Showing papers in "Thyroid in 1996"
TL;DR: Primary cultures of aortic endothelial and vascular smooth muscle cells exposed to T3 showed no nitric oxide production as measured by cellular cGMP content and nitrite release, suggesting that T3 acted directly on the VSM cell to cause vascular relaxation.
Abstract: The enhanced cardiovascular hemodynamics associated with triiodo-L-thyronine (T3) treatment is in part mediated by a decrease in systemic vascular resistance. To determine the molecular mechanisms for the vasoactive properties of T3, we studied primary cultures of aortic endothelial and vascular smooth muscle (VSM) cells. Active tension development by the VSM cells was measured by deformation lines within a siloxane matrix on which the cells were grown. Exposure to T3 (10(-10) M) resulted in cellular relaxation within 10 min. Hormone binding studies to purified VSM cell plasma membranes identified two binding sites specific for T3 with Kd of 1 x 10(-11) and 6.1 x 10(-8) M. L-Thyroxine and reverse T3 did not compete for the L-T3 binding sites. To determine an intracellular signaling pathway of T3 action, cAMP and cGMP content were measured in VSM cell cultures treated with T3. No quantitative changes were observed in a time frame known to cause VSM cell relaxation. The level of myosin light chain phosphorylation is a major determinant of smooth muscle contraction. Thus, treatment of VSM cells with isoproterenol, a vasodilator, caused a significant decrease in radiolabeled phosphate incorporation into the myosin light chains, whereas T3 had no effect on phosphorylation of these proteins. Primary cultures of vascular endothelial cells exposed to T3 showed no nitric oxide production as measured by cellular cGMP content and nitrite release, suggesting that T3 acted directly on the VSM cell to cause vascular relaxation.
302 citations
TL;DR: The physiologic significance at the cellular level of certain of thyroid hormone actions has been demonstrated, for example, in the cases of myocardiocyte Na+ current, red cell Ca2+ content, and the control by hormone-induced alterations in actin solubility of cell surface activity of iodothyronine 5'-monodeiodinase activity and the intracellular distribution of protein disulfide isomerase activity.
Abstract: Nongenomic actions of thyroid hormone are by definition independent of nuclear receptors for the hormone and have been described at the plasma membrane, various cell organelles, the cytoskeleton, and in cytoplasm. The actions include alterations in solute transport (Ca2+, Na+, glucose), changes in activities of several kinases, including protein kinase C, cAMP-dependent protein kinase and pyruvate kinase M2 (PKM2), effects on efficiency of specific mRNA translation and mRNA t1/2, modulation of mitochondrial respiration, and regulation of actin polymerization (promotion of formation of F-actin). Iodothyronines also can regulate nongenomically the state of contractile elements in vascular smooth muscle cells (VSMC). The physiologic significance at the cellular level of certain of these actions has been demonstrated, for example, in the cases of myocardiocyte Na+ current, red cell Ca2+ content, and the control by hormone-induced alterations in actin solubility of cell surface activity of iodothyronine 5'-monodeiodinase activity and the intracellular distribution of protein disulfide isomerase activity. The physiologic significance of these actions at the organ or system level is less clear, but extranuclear effects of thyroid hormone on myocardial Na+ channel, sarcoplasmic reticulum Ca(2+)-ATPase activity, and contractile state of VSMC may each contribute to acute effects of thyroid hormone on cardiac output that have recently been described clinically. The molecular mechanisms for nongenomic actions are incompletely understood; relevant binding sites and signal transduction pathways have been described for hormone actions on plasma membrane Ca(2+)-ATPase activity, and PKM2 monomer is known to bind T3 and, as a result, prevent activation of the kinase via tetramer formation. Nongenomic actions of thyroid hormone may have different structure-activity relationships of iodothyronines from those effects that depend upon nuclear receptors; they may have different time courses and may invoke complex signal transduction pathways before the action is detected.
248 citations
TL;DR: There was no difference in local/regional relapse free rate between patients receiving external radiation and those that did not, but in 40 high risk patients (microscopic residual disease, extraglandular invasion, or lymph node involvement), the local/Regional relapsefree rate was 86% at 10 years with postoperative external beam radiation.
Abstract: Records of 73 patients with medullary thyroid cancer were reviewed to assess prognostic factors and the role of external beam radiation therapy. Patients were treated between 1954 and 1992. The med...
244 citations
TL;DR: Patients with GDhigh showed a shift to a more Th2-driven cytokine pattern, and the increase mRNA levels of Th1-related cytokines found in HT indicate predominantly T cell-mediated cytotoxic processes.
