Targeting thyroid diseases with TSH receptor analogs.

Science.gov (United States)

Galofré, Juan C; Chacón, Ana M; Latif, Rauf

2013-12-01

The thyroid-stimulating hormone (TSH) receptor (TSHR) is a major regulator of thyroid function and growth, and is the key antigen in several pathological conditions including hyperthyroidism, hypothyroidism, and thyroid tumors. Various effective treatment strategies are currently available for many of these clinical conditions such as antithyroid drugs or radioiodine therapy, but they are not devoid of side effects. In addition, treatment of complications of Graves' disease such as Graves' ophthalmopathy is often difficult and unsatisfactory using current methods. Recent advances in basic research on both in vitro and in vivo models have suggested that TSH analogs could be used for diagnosis and treatment of some of the thyroid diseases. The advent of high-throughput screening methods has resulted in a group of TSH analogs called small molecules, which have the potential to be developed as promising drugs. Small molecules are low molecular weight compounds with agonist, antagonist and, in some cases, inverse agonist activity on TSHR. This short review will focus on current advances in development of TSH analogs and their potential clinical applications. Rapid advances in this field may lead to the conduct of clinical trials of small molecules related to TSHR for the management of Graves' disease, thyroid cancer, and thyroid-related osteoporosis in the coming years. Copyright © 2012 SEEN. Published by Elsevier Espana. All rights reserved.

Association between TSH-Receptor Autoimmunity, Hyperthyroidism, Goitre, and Orbitopathy in 208 Patients Included in the Remission Induction and Sustenance in Graves’ Disease Study

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Peter Laurberg

2014-01-01

Full Text Available Background. Graves’ disease may have a number of clinical manifestations with varying degrees of activity that may not always run in parallel. Objectives. To study associations between serum levels of TSH-receptor autoantibodies and the three main manifestations of Graves’ disease (hyperthyroidism, goiter, and presence of orbitopathy at the time of diagnosis of hyperthyroidism. Methods. We describe a cohort of 208 patients with newly diagnosed Graves’ hyperthyroidism. Patients were enrolled in a multiphase study of antithyroid drug therapy of Graves’ hyperthyroidism, entitled “Remission Induction and Sustenance in Graves’ Disease (RISG.” Patients were systematically tested for degree of biochemical hyperthyroidism, enlarged thyroid volume by ultrasonography, and the presence of orbitopathy. Results. Positive correlations were found between the levels of TSH-receptor autoantibodies in serum and the three manifestations of Graves’ disease: severeness of hyperthyroidism, presence of enlarged thyroid, and presence of orbitopathy, as well as between the different types of manifestations. Only around half of patients had enlarged thyroid gland at the time of diagnosis of hyperthyroidism, whereas 25–30% had orbitopathy. Conclusions. A positive but rather weak correlation was found between TSH-receptor antibodies in serum and the major clinical manifestation of Graves’ disease. Only half of the patients had an enlarged thyroid gland at the time of diagnosis.

Targeting the thyroid gland with thyroid-stimulating hormone (TSH)-nanoliposomes.

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Paolino, Donatella; Cosco, Donato; Gaspari, Marco; Celano, Marilena; Wolfram, Joy; Voce, Pasquale; Puxeddu, Efisio; Filetti, Sebastiano; Celia, Christian; Ferrari, Mauro; Russo, Diego; Fresta, Massimo

2014-08-01

Various tissue-specific antibodies have been attached to nanoparticles to obtain targeted delivery. In particular, nanodelivery systems with selectivity for breast, prostate and cancer tissue have been developed. Here, we have developed a nanodelivery system that targets the thyroid gland. Nanoliposomes have been conjugated to the thyroid-stimulating hormone (TSH), which binds to the TSH receptor (TSHr) on the surface of thyrocytes. The results indicate that the intracellular uptake of TSH-nanoliposomes is increased in cells expressing the TSHr. The accumulation of targeted nanoliposomes in the thyroid gland following intravenous injection was 3.5-fold higher in comparison to untargeted nanoliposomes. Furthermore, TSH-nanoliposomes encapsulated with gemcitabine showed improved anticancer efficacy in vitro and in a tumor model of follicular thyroid carcinoma. This drug delivery system could be used for the treatment of a broad spectrum of thyroid diseases to reduce side effects and improve therapeutic efficacy. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

Elaboration of a radioligand receptor assay for TSH and thyroid-stimulating immunoglobulins

International Nuclear Information System (INIS)

Wille, A.

