receptors are modular proteins that contain one DNA-binding domain (DBD) and one ligand-binding domain (LBD) (Fig. 5). The N-terminal domain (A B) contains a cell-specific and promoter-specific transactivation domain termed AF-1 that functions autonomously and in a ligand-independent manner. It is the least conserved domain (< 15 sequence homology) across the superfamily. The centrally located DBD (C domain) has a highly conserved sequence (> 50 sequence...

Anatomical And Morphological Relationships

Thyroid Gland Figure 6-1 shows the location and structure in humans of the thyroid gland. In adults the thyroid gland weighs 10-20 g. It consists of brownish-red right and left pear-shaped lobes. The two lobes are connected by an isthmus and lie on the lower part of the larynx and the upper part of the trachea. From the inner capsule of the thyroid, septa extend into the gland, dividing it into lobules of varying shape and size. The separate lobules are composed of follicles, which are the

Inhibition Of Skeletal Muscle Differentiation By Class Ii Hdacmef2 Interactions

Schematic diagram of a class II HDAC. The structure of class II HDACs is shown, with binding sites for other transcriptional activators and repressors and for the 14-3-3 protein. CtBP, carboxy-terminal binding protein HP1, heterochro-matin protein 1 MEF2, myocyte enhancer factor 2 NES, nuclear export sequence NLS, nuclear localization sequence SMRT NCoR, silencing mediator for retinoid and thyroid receptors nuclear receptor corepressor. Fig. 2. Schematic diagram of a class II HDAC. The structure of class II HDACs is shown, with binding sites for other transcriptional activators and repressors and for the 14-3-3 protein. CtBP, carboxy-terminal binding protein HP1, heterochro-matin protein 1 MEF2, myocyte enhancer factor 2 NES, nuclear export sequence NLS, nuclear localization sequence SMRT NCoR, silencing mediator for retinoid and thyroid receptors nuclear receptor corepressor.

Biological And Molecular Actions

Thyroid hormones produce a wide array of physiological effects in virtually all of the body's organs and metabolic pathways these are summarized in Table 64. Principal effects include the modulation of oxygen consumption, as well as carbohydrate, protein, and fat metabolism. In addition, thyroid hormones modulate the degradation and synthesis rates of many other growth factors and hormones, which results in many secondary effects. The biological effects of thyroid hormone are divisible into two general categories One of the hallmarks of thyroid hormone action occurs during the process of metamorphosis in amphibians (tadpoles frogs) and in supporting fetal development in animal models. In humans, the requirement for thyroid hormone is emphasized by the occurrence of cretinism in the absence of adequate amounts of T3. Many of the developmental effects of thyroid hormone cannot be reversed by later application of thyroid hormone, which suggests that the hormone is only able to act in a...

Elfpplflevf Edqev 410

Figure 6-19 Schematic model of the structural domains of the thyroid receptor as determined via X-ray crystallographic techniques. The ligand binding domain of the thyroid receptor is composed of 255 amino acids which represent residues 156-410 in the intact thyroid receptor. This figure illustrates the 12 a-helices, designated Hi to Hi2 and the 4 3-strands, designated S, to S4 which comprise the secondary structure. The amino acid residues at the beginning and at the end of each a-helix are indicated using the one-letter code (see Appendix E). The inset box provides the primary amino acid sequence of the thyroid c*i receptor ligand binding domain. The actual three-dimensional ribbon structure of the rat a thyroid receptor ligand binding domain with a thyroid hormone agonist is shown on the front cover of this book it begins with the red color for the a-helix, at the N-terminus and progresses down the colors of the visible spectrum to the royal blue color for a-helix 2 at the carboxy...

Venous Thromboembolism

Venous thromboembolism (VTE) has long been known as a complication ofcancer. Venous thromboembolisms are usually divided into deep venous thrombosis (DVT) and pulmonary embolism (PE). When DVTs affect the proximal veins of the lower extremities they are usually treated as a PE. We discuss VTE with all brain tumor patients at the initial consultation. Mechanism of action for VTE includes, venous stasis (immobility), intimal injury, and alterations in coagulation. In brain tumor patients, Sawaya et al. (46) has shown alterations in the fibrinolytic system and an underlying coagulopathy as causes of VTE. Other associations include age, prior DVT, smoking, oral contraceptives, and obesity. During surgery, brain tumor patients often have induced dehydration and hyperosmolality that increase the VTE risk. Malignant brain tumor patients have also been shown to display an increased risk of VTE with reports of upward of 28 of patients having symptomatic events (47). At our institution we have...