Abstract: Intrathyroidal lymphocytes are a source of cytokines thought to stimulate or maintain the immune process within the thyroid in Graves' disease (GD) and Hashimoto's thyroiditis (HT). Quantitative assessment of the cytokine profile may provide important clues as to the Th1/Th2 balance prevailing in these diseases. We analyzed cytokine mRNA expression levels in thyroid tissue samples from 13 patients with GD, 2 with HT, 5 with nontoxic multinodular goiter (NTG), and 4 with thyroid autonomy (nodular = TAnod and perinodular = TAperi tissue) using multispecific competitor fragments with primer sequences for IL-1 beta, IL-2, IL-4, IL-6, IL-8, IL-10, IFN-gamma, CD25, and CD3 delta-chain mRNA. Patients with GD were subdivided into two groups according to their serum levels of antibodies to thyroperoxidase (anti-TPO; GDhigh > 4000 U/mL, GDlow < or = 200 U/mL). These levels correlated positively with the CD3 delta-chain mRNA levels (r = 0.83) and with the T cell infiltration (r = 0.71) as determined by immunohistochemistry. Patients with GDhigh demonstrated 2- to 4-fold higher IL-4 mRNA levels (as compared to all other investigated groups) and significantly higher IL-10 mRNA levels as compared to HT, GDlow, and TAnod patients. Patients with GDhigh also had significantly higher levels of IFN-gamma, IL-1 beta, IL-8, and CD25 mRNA as compared to GDlow. The highest IFN-gamma, IL-2, and CD25 mRNA levels were found in HT. The lowest mRNA levels of all the investigated groups were detected in TAnod. No significant differences in IL-6 and IL-8 mRNA levels were found between most of the patient groups. In summary, patients with GDhigh showed a shift to a more Th2-driven cytokine pattern. In contrast, the increase mRNA levels of Th1-related cytokines found in HT indicate predominantly T cell-mediated cytotoxic processes.
142 citations
TL;DR: The evidence establishes a direct morphologic connection between central thyronergic and noradrenergic systems, supporting earlier proposals that triiodothyronine or its proximate metabolites may serve as cotransmitters with norepinephrine in the adrenergic nervous system.
Abstract: During brain development, before the apparatus of neurotransmission has been set into place, many neurotransmitters act as growth regulators. In adult brain, their role in neurotransmission comes to the fore but neuronal plasticity and other growth-related processes are their continuing responsibility. This has been clearly demonstrated for catecholamines. Previous as well as recent evidence now indicates that thyroid hormones may participate in the developing and adult brain through similar mechanisms. Immunohistochemical mapping of brain triiodothyronine (antibody specificity established by numerous appropriate tests) demonstrated that the hormone was concentrated in both noradrenergic centers and noradrenergic projection sites. In the centers (locus coeruleus and lateral tegmental system) triiodothyronine staining, like that of tyrosine hydroxylase, was heavily concentrated in cytosol and cell processes. By contrast, in noradrenergic targets, label was most prominent in cell nuclei. Combined biochemical and morphologic data allows a construct of thyroid hormone circuitry to unfold: The locus coeruleus is conveniently located just beneath the ependyma of the 4th ventricle. Thyroxine, entering the brain via the choroid plexus, is preferentially delivered to subependymal brain structures. High concentrations of locus coeruleus norepinephrine promote active conversion of thyroxine to triiodothyronine, leading to the preeminence of the locus coeruleus as a site of triiodothyronine concentration. Results of treatment with the locus coeruleus neurotoxin DSP-4 established that axonal transport accounts for delivery of both triiodothyronine and norepinephrine from locus coeruleus to noradrenergic terminal fields. The apparatus for transduction of thyronergic and noradrenergic signals at both membrane and nuclear sites resides in the postsynaptic target cells. Upon internalization of hormone in post-synaptic target cells, genomic effects of triiodothyronine, norepinephrine, and/or their second messengers are possible and expected. The evidence establishes a direct morphologic connection between central thyronergic and noradrenergic systems, supporting earlier proposals that triiodothyronine or its proximate metabolites may serve as cotransmitters with norepinephrine in the adrenergic nervous system.
111 citations
TL;DR: A low prevalence of mutations in all ras gene family members in human thyroid neoplasms is established and may explain the relatively indolent biologic behavior of many thyroid tumors and supports an alternate early genetic mutation that is more characteristic of these neoplasm.
Abstract: Ras proteins are signal-transducing proteins that share common properties with membrane-anchored G proteins. Mutations at codon 12/13 or codon 61 alter GTP-binding or GTPase activity, respectively. Such activating mutations are present in nearly 30-50% of various malignancies including colon, breast, and lung carcinomas. There are conflicting data regarding the prevalence of ras mutations in the thyroid and their possible pathogenetic role in the different tumor types. To address this question, we examined 45 morphologically characterized thyroid carcinomas, adenomas, and hyperplastic nodules using a highly sensitive single-stranded conformation polymorphism (SSCP) approach combined with DNA sequencing. DNA from cell lines with known mutations served as controls. A G to A H13 codon substitution replacing an Asp for a Gly residue was detected in 1 papillary carcinoma. Although no H12 or H61 codon substitutions were identified, 2 discrete alterations were identified in codons H17 and 22. No N12/13 codon sub...
99 citations
TL;DR: The cardiac structure and function overall remains for practical purposes normal in subclinical hypothyroidism, however, the latter may be responsible for a mild prolongation of the preejection period during exercise and a slightly smaller left ventricular diastolic dimension at rest, changes that may not be of clinical significance in patients without underlying heart disease.