1980-01-01

125 J-TSH is bound by membrane preparations from human thyroid glands. The removal of the radioactive hormone from the bond, interpreted by means of a standard curve, is an indicator of the unknown quantity of TSH or TSI. The specific binding of the TSH to the membrane proceeds as a function of hydrogen ion concentration, temperature, and incubation time. Since all globulins exhibit an unspecific binding to the membranes, it is necessary to separate the gamma globulin fraction from the serum in order to detect the TSI. The separation is achieved by QAE Sephadex A-50 columns. The displacement characteristics of the gamma globulin fractions are determined in the radioligand receptor assay. The classification into normal and pathological findings is done in accordance with the TSI index of Smith and Hall. The poor detection of TSI in the sera studied is attributed to the fact that the group of patients of this study had already been treated at the time the blood sera were taken. The TSH content of homogenates from human, postmortally taken pituitary glands is determined by the RRA and compared with the TSH values of the RIA. The comparison shows a positive correlation, with the TSH data of the RRA being above those of the radioimmunoassay. (orig./MG) [de

Incidence of radiation-induced Graves' disease in patients treated with radioiodine for thyroid autonomy before and after introduction of a high-sensitivity TSH receptor antibody assay

International Nuclear Information System (INIS)

Dunkelmann, Simone; Wolf, Ricarda; Koch, Annedore; Kittner, Christian; Groth, Peter; Schuemichen, Carl

2004-01-01

Autoimmune hyperthyroidism may occur several months after radioiodine therapy (RIT) for functional thyroid autonomy. Exacerbation of pre-existing subclinical Graves' disease (GD) has been held responsible for this phenomenon. Determination of TSH receptor antibody using solubilised porcine epithelial cell membranes is insensitive and may have failed to diagnose GD in these patients before RIT. Following the introduction of a more sensitive assay, using the human TSH receptor as an antigen, it has been expected that the incidence of radiation-induced GD after RIT for functional thyroid autonomy will be reduced. In a first group of 1,428 patients treated between November 1993 and March 1997 (group I) we used the porcine TRAb assay to exclude GD, while in a second group comprising 1,408 patients treated between January 2000 and December 2001 (group II), GD was excluded using the human TRAb assay. A matched control group of 231 patients was derived from group II. In group I a total of 15 (1.05%) patients developed obvious or suspected radiation-induced GD, while in group II 17 (1.2%) did so; the interval until development of GD was 8.4 and 8.8 months, respectively, after RIT. Serum anti-thyroid peroxidase levels before RIT were elevated in 36.4% of group I patients and 47.1% of group II patients, but in only 5.6% of the control group. Other non-specific signs of mild immunopathy of the thyroid were seen retrospectively in 73.3%, 64.7% and 16.0% of the patients in these three groups, respectively. In conclusion, the introduction of a high-sensitivity TRAb assay did not reduce the incidence of autoimmune hyperthyroidism occurring late after RIT for functional thyroid autonomy, but mild immunopathy of the thyroid is seen more frequently in these patients and seems to be a predisposing factor in the development of radiation-induced GD. (orig.)