Alumediated interchromosomal recombination in Ewing sarcoma

Gene fusion is a phenomenon arising from interchromosomal reorganisation. The fusion of RET and ELE1 genes occurs in radiation-induced thyroid carcinomas. We know from the investigation by Nikiforov et al. (1999) that the breakpoints culminating in the formation of the fusion gene seem to be distributed in the introns of the genes in a rather random manner. However, they do point out that there is a cluster of breakpoints in the Alu repeats of ELE1 gene.

Imatinib Mesylate Gleevec

In order to gather more information regarding the molecular mechanism of action of imatinib mesylate, anaplastic thyroid carcinomas (ATCs) were studied utilizing TMAs. Out of 12 tumors that were histologically proven to be ATCs, and had been treated with imatinib, 6 of them expressed at least one imatinib-sensitive tyrosine kinase. Imatinib reduced the metastatic potential, and halved the proliferation of thyroid cells without affecting apoptosis. Imatinib's antitumor activity may be a therapeutic option for some ATC patients (Rao et al., 2006).

Component Malignancies

Component malignancies in CS include breast, thyroid (16), and endometrial carcinomas (Table 2) (17). The most common malignancy seen in CS is adenocarcinoma of the breast, with lifetime risks in female CS patients estimated to be 25 to 50 compared with the lifetime risk of 12 to 13 in the general population (18,19). As commonly described in other hereditary breast cancer predisposition syndromes, the average age of breast cancer diagnosis is lower in patients with CS compared with that in sporadic cases. In CS, the average age of diagnosis is between 38 and 46 years while the average age of diagnosis is 55 to 65 years in sporadic cases (19). There has only been a single systematic study looking at histologies in CS-related breast carcinomas, but without knowing the germline PTEN status (20). In this study of 59 breast neoplasias belonging to 19 unrelated CS cases, 35 (59 ) had some malignant pathology. All cases of invasive breast cancer were ductal histology, with the exception of a...

Lymphovascular Drainage

Superior cornu of thyroid cartilage Cut portion of cricoid lamina Inferior cornu of thyroid cartilage Tracheal rings Superior cornu of thyroid cartilage Cut portion of cricoid lamina Inferior cornu of thyroid cartilage Tracheal rings Lamina of thyroid cartilage Lamina of thyroid cartilage

Alu elements in genetic transcription

The promoters of certain genes that contain binding sites for thyroid hormone receptor, ER and RA receptors also contain Alu repeats. Norris et al. (1995) reported that a class of Alu elements seemed to function as enhancers of oestrogen-dependent transcription, and further that they might have diverged into a special class of repeats. Norris et al. (1995) found that anti-oestrogens abolished this enhancer activity. Li, Yeh et al. (2000) have characterised the ERP promoter and have identified an Alu sequence containing an enhancer of ER-dependent transcription. However, there is a possibility that Alu repeats might be involved in other pathways of oestrogen function, namely via inactivation of progesterone receptors. Alu insertions may be found in PgR (Rowe etal., 1995). The thyroid hormone receptors, ER and RA bind to the nucleotide sequence AGGTCA. This motif may be duplicated and distributed with defined spacing and orientation, and they occur in Alu repeats (Babich et al., 1999).

Clinical Investigations

Serological studies for Epstein-Barr virus antigens are useful in nasopharyngeal carcinoma both in assessing the effects of therapy and in detecting recurrence. Baseline function of the thyroid gland should be determined prior to radical surgery or radiotherapy to the neck.

Nonmalignant Solid Organ Involvement

Benign thyroid lesions including adenomas, hamartomas, and multinodular goiter occur in 50 to 67 of all affected patients (16). It is suspected that Hashimoto thyroiditis occurs at an increased frequency in CS, especially in patients who are of non-Asian ancestry this belief is supported by early literature describing Hashimoto thyroiditis as a component of BRRS (8). Currently, functional disorders of the thyroid resulting in hyperthyroidism or hypothyroidism in the absence of adenomas or goiter are not considered components of CS.