Abstract: Cardiac atrial and ventricular parameters were determined by Doppler two-dimensional echocardiography at rest and exercise in 8 patients with subclinical hypothyroidism (SCH) (6 women and 2 men; age range: 28-48 years) before and 3 months after achievement of a euthyroid state with incremental adjustment of L-thyroxine therapy. None of the patients had known heart disease. At 3 months of L-thyroxine therapy, TSH levels decreased from 14.8 +/- 9.4 mIU/L to 3.0 +/- 1.5 mIU/L and FTI increased from 7.1 +/- 1.8 to 8.1 +/- 1.9. The cardiac studies were performed at rest, and during incremental exercise load (50, 100, 150 W workload) on a Quinton exercise bicycle. No significant differences were found between the subclinical hypothyroid and euthyroid states in systolic blood pressure at rest (104.8 +/- 12.3 vs 105 +/- 10.1 mm Hg) and exercise (158 +/- 24.9 vs 158.5 +/- 20.9 mm Hg) or diastolic blood pressure at rest (70 +/- 4.7 vs 69 +/- 5.7 mm Hg) and exercise (86 +/- 11.4 vs 89.2 +/- 7.3 mm Hg). All echocardiographic atrial and ventricular parameters were similar before and during L-thyroxine therapy with the exception of a small but significant change in left ventricular diastolic dimension (4.5 +/- 0.3 vs 4.8 +/- 0.4 cm; p < 0.05). All Doppler parameters were not significantly affected by L-thyroxine therapy with the exception of preejection period at stage III exercise (51 +/- 17 vs 39 +/- 13 msec; p < 0.05). Preejection period at other stages of exercise showed trends toward similar differences between subclinical hypothyroidism and euthyroidism, but the differences were not statistically significant. We conclude that the cardiac structure and function overall remains for practical purposes normal in subclinical hypothyroidism. However, the latter may be responsible for a mild prolongation of the preejection period during exercise and a slightly smaller left ventricular diastolic dimension at rest, changes that may not be of clinical significance in patients without underlying heart disease.
92 citations
TL;DR: The histological diagnosis of Hashimoto's thyroiditis can most precisely be predicted by the newly developed radioassay for TgAb.
Abstract: Measurements of antithyroglobulin and antimicrosomal (antiperoxidase) antibodies have been performed widely for the clinical diagnosis of autoimmune thyroid diseases. The present study was designed to compare these antibody titers with histological findings of the thyroid in patients with diffuse goiter who were suspected of having Hashimoto's thyroiditis. One hundred and ten euthyroid or hypothyroid patients (10 males and 100 females; age 48 +/- 15 (SD) years old) with diffuse goiter were studied for the measurement of antithyroglobulin and antimicrosomal or antiperoxidase antibodies by a hemagglutination technique (TGHA and MCHA, respectively) and by a newly developed radioassay (TgAb and TPOAb, respectively). The antibody titers were compared with the histological findings obtained by needle biopsy. TgAb, TPOAb, TGHA, and MCHA were detected in 80 (96.4%), 61 (73.5%), 37 (44.6%), and 54 (65.1%) of 83 patients with histologically proven Hashimoto's thyroiditis, respectively, but in only one (3.7%) of 27 patients without any inflammatory changes in the biopsy specimen. In 55 patients with negative TGHA and MCHA, the TgAb positivity was more closely associated with the histological diagnosis of Hashimoto's thyroiditis than the TPOAb positivity was, the incidence of each antibody in Hashimoto's thyroiditis being 89.7% (26/29) and 27.6% (8/29), respectively. In conclusion, the histological diagnosis of Hashimoto's thyroiditis can most precisely be predicted by the newly developed radioassay for TgAb.
90 citations
TL;DR: The long acting SS octreotide was effective in reducing soft tissue inflammation and providing symptomatic relief in GO but not as effective as corticosteroid in reducing muscle size.
Abstract: Uncontrolled study has demonstrated the usefulness of somatostatin in the treatment of mild Graves' ophthalmopathy (GO). We performed a prospective study to evaluate the usefulness of somatostatin as compared to corticosteroid in the treatment of moderately severe GO. All patients were rendered euthyroid and observed for 3 months to exclude spontaneous improvement without active treatment. They were randomized to receive either somatostatin (SS, octreotide 200 micrograms q8h subcutaneously, n = 8) or corticosteroid (CS, prednisone 1 mg/kg/day in decreasing doses, n = 10). Assessments of soft tissue inflammation, exophthalmos, palpebral aperture, intraocular pressure, diplopia, cornea, and visual acuity were made every 4 weeks for 3 months. MRI of the orbit was performed before and after treatment. Both SS and CS therapy decreased the palpebral aperture and activity score after 3 months (p < 0.05), but those treated with CS had a lower activity score after treatment when compared to SS [2.5 (1-7) v.s. 3.5 (0-4), median (range), p < 0.05]. Only CS, but not SS, was able to reduce intraocular pressure and muscle size as documented by MRI, but no significant reduction in proptosis was observed in either group. Also, patients' self-assessments of the eye changes after treatment were similar between the two groups. Both groups showed significant elevation of urinary glycosaminoglycan (GAG) excretion before therapy (SS 24.6 +/- 10.8; CS 27.8 +/- 11.4 mg/24 h), which was reduced after treatment (SS 12.5 +/- 7.3; CS 10.8 +/- 6.3 mg/24 h, p < 0.05). However, no significant correlation could be observed between the degree of GAG reduction and the clinical outcome of the patients. In conclusion, the long acting SS octreotide was effective in reducing soft tissue inflammation and providing symptomatic relief in GO but not as effective as corticosteroid in reducing muscle size. In view of the minimal side-effects and similar efficacy as compared to corticosteroid in patients with minimal extraocular muscle enlargement, it is suggested that a trial of SS may be considered in selected patients with GO.