Radioreceptor assay study of thyrotropin receptor antibody (TRAb) in Grave's diseases

International Nuclear Information System (INIS)

Lu Chao; Lin Xiangtong

1989-01-01

Here was reported the assay system using pig thyroid TSH receptor and 125 I-bTSH purified by receptor of thyroid cell membrane for the study of TRAb activity. The binding rate of ASH soluble receptor with 125 I-bTSH was 22.2 ∼ 37.4%, while as the control was only 1.0 ∼ 2.1%. TRAb was measured clinically in 48 cases of Grave's diseases and 25 normal persons. The TSH binding inhabitory index(TRII) was introduced for reflection of TRAb activity. The results showed that TBII was positure in 30 of 48 patients of Grave's diseases, the detctactibility was 79.2%

Thyroid hyperfunctioning adenomas with and without Gsp/TSH receptor mutations show similar clinical features.

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Arturi, F; Capula, C; Chiefari, E; Filetti, S; Russo, D

1998-01-01

Activating mutations of Gs alpha protein (gsp) and TSH receptor (TSH-R) identified in autonomously hyperfunctioning thyroid adenomas have been proposed as the primary event responsible for this disease. Since mutations have not been detected in 100% (ranging from less than 10% to 90%) of the patients, we evaluated whether the presence of gsp and TSH-R mutations cause differences in the clinical and biochemical parameters of the affected patients. Fifteen consecutive patients (11 women and 4 men) with autonomously hyperfunctioning thyroid adenomas who underwent thyroidectomy, previously examined for the presence of gsp or TSH-R mutations, were investigated. In all of the patients we examined plasma free T3, free T4, TSH levels and ultrasound volume of the nodules. The patients with mutations in gsp or TSH-R were similar to the patients without mutations for clinical presentation, sex distribution and mean age. Furthermore, basal serum FT3, TSH and tumor volume in the patients with mutations were not significantly different from the group without mutations. Our preliminary data demonstrate that no significant differences are present in the two groups of patients examined, suggesting that factors other than gsp or TSH-R mutations play a role in the clinical presentation of the disease.

Evidence for cooperative signal triggering at the extracellular loops of the TSH receptor.

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Kleinau, Gunnar; Jaeschke, Holger; Mueller, Sandra; Raaka, Bruce M; Neumann, Susanne; Paschke, Ralf; Krause, Gerd

2008-08-01

The mechanisms governing transition of the thyroid stimulating hormone (TSH) receptor (TSHR) from basal to active conformations are poorly understood. Considering that constitutively activating mutations (CAMs) and inactivating mutations in each of the extracellular loops (ECLs) trigger only partial TSHR activation or inactivation, respectively, we hypothesized that full signaling occurs via multiple extracellular signal propagation events. Therefore, individual CAMs in the extracellular region were combined to create double and triple mutants. In support of our hypothesis, combinations of mutants in the ECLs are in some cases additive, while in others they are even synergistic, with triple mutant I486A/I568V/V656F exhibiting a 70-fold increase in TSH-independent signaling. The proximity but likely different spatial orientation of the residues of activating and inactivating mutations in each ECL supports a dual functionality to facilitate signal induction and conduction, respectively. This is the first report for G-protein coupled receptors, suggesting that multiple and cooperative signal propagating events at all three ECLs are required for full receptor activation. Our findings provide new insights concerning molecular signal transmission from extracellular domains toward the transmembrane helix bundle of the glycoprotein hormone receptors.

Decrease in TSH Receptor Autoantibodies during Antithyroid Treatment

DEFF Research Database (Denmark)

Christensen, Niels Juel; Habekost, Gurli; Bratholm, Palle

2011-01-01

We have previously shown that a long noncoding RNA transcript Heg is negatively correlated with TSH receptor autoantibodies (TRAb) in patients with untreated Graves' disease and with CD14 mRNA in treated patients and controls. Thus patients with high concentrations of Heg RNA have low levels...... of TRAb or CD14 mRNA, respectively. Here we show that an additional factor, gene expression of Cdk1 in mononuclear cells, is positively related to concentrations of TRAb in patients with untreated Graves' disease. Cdk1 mRNA is very important for regulation of cell cycle activity. It is well known...

TSH-Mediated TNFα Production in Human Fibrocytes Is Inhibited by Teprotumumab, an IGF-1R Antagonist.