Ovarian factor infertility

An ovarian factor is suggested by irregular cycles, abnormal BBT charts, midluteal phase serum progesterone levels less than 3 ng mL, or luteal phase defect documented by endometrial biopsy. Ovulatory dysfunction may be intrinsic to the ovaries or caused by thyroid, adrenal, prolactin, or central nervous system disorders. Emotional stress, changes in weight, or excessive exercise should be sought because these disorders can result in ovulatory dysfunction. Luteal phase deficiency is most often the result of inadequate ovarian progesterone secretion.

Resection Specimens

Total laryngectomy is the operation of choice in cases of radiotherapy failure, bulky T3 and T4 lesions, subglottic tumours and cord immobility and post-radiation perichondritis (crippled larynx). The ipsilateral lobe of thyroid is included when there is a likelihood of extralaryngeal spread in the subglottic region. The larynx will be included in major resections of hypopharynx.

Genotype Phenotype Correlation in CS

Approximately two-thirds of germline PTEN mutations are found in exons 5, 7, and 8, and approximately 40 of all CS mutations are located in exon 5, although this exon represents only 20 of the coding sequence (1,14). This reflects the biological significance of this domain, which encodes the phosphatase core motif. There is a correlation between the presence of germline PTEN mutations and breast carcinoma in probands meeting operational criteria for CS (14). In other words, the risk of breast cancer may be higher in those patients and families with a clinical diagnosis of CS who harbor germline PTEN mutations. Additionally, mutations within the phosphatase core motif and 5' of it appear to be associated with involvement of five or more organs, suggesting a correlation between mutations in this region of PTEN and disease severity (14). A recent study has demonstrated that promoter mutations are present in 10 of mutation negative patients with CS (47). Importantly, the functional...

Other Potential Regulators

GHRs are also regulated by thyroid hormones. The growth-promoting effects of exogenously administered GH are blunted in hypothyroid rats, hepatic GH binding sites are reduced in hypothyroidism, and elevated binding is observed in hyperthyroid rats (54). The authors have recently observed reduced GHR mRNA expression in the ARC in response to thyroidectomy, an effect that is rapidly restored by thyroid hormone replacement (P. A. Bennett, unpublished observations).

Clinical Presentation

Disease affecting the thyroid gland can present as enlargement (called goitre) that may be diffuse or nodular or as a consequence of hormonal imbalance rarely there may be pain. Hypothyroidism is characterised by lethargy, mental slowness or depression, intolerance of cold or weight gain Figure 17.1. Thyroid gland and parathyroid glands. a. View of thyroid gland from anterior aspect to show relation to larynx and regional lymph nodes. b. View of thyroid gland from posterior aspect to show location of parathyroid glands. Figure 17.1. Thyroid gland and parathyroid glands. a. View of thyroid gland from anterior aspect to show relation to larynx and regional lymph nodes. b. View of thyroid gland from posterior aspect to show location of parathyroid glands. Tumours of the thyroid gland usually present with a solitary nodule with normal thyroid function although some tumours can secrete hormones. Occasionally metastasis to cervical lymph nodes or bone may represent the initial symptom of...

Retinoic Acid Receptors and Gene Regulation

Vitamin A exerts its effects via retinoic acid and retinoid receptors, which are found in the nucleus of the cell. Retinol is converted to all-trans-retinoic acid and 9-cis retinoic acid in the cytoplasm. Retinoic acid influences gene activation through specific receptors which belong to the superfamily of thyroid and steroid receptors (231). Retinoic acid receptors (RARs) act as transcriptional activators for many specific target genes. The R AR is expressed as isoforms, referred to as RAR a, P, and y, and retinoid-x receptor (RXR) is also expressed as isoforms, referred to as RXR a, P, and y (232). All-trans retinoic acid is a ligand for RARs, whereas 9-cis retinoic acid is a ligand for both RARs and RXRs. 9-cis-retinoic acid is functionally distinct from all-trans-retinoic acid, and inter-conversion may exist between the two isomers. Each RAR and RXR has a specific DNA-binding domain by which these nuclear receptors may effect transcriptional activity. The DNA sequences which...