90 citations
TL;DR: In this article, the authors investigated the effect of intralipid and subcutaneous (sc) heparin on the generation of free fatty acids (FFA) in the presence of sufficient substrate (serum TG greater than approximately 180 mg/dL).
Abstract: Heparin can cause an artifactual elevation in the concentration of unbound (free) thyroxine (T4) in the plasma, particularly when measured by equilibrium dialysis. The lipase released into the plasma by heparin acts on substrate (triglycerides; TG) in the plasma in vitro to release nonesterified (free) fatty acids (FFA), which, in high concentrations, inhibit the binding of T4 to its plasma binding proteins. This artifact occurs only in the presence of sufficient substrate (serum TG greater than approximately 180 mg/dL), and is most pronounced in methods requiring long incubation times. We observed this artifact in a patient receiving intralipid and subcutaneous (sc) heparin. Plasma-free T4, when measured by equilibrium dialysis, was elevated, but was normalized when the in vitro generation of FFA during equilibrium dialysis was prevented by prior treatment of the sample with protamine to inhibit lipoprotein lipase and with an antibody to hepatic triglyceride lipase. This observation caused us to investigate formally whether heparin, at standard sc doses or at iv doses even lower than those that are commonly used to flush iv lines (100-300 U), could also cause this artifact. We gave increasing doses of heparin at weekly intervals to each of three normal volunteers and measured FFA generation in their plasma (supplemented with 250 mg/dL triglycerides) under conditions simulating equilibrium dialysis. We found that, indeed, iv doses of heparin as low as 0.08 U/kg (5.6 U in a 70-kg subject) as well as a standard dose of sc heparin (5000 U) could release significant lipase activity into the plasma and, in the setting of sufficient substrate, cause enough in vitro generation of FFA to artifactually increase the serum-free T4 concentration when measured by equilibrium dialysis. These results indicate that equilibrium dialysis may not always be the best method for assessing serum-free T4 concentrations in hospitalized patients, and should be taken into account when interpreting previous studies demonstrating inhibitors of T4-serum protein binding in sera from hospitalized patients.
88 citations
TL;DR: It is demonstrated that PEI may be a safe and effective procedure in the treatment of large TCN.
Abstract: To evaluate the effect of percutaneous ethanol injection (PEI) in the treatment of large compressive thyroid cystic nodules (TCN), we studied 20 patients, potential candidates for surgery (tracheal...
TL;DR: It is concluded that p53 immunohistochemistry cannot be used for diagnostic and prognostic purposes in thyroid tumors and WAF1/p21 immunohISTochemistry contributes to the information of the functional status of p53, and may facilitate the interpretation of results from p53 Immunohistochemical in these tumors.
Abstract: We have investigated p53 expression in 178 thyroid tumors from 162 patients by immunohistochemistry using two antibodies, DO1 and CM1 In addition, 35 tumors were analyzed for expression of WAF1/p2
TL;DR: The influence of L-T4 on both thyroid autoantibody levels and thyroid volume might be explained by reduction of antigenic substance through a decreased stimulation of thyroid tissue by circulating TSH as was seen in CH but not in SH patients.