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Hong Chen

Full Text Available Fibrocytes (FC are bone marrow-derived progenitor cells that are more abundant and infiltrate the thyroid and orbit in Graves orbitopathy (GO. FCs express high levels of thyrotropin receptor (TSHR and insulin-like growth factor-1 receptor (IGF-1R. These receptors are physically and functionally associated, but their role in GO pathogenesis is not fully delineated. Treatment of FCs with thyroid stimulating hormone (TSH or M22 (activating antibody to TSHR induces the production of numerous cytokines, including tumor necrosis factor α (TNFα. Teprotumumab (TMB is a human monoclonal IGF-1R blocking antibody currently in clinical trial for GO and inhibits TSHR-mediated actions in FCs.To characterize the molecular mechanisms underlying TSH-induced TNFα production by FCs, and the role of IGF-1R blockade by TMB.FCs from healthy and GD patients were treated with combinations of TSH, M22, MG132 and AKTi (inhibitors of NF-κB and Akt, respectively, and TMB. TNFα protein production was measured by Luminex and flow cytometry. Messenger RNA expression was quantified by real time PCR.Treatment with TSH/M22 induced TNFα protein and mRNA production by FCs, both of which were reduced when FCs were pretreated with MG132 and AKTi (p<0.0001. TMB decreased TSH-induced TNFα protein production in circulating FCs from mean fluorescent index (MFI value of 2.92 to 1.91, and mRNA expression in cultured FCs from 141- to 52-fold expression (p<0.0001. TMB also decreased M22-induced TNFα protein production from MFI of 1.67 to 1.12, and mRNA expression from 6- to 3-fold expression (p<0.0001.TSH/M22 stimulates FC production of TNFα mRNA and protein. This process involves the transcription factor NF-κB and its regulator Akt. Blocking IGF-1R attenuates TSH/M22-induced TNFα production. This further delineates the interaction of TSHR and IGF1-R signaling pathways. By modulating the proinflammatory properties of FCs such as TNFα production, TMB may be a promising

Autoimmune Thyroid Diseases in Patients Treated with Alemtuzumab for Multiple Sclerosis: An Example of Selective Anti-TSH-Receptor Immune Response

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Mario Rotondi

2017-09-01

Full Text Available Alemtuzumab, a humanized anti-CD52 monoclonal antibody, is approved for the treatment of active relapsing-remitting multiple sclerosis (MS. Alemtuzumab induces a rapid and prolonged depletion of lymphocytes from the circulation, which results in a profound immuno-suppression status followed by an immune reconstitution phase. Secondary to reconstitution autoimmune diseases represent the most common side effect of Alemtuzumab treatment. Among them, Graves’ disease (GD is the most frequent one with an estimated prevalence ranging from 16.7 to 41.0% of MS patients receiving Alemtuzumab. Thyrotropin (TSH receptor (R-reactive B cells are typically observed in GD and eventually present this autoantigen to T-cells, which, in turn, secrete several pro-inflammatory cytokines and chemokines. Given that reconstitution autoimmunity is more frequently characterized by autoantibody-mediated diseases rather than by destructive Th1-mediated disorders, it is not surprising that GD is the most commonly reported side effect of Alemtuzumab treatment in patients with MS. On the other hand, immune reconstitution GD was not observed in a large series of patients with rheumatoid arthritis treated with Alemtuzumab. This negative finding supports the view that patients with MS are intrinsically more at risk for developing Alemtuzumab-related thyroid dysfunctions and in particular of GD. From a clinical point of view, Alemtuzumab-induced GD is characterized by a surprisingly high rate of remission, both spontaneous and after antithyroid drugs, as well as by a spontaneous shift to hypothyroidism, which is supposed to result from a change from stimulating to blocking TSH-receptor antibodies. These immune and clinical peculiarities support the concept that antithyroid drugs should be the first-line treatment in Alemtuzumab-induced Graves’ hyperthyroidism.

Acetylcholine receptor antibody

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... medlineplus.gov/ency/article/003576.htm Acetylcholine receptor antibody To use the sharing features