Nonneoplastic Conditions

Hashimoto's thyroiditis a common cause of hypothyroidism and is characterised by hypothy-roidism and firm diffuse goitre. It affects females much more often than males and usually presents between the ages of 30 and 50 years. It is an autoimmune disease the hypothyroidism is probably due to a combination of inactivation of the TSH receptor by autoantibodies and destruction of functioning gland. A proportion of patients may be euthyroid or hyperthyroid at presentation but hypothyroidism is inevitable. The gland is symmetrically and diffusely enlarged, weighing between 50 and 100 g. Histologically there is diffuse lymphoplasmacytic infiltration with germinal centre formation. The follicles are small and sparse with reduced or absent colloid. Hurthle cell change is widespread. A rare variant shows much fibrosis, affecting older patients and often males. Multinodular goitre a common cause of thyroid gland enlargement. Probably the end result of persistent stimulation of the glandular...

Neoplastic Conditions

Thyroid cancer Risk factors for thyroid carcinoma include irradiation (particularly in first two decades of life), underlying thyroid disease (especially Hashimoto's thyroiditis), family history of thyroid cancer including rare inherited syndromes such as Multiple Endocrine Neoplasia syndromes 2A and 2B, or non-MEN familial medullary thyroid carcinoma. Thyroid carcinomas are classified into three broad types differentiated thyroid cancer, medullary thyroid carcinoma and anaplastic carcinoma. Differentiated thyroid cancer encompasses papillary carcinoma, follicular carcinoma and their variants. Papillary carcinoma commonest thyroid malignancy, F M 3 1, 20-50 years. A few cases arise against a background of familial adenomatous polyposis syndromes. Very variable macroscopic appearances from tiny grey-white foci to tumours replacing the entire gland, but many are 2-3 cm diameter, white, firm, granular, infiltrative masses. Cystic degeneration is common, especially in nodal metastases....

Management of Malignancy in CS

Thyroid cancer should be treated with total thyroidectomy. Additionally, it is expert opinion that patients with thyroid adenomas, in whom surgery is deemed necessary, also be treated with complete thyroidectomy given the very high prevalence of benign thyroid neoplasias in CS that may make surveillance after hemithyroidectomy extremely difficult. In addition, the risk of developing a malignancy in the remaining thyroid tissue and the difficulty of repeated thyroid resection support this opinion.

Blocks for histology

In cases of neoplastic disease, the histology should represent the tumour, its relationship to its own capsule (if any), the capsule of the thyroid gland and adjacent structures (Figure 17.2). Focal abnormalities of the thyroid parenchyma need to be sampled as do adjacent lymph nodes and the parathyroid glands. Figure 17.2. Total thyroidectomy specimen. a. Recommended block selection to include isthmus, pyramidal lobe and contralateral lobe if present. Tissue block composites depend on the size of the tumour. b. Small. c. Large. Include other nodules. Figure 17.2. Total thyroidectomy specimen. a. Recommended block selection to include isthmus, pyramidal lobe and contralateral lobe if present. Tissue block composites depend on the size of the tumour. b. Small. c. Large. Include other nodules.

Histopathology report

Final reports of thyroid specimens should include details on other pathology such as Hashimoto's thyroiditis or radiation injury. TNM classification of tumour spread of thyroid gland. Papillary, follicular and medullary carcinoma. pT4 tumour extends beyond thyroid capsule with invasion of pT4a tumour limited to thyroid*. pT4b tumour beyond thyroid capsule+.

Cholesterol Synthesis Is Controlled By Regulation Of HmgcoA Reductase

Regulation of cholesterol synthesis is exerted near the beginning of the pathway, at the HMG-CoA reductase step. The reduced synthesis of cholesterol in starving animals is accompanied by a decrease in the activity of the enzyme. However, it is only hepatic synthesis that is inhibited by dietary cholesterol. HMG-CoA reductase in liver is inhibited by mevalonate, the immediate product of the pathway, and by cholesterol, the main product. Cholesterol (or a metabolite, eg, oxygenated sterol) represses transcription of the HMG-CoA reductase gene and is also believed to influence translation. A diurnal variation occurs in both cholesterol synthesis and reductase activity. In addition to these mechanisms regulating the rate of protein synthesis, the enzyme activity is also modulated more rapidly by posttransla-tional modification (Figure 26-4). Insulin or thyroid hormone increases HMG-CoA reductase activity, whereas glucagon or glucocorticoids decrease it. Activity is reversibly modified by...

Gross Description

Bilateral pleural effusions were noted with adhesions more prominent on the right side. The parenchyma had a red, congested appearance, but no discrete lesions were noted. The liver weighed 1920 g and had a dark red cut surface. The kidneys weighed 280 g combined and exhibited multiple cortical scars in keeping with remote renal infarctions. The spleen weighed 280 g. The thyroid weighed 25 g and had a multinodular appearance.