Abstract: The changes in the serum thyroid autoantibodies, antithyroglobulin (TgAb) and antithyroid-peroxidase (TPOAb), lipid profile, and thyroid volume following L-thyroxine (L-T4) therapy is still a controversial matter We studied 23 patients with goiter due to Hashimoto's thyroiditis; 10 had clinical hypothyroidism (CH) and 13 had subclinical hypothyroidism (SH) Both groups received L-T4 (20 to 25 micrograms/kg/day) for a median period of 6 months Serum concentration of TgAb (normal value: < 200 mUI/mL) and TPOAb (normal value: < 150 mUI/mL) were measured by a sensitive IRMA using 125I protein-A Thyroid volume was determined by ultrasound (normal value: 8-14 mL) At the end of the observation period the median serum TSH concentration decreased significantly in both groups (429 to 055 in CH and 24 to 074 mU/L in SH patients) and serum FT4I levels increased only in the CH group (087 to 21; p < 005) Serum TgAb concentration did not change in SH patients (72 to 218 mUI/mL) but declined in CH patients (3645 to 75 mU/mL; p < 005) TPOAb levels also fell in the CH group (871 to 194 mUI/mL; p < 005) and no significant change was noted in SH patients (260 to 116 mUI/mL) Further, a significant correlation was obtained between TSH and either TPOAb concentration (rs = 0569, p < 001) or thyroid volume (rs = 0488, p < 005) in the CH group but not in SH patients (rs = 0232, NS) LDL-cholesterol was higher in the CH (1594 mg/dL) compared with the SH group (116 mg/dL) Moreover, only in the CH patients was there a significant fall in total cholesterol (2245 to 1655 mg/dL, p < 005) and in LDL-cholesterol (1594 to 1043 mg/dL, p < 005) values The thyroid volume decreased in all patients with CH and in 77% (10/13) of SH patients and a significant median in the thyroid volume decrease was found (397% of initial volume in the CH group and 809% in SH patients; p < 001) The influence of L-T4 on both thyroid autoantibody levels and thyroid volume might be explained by reduction of antigenic substance through a decreased stimulation of thyroid tissue by circulating TSH as was seen in CH but not in SH patients The benefits of the administration of L-T4 replacement therapy in SH patients due to Hashimoto's thyroiditis remain to be clarified
TL;DR: Although frank hyperthyroidism following contrast radiography was uncommon, there was a significant trend towards thyroid stimulation rather than suppression after iodine exposure, which may be related to the age of the patients studied.
Abstract: To observe the effect of iodine in nonionic contrast media on thyroid function, we measured free thyroxine (FT4) and thyroid stimulating hormone (TSH) following nonionic contrast radiography in 73 patients (49 males; 24 females) aged 50 to 84 years, mean 65.7 years. FT4 was significantly (p < 0.01) raised above baseline at 8 weeks but not 4 weeks following contrast injection (mean +/- standard deviation, 17.1 +/- 5.9 and 14.3 +/- 4.0 vs 13.3 +/- 2.7 pmol/L at baseline); however, TSH was significantly (p < 0.03) depressed at both 4 and 8 weeks (1.09 +/- 0.68 and 1.21 +/- 1.56 vs 1.40 +/- 0.90 mIU/L). T3 did not change significantly. FT4 rose by more than 20% in 15/73 and TSH fell by more than 20% in 41/73 compared to a fall of FT4 in 3/73 and a rise in TSH of 8/73 (p < 0.005 and < 0.001, respectively). Two patients became hyperthyroid and in four others either FT4 was elevated or TSH suppressed, one of whom developed atrial fibrillation. Although frank hyperthyroidism following contrast radiography was uncommon, there was a significant trend towards thyroid stimulation rather than suppression after iodine exposure. This may be related to the age of the patients studied.
TL;DR: Reducing thyroxine replacement dosage to half the usual amount, in patients with thyroid cancer, allows after 5 weeks in most patients sufficient elevation of TSH for whole body scanning and measurement of TG levels, and makes this key procedure much more tolerable to patients.
Abstract: Patients who have undergone thyroidectomy for thyroid carcinoma are frequently subjected to periods of induced severe hypothyroidism in preparation for 131I whole body scanning and measurement of s...
TL;DR: A 57-year-old woman with no previous personal or family history of thyroid disease developed typical subacute thyroiditis, with pain and tenderness in the anterior cervical region, fever, mild thyrotoxicosis, which led to recurrence of hyperthyroidism, suggesting that a genetic susceptibility to the disease must exist in such an instance.
Abstract: A 57-year-old woman with no previous personal or family history of thyroid disease developed typical subacute thyroiditis, with pain and tenderness in the anterior cervical region, fever, mild thyrotoxicosis; thyroid autoantibodies were negative, serum thyroglobulin (TG) levels were increased, radioactive iodine uptake (RAIU) values were decreased, urinary iodine excretion was normal, and erythrocyte sedimentation rate (ESR) elevated. Symptoms subsided with glucocorticoid treatment, with normalization of serum thyroid hormone and TG levels. Four months later, while still on a low dose of glucocorticoid, she had recurrence of hyperthyroidism, with no thyroid pain or tenderness, high RAIU values, positive thyroid-directed autoantibodies including TSH-receptor antibody. HLA typing showed positivity for B35 and DR3, suggesting a genetic susceptibility for both subacute thyroiditis and Graves' disease. The development of Graves' disease after subacute thyroiditis is extremely rare, suggesting that a genetic su...
TL;DR: To address the concern of T3 administration possibility exacerbating a hypermetabolic state, basal metabolic rate was measured in a group of advanced heart failure patients and was found to be generally within the normal range, but some patients had an increase in cardiac output, consistent with a peripheral vasodilatory effect.
Abstract: Though thyroid hormone abnormalities have been identified in many cardiac conditions, the role of thyroid hormones in congestive heart failure has not been well defined. In a population of patients with advanced heart failure, a reduction in triiodothyronine (T3) with an increase in reverse T3 was identified in many patients, with an abnormally low ratio of T3/reverse T3 being the strongest predictor of mortality. Normalization of thyroid indices appeared to be necessary for prolonged survival to occur. To address the concern of T3 administration possibility exacerbating a hypermetabolic state, basal metabolic rate was measured in a group of advanced heart failure patients and was found to be generally within the normal range. A preliminary safety study of short-term intravenous T3 administration (bolus +/- 6 h infusion, total dose 0.15-2.7 micrograms/kg) was then performed in 23 patients under hemodynamic and electrocardiographic monitoring. There were neither adverse events nor substantial hemodynamic changes, but some patients had an increase in cardiac output, consistent with a peripheral vasodilatory effect. With this foundation, further investigation into the possible role of T3 and its analogs in congestive heart failure therapy may be pursued.
TL;DR: It seems likely that a tendency toward hypothyroidism can predispose to depression, but when depression occurs in a euthyroid patient, the thyroid axis is often invoked in the process of restitution.
Abstract: Hormones of the thyroid axis have been used to treat patients with any of several mental illnesses. However, in recent decades interest has focused almost exclusively on depression, though thyroid hormones, mainly thyroxine (T4), are used with lithium in rapid cycling bipolar disorder, a condition in which depression and mania rapidly alternate. In depression L-triiodothyronine (T3) has been used in preference to T4 because of its rapid onset and offset of action. In women starting treatment, T3 hastens the onset of therapeutic action of standard antidepressant drugs. It fails to do so in depressed men, who anyway respond faster than women to standard antidepressants. Standard drugs fail to produce satisfactory improvement in one-quarter to one-third of depressed patients. Then, in both men and women, T3 converts about two-thirds of drug failures to successes in rapid fashion. Lithium, which has antithyroid properties, produces a similar conversion rate. The majority of depressed patients are grossly euthyroid, but many show one or another subtle change in thyroid axis activity. However, the thyroid state of patients has not been matched systematically with their response to thyroid hormone augmentation. It seems likely that a tendency toward hypothyroidism can predispose to depression, but when depression occurs in a euthyroid patient, the thyroid axis is often invoked in the process of restitution.
TL;DR: This patient probably represents the first ectopic TSH-secreting pituitary tumor to be reported and was ultimately shown histologically and immunohistochemically to be an ectopic pituitsary tumor.
Abstract: A woman developed what appeared to be typical Graves' disease in 1965 at the age of 45 years. After 9 years of antithyroid drug therapy, she was treated with radioiodine. Ten years later (1985) she developed postablative hypothyroidism. Despite replacement doses of thyroxine that resulted in thyroid hormone levels that were in the hyperthyroid range, TSH levels remained elevated. Initial biochemical studies, including a high alpha-subunit to TSH ratio, suggested a pituitary TSH-secreting tumor, but a CT scan of the sella turcica was normal. In 1994, while undergoing an otolaryngologic examination, the patient was found to have a nasopharyngeal mass lesion, which was ultimately shown histologically and immunohistochemically to be an ectopic pituitary tumor. Resection of the mass restored TSH and alpha-subunit levels to normal. This patient probably represents the first ectopic TSH-secreting pituitary tumor to be reported.
TL;DR: The impact of T3 therapy to initially unstable donors allowed for rapid inotropic reduction and recovery of the heart, thus enlarging the donor organ pool and improving the outcome of the recipients following cardiac transplantation.
Abstract: In clinical heart transplantation, the heart is procured from brain dead (BD) organ donors who acutely experienced a variety of critical illnesses. In all of these conditions, a profound derangemen...
TL;DR: Results provide definitive evidence that TPO is involved in the MN-induced black thyroid, and MN is an inhibitor of TPO-catalyzed iodination in model systems, with a potency comparable to that of MMI and PTU.
Abstract: Minocycline (MN), a member of the tetracycline family of antibiotics, is known to induce a black discoloration of the thyroid in several species, including humans. Antithyroid effects of MN have also been reported. The aim of the present study was two-fold: (1) to determine whether thyroid peroxidase (TPO) is involved in the MN-induced black thyroid, and (2) to obtain information on the effect of MN on TPO-catalyzed iodination and coupling in model systems containing highly purified TPO. Treatment of MN with TPO in the presence of the H2O2 generating system, glucose-glucose oxidase, resulted in the formation of a black product (or products). In phosphate buffer, pH 7.0, the color intensity reached its peak in about 90 min. Control samples without TPO showed little or no color change during this interval. Formation of the black product(s) did not require the presence of iodide. Other members of the tetracycline family were not oxidized to dark products by the TPO system. These results provide definitive ev...
TL;DR: Recently, the "Cold SSCP" method, nonradioactive single-stranded conformation polymorphism analysis, is utilized and a novel mutation, a 6-bp deletion preceding the cysteine-634, is identified in a sporadic MTC.