Pituitary and Placenta

Pit-1 is a 33kd pituitary-specific transcription factor that is necessary for GH, thyroid-stimulating hormone (TSH), and prolactin gene transcriptional activation, and for somatotroph, lactotroph, and thyrotroph establishment (32). The protein is a product of the POU-domain gene family and has three regions a transcriptional activation domain, a 60 amino acid sequence necessary for high-affinity DNA binding known as the POU homeodomain (POU-HD), and a 76 amino acid highly-conserved region that potentiates POU-HD binding, known as the POU specific domain (33). In humans, the gene encoding pit-1 has been mapped to chromosome 3p11.

Microscopic Description

Sections from the heart showed adipose tissue infiltration of the atria, myocyte hypertrophy more prominent in the left ventricle and replacement and perivascular fibrosis. In addition, there were myxomatous changes of the mitral valve with subvalvular thickening of the mural endocardium. The lungs showed mild emphysematous changes and hemosiderin-laden macrophages within alveolar spaces. Sections from the liver revealed moderate centrilobular fatty change, congestion and mild periportal lymphocytic infiltrates. The thyroid was multinodular with a lymphocytic infiltrate.

End Organ Targets and Receptors

The IGF-1 gene, located on the long arm of chromosome 12, spans 95 kb and contains at least six exons (102,103). Although GH appears to be the primary regulator of IGF-1 gene expression, transcriptional control is complex. It is influenced by nutritional status, GH, hCS, prolactin, glucocorticoids, sex steroids, thyroid hormones and insulin (104-107). The IGF-2 gene is 35 kb in length, contains nine exons, and is located adjacent to the insulin gene on the short arm of chromosome 11 (102,108).

Suggested Readings

Thyroid disease and the heart. Heart. 2000 84 45560. 4. Klein I, Ojamaa K. Thyroid hormone and the cardiovascular system. N Engl J Med. 2001 344 501-9. 5. Gomberg-Maitland M, Frishman WH. Thyroid hormone and cardiovascular disease. Am Heart J. 1998 135(2 Pt 1) 187-96.

Background And Relevant Pharmacokinetics

Iodine is an essential trace element required for the proper functioning of the thyroid gland. It is mainly consumed as iodide salts obtained from sea salt, shellfish and seawater fish and vegetables, which are more bioavailable than the organic form of iodine. The iodine content of soil is considered to be one of the most variable of all mineral levels, influenced by local geography and the type and quantity of fertiliser used in agriculture (Gropper et al 2005). The amount of iodine present in local drinking water (0.1-100 ig L) is reported to be a good indication of soil levels (Geissler & Powers 2005). In iodine-deficient areas, the iodide concentration in drinking water is < 2 Jg L (< 1 5.8 nmol L), whereas in areas close to the sea, the drinking water contains4to 10 g L (31.5-78.8 nmol L) (Beers 2005). Iodide is rapidly absorbed from the small intestine and distributed via the blood to a range of tissues, most notably the thyroid, which traps absorbed iodide through an...

Transcriptional Repressors and Repression Mechanisms

In addition to the factors mentioned above, DNA-binding repressors also directly interact with TBP or GTFs to inhibit transcription (Fig. 9. ID). This mechanism is called direct repression. For instance, Even-skipped (Eve), a Drosophila homeodomain protein, interacts with TBP in vitro and in tissue culture (Austin and Biggin, 1995 Li and Manley, 1998 Um et al, 1995). A repression domain of Eve directly contacts the C-terminal region of TBP, leading to inhibition of TFIID binding to the promoter. This repression is independent of the distance between the promoter and the Eve binding sites in vitro transcription assays. Unliganded thyroid hormone receptor (TR) also interacts with TBP and inhibits the formation of preinitiation complex in vitro, however TR bound to its ligand activates transcription by interacting with TFIIB (Baniahmad et al, 1993 Fondell et al, 1996 Fondell et al, 1993). Similarly, TFIIEbeta binds to a dimeric form of Kr ppel in vitro, a Drosophila zinc finger protein,...

Secondary Deficiency

Low selenium intake Low dietary intake of selenium is a factor that exacerbates the effects of iodine deficiency. Selenium is found in the thyroid gland in high concentrations, and while iodine is required for thyroid hormone synthesis, selenium-dependent enzymes are required for the peripheral conversion of thyroxine (T4) to its biologically active form triiodothyronine (T3) (Higdon 2003), as well as the general recycling of iodine. Selenium deficiency results in decreased T4 catabolism, which leads to increased production of peroxide and thyroid cell destruction, fibrosis and functional failure.