Abstract: RET germline mutations were found to predispose to the development of three variants of multiple endocrine neoplasia type 2, MEN2A, MEN2B, and familial medullary thyroid carcinoma (FMTC). We have screened for RET mutations at exons 10, 11, 13, and 16 in leukocyte DNA extracted from 37 individuals, and have identified RET germline mutations in 12 affected individuals from 9 unrelated families. No RET germline mutation was found in 19 individuals with apparent sporadic diseases. We have also screened for RET mutations at exons 10, 11, and 16 in tumor DNA extracted from 13 freshly frozen medullary thyroid carcinomas (MTC). RET mutation was detected in every tumor, either inherited or sporadic, indicating that RET plays an important role in the development of both inherited and sporadic MTC. We initially screened for RET mutations by direct DNA sequencing of the genomic PCR products amplified from patients' leukocyte or tumor DNA. Recently, we utilized the "Cold SSCP" method, nonradioactive single-stranded conformation polymorphism analysis, to screen for RET mutations and have identified a novel mutation, a 6-bp deletion preceding the cysteine-634, in a sporadic MTC.
TL;DR: To the knowledge, this is the first time that a mutation in the thyroglobulin gene has been described in a patient with endemic simple goiter and further confirms the association between the exon 10 mutation and development of goiter.
Abstract: Iodine deficiency is the most relevant etiologic factor in endemic goiter. However, the fact that not all residents in the same area eventually develop goiter suggests that individual factors might also be involved in the etiology of endemic goiter. We have previously reported a point mutation in thyroglobulin exon 10 associated with nonendemic simple goiter. In an attempt to determine whether the mutation in thyroglobulin exon 10 might be linked to endemic goiter, we studied the genomic organization of thyroglobulin exon 10 in 36 patients diagnosed with endemic goiter by Southern blot, PCR, and sequencing analysis. We also analyzed by Southern blot the organization of the genomic region that contains thyroglobulin exons 1 to 11. In one case, we observed a point mutation in thyroglobulin exon 10. Sequencing analysis revealed a mutation at position 2610 of the cDNA, which implies a G to T substitution. This single base change results in a glutamine to histidine substitution and is the same as that previously reported by our group in patients with nonendemic goiter. To our knowledge, this is the first time that a mutation in the thyroglobulin gene has been described in a patient with endemic simple goiter and further confirms the association between the exon 10 mutation and development of goiter.
TL;DR: It is suggested that different regulation of thyroid hormone transport into the relevant tissues, i.e., liver and pituitary, may play a role in maintenance of the low T3 production during NTI and fasting and that these different thyroid hormone carriers allow tissue-specific regulation of the intracellular availability of T3.
Abstract: Nonthyroidal illness (NTI) and fasting in man are characterized by a low serum concentration of T3 and an increased serum concentration of rT3. Since the serum level of T3 is one of the most important factors that determine the metabolic rate, the low serum T3 during NTI or fasting results in reduction of the energy consumption of the body. This can be regarded as an adaptive mechanism to save energy, and thus to conserve protein and to protect organ function. The low serum T3 concentration should preferentially be maintained until recovery from illness or adequate calorie supply. This implies that the low serum T3 should not result in a rise in serum TSH. We postulate that different regulation of thyroid hormone transport into the relevant tissues, i.e., liver and pituitary, may play a role in maintenance of the low T3 production during NTI and fasting. This hypothesis is further elaborated in this paper by comparing (i) the properties of the thyroid hormone uptake mechanism in rat and human hepatocytes, perfused rat liver, and rat anterior pituitary cells, and (ii) the effects of fasting and conditions that mimic NTI on thyroid hormone transport in the same preparations. In addition, the consequences of changes in thyroid hormone transport and peripheral thyroid hormone metabolism during fasting and NTI for the serum level of rT3 and for TSH secretion are discussed. The data are compatible with the existence of different transport systems for thyroid hormone in liver and pituitary. We suggest that these different thyroid hormone carriers allow tissue-specific regulation of the intracellular availability of T3.
TL;DR: Octreotide therapy was particularly successful in patients with soft tissue involvement of GO (class II or III disease), and mean proptosis and ophthalmopathy index scores were significantly decreased after 3 months of octanotide therapy, suggesting that octreotide may have immunomodulatory properties.
Abstract: Efficacy of octreotide treatment for Graves' ophthalmopathy (GO) and the effects of this treatment on the serum levels of the circulating intercellular adhesion molecule-1 (sICAM-1) were evaluated. Ten patients with GO were treated with octreotide three daily SC injections of 100 micrograms, for 3 months. Octreotide treatment was initiated after restoration of euthyroidism with antithyroid drugs. All patients were treated with methimazole to maintain euthyroidism during the study. Sera were collected from all patients before and 3 months after initiation of the study, and from 20 age- and sex-matched healthy subjects for sICAM-1 measurement. sICAM-1 was measured by a sandwich ELISA method. Proptosis in all patients was evaluated by orbital CT scan before and 3 months after initiation of the study. Two of 10 patients did not respond to octreotide therapy, while the remaining eight patients showed regression or improvement after therapy. Octreotide therapy was particularly successful in patients with soft tissue involvement of GO (class II or III disease). Mean proptosis and ophthalmopathy index scores were significantly decreased after 3 months of octreotide therapy. Mean sICAM-1 levels were significantly higher in patients before octreotide therapy (470.5 +/- 52.6 ng/mL, p < 0.0001) when compared to normal subjects (186.5 +/- 53.3 ng/mL). Mean sICAM-1 levels were significantly decreased 3 months after octreotide therapy (from 478.7 +/- 52.6 to 415 +/- 42.8 ng/mL, p = 0.012) in the 8 patients who responded to therapy. In contrast, sICAM-1 levels remained unchanged or increased in two patients with poor response to octreotide therapy. Our results suggest that octreotide therapy could be a treatment modality in patients with GO. The mechanism by which octreotide acts on GO is not clear. The observed decrease in sICAM-1 levels during octreotide therapy suggests that octreotide may have immunomodulatory properties. Further investigation is needed to determine the optimal dose and duration of octreotide therapy.
TL;DR: The results suggest that the expression of TSH-R in the orbit, especially fibroblasts, may play a role in the pathogenesis and clinical manifestations of the ophthalmopathy in patients with TAO, although a secondary effect, involving fibro Blasts in TAO is also possible.
Abstract: We have studied the cellular localization of thyrotropin receptor (TSH-R) mRNA in orbital fat and extraocular muscle tissues from patients with thyroid-associated ophthalmopathy (TAO) using Northern blot, reverse transcriptase polymerase chain reaction (RT-PCR), and in situ hybridization, and we correlated the findings with clinical estimates of ophthalmopathy. Although we failed to detect TSH-R mRNA in orbital tissues by Northern blot, TSH-R cDNA was amplified in orbital fat tissue from 13 of 25 patients with TAO and from 2 of 4 control subjects, in eye muscle tissue from 2 out of 7 patients with TAO, and in cultured orbital fibroblasts and subcutaneous fibroblasts from TAO patients. In situ hybridization showed that TSH-R mRNA was detected in cultured orbital fibroblasts as well as skin fibroblasts obtained from the patient. Furthermore, the expression of TSH-R mRNA in orbital fat tissue from patients with TAO significantly correlated with the orbital fat volume and the severity of ophthalmopathy, especially the extent of eye muscle dysfunction. These results suggest that the expression of TSH-R in the orbit, especially fibroblasts, may play a role in the pathogenesis and clinical manifestations of the ophthalmopathy in patients with TAO, although a secondary effect, involving fibroblasts in TAO is also possible.
TL;DR: To deliver optimal radioiodine activity in hemodialyzed patients with thyroid carcinoma, the behavior ofRadioiodine was followed during six treatments and the whole body dose was calculated from the total activity determined during 10 days after 131I administration.
Abstract: To deliver optimal radioiodine activity in hemodialyzed patients with thyroid carcinoma, the behavior of radioiodine was followed during six treatments. During hemodialysis, blood activity decreases with a half-life of 3.4 +/- 0.5, (1SD) h. The whole body dose was calculated from the total activity determined during 10 days after 131I administration. A reasonable strategy may consist in delivering 25% of the currently prescribed activity (925 MBq-25 mCi) and to perform the first dialysis session after 24 h to reduce total body irradiation.
TL;DR: Several tumor-seeking radioisotopic agents other than radioiodine have shown promise for improving the detection of metastases, and some of these agents offer a useful adjunct to 131I in the management of selected patients, particularly in those with suspected metastatic disease and negative 131I scans.
Abstract: The avidity of differentiated thyroid carcinoma for iodine is the basis for the use of radioiodine (131I) both for the detection and the treatment of recurrent thyroid cancer in patients following ...
TL;DR: A patient with longstanding Hashimoto's thyroiditis who was treated with L-thyroxine at a dosage of 0.05 mg/day developed a decreased serum TSH concentration and developed mild hyperthyroidism due to Graves' disease simultaneously suggests an underlying derangement in immune regulation common to both diseases.
Abstract: A patient with longstanding Hashimoto's thyroiditis who was treated with L-thyroxine at a dosage of 0.05 mg/day developed a decreased serum TSH concentration. L-Thyroxine was discontinued. Within 1 month, the patient developed mild hyperthyroidism due to Graves' disease. A hemorrhagic disorder occurred simultaneously with bleeding into muscle, joints, and skin. The bleeding disorder was identified as an acquired factor VIII deficiency due to a factor VIII inhibitor. The bleeding disorder resolved after treatment with prednisone, cyclophosphamide, and intravenous gamma globulin. Graves' disease also resolved but without specific treatment with either antithyroid drugs or radioactive iodine. The development of these two autoimmune disorders in this patient simultaneously suggests an underlying derangement in immune regulation common to both diseases.
TL;DR: It is suggested that heat shock protects FRTL-5 cells from hypoxic injury, perhaps by inhibiting the initial rate of iodide uptake and second messengers, and HSP-70 plays an essential role in the process of protection.
Abstract: Chronic hypoxia inhibits rat thyroid function in vivo. To determine possible mechanisms, we studied the effect of hypoxia on iodide uptake, the involvement of second messengers, and cell membrane p...