Familial adenomatous polyposis coli FAP

FAP is a highly penetrant autosomal dominant disorder, clinically characterised by the development of hundreds to thousands of adenomatous polyps of the colon and rectum. This rare syndrome has an annual incidence of around 1 7000 live births (Bisgaard et al., 1994). However malignancy is virtually inevitable if surgery is not undertaken and thus accounts for 0.2 of all colorectal neoplasia. There are a number of extra-colonic features such as multiple craniofacial and long bone osteomata, epidermoid cysts, retinal pigmentation, gastroduodenal polyposis and malignancy, desmoid tumors and an increased risk of peri-ampullary, papillary thyroid, brain tumors and sarcomas.

Glucocorticoid Receptor

The glucocorticoid receptor is a member of the nuclear steroid-thyroid receptor gene gamily (Chapter 1). Like the other receptors in this superfamily, the glucocorticoid receptor can be divided into functional domains (Figure 1-26). The major functional regions consist of the ligand-binding domain (C-terminal), the DNA-binding domain (central), and the antigenic domain (N-terminal). Bars in the figure locate additional functions, including transactivation and dimerization. The glucocorticoid receptor superfamily consists of the glucocorticoid receptor, the progesterone receptor, the mineralocorticoid receptor, and the androgen receptor. These receptors can bind to the palindromic hormone response element shown in Table 1-10, which differs from the response elements for the estradiol receptor-thyroid hormone receptor superfamily. These elements differ by only a few bases. In the case of the thyroid-responsive element, the sequence is the same as that for the estradiol receptor, except...

Rare dominant disorders

Cowden disease is a rare autosomal dominant disorder characterized by the development of oral and facial papules in concert with hamartomatous lesions of the thyroid, breast, skin and digestive tract and occasionally with neurological features. Mapping to chromosome 10q22-24 (Nelen et al., 1996) led to the identification of PTEN in which

General Skeletal Abnormalities

Cretinism (see Chapter 11 ) occurs when there is a deficiency in fetal thyroid hormone (T3 and T4) or thyroid agenesis. It results in growth retardation, skeletal abnormalities, mental retardation, and neurologic disorders. Cretinism is rare except in areas where there is a lack of iodine in the water and soil.

The Platelet Derived Growth Factor Receptor Beta Translocations

The t(5 i2)(q33 pi2) is observed in i of patients with chronic myelomonocytic leukemia (CMML). In i994, the molecular consequences of this translocation were elucidated. The gene encoding the beta chain of the platelet derived growth factor receptor (PDGFRB) is involved on chromosome 5. A novel ETS-like (Erythroblastosis Virus Transforming Sequence) transcription factor, TEL (translocated ETS in leukemia, also known as ETV6), is the gene affected on chromosome i2. The translocation creates a fusion gene and the encoded fusion protein contains the 5' portion of TEL and the 3' portion of PDGFRB (Golub et al. i994). Biochemical studies have revealed that the PDGFRB kinase activity is perturbed and contributes to the transformed pheno-type. TEL encodes a transcriptional repressor, and is promiscuously involved in translocations with some 4o genes in hematologic malignancies (Rowley 2ooo). Interest has increased in identifying this translocation, which predicts for a response to imatinib...

Clinical Aspects

Thyroid hormone deficiency may result in a wide variety of clinical and physiological disturbances in virtually every organ system. The classic disease state is myxedema the accumulation of mucinous edema results in facial periorbital and peripheral edema involving both the hands and feet. The periorbital edema contributes to the patient's haggard appearance and includes a droop of the upper eyelid. Table 6-6 lists the major causes of hypothyroidism. Hashimoto's disease is an autoimmune thyroid disease in which the subject has circulating thyroid antibodies. It is not known whether these antibodies functionally contribute to the state of hypothyroidism. The typical Human growth hormone* TSHa*, TSH 3* (thyroid-stimulating hormones) EGF receptor* Myosin heavy chain 3 In most cases, the effects of T3 + the thyroid receptor were assessed by determinations of steady-state mRNA levels. For those genes with an asterisk (*), the presence of an HRE or hormone response element has been...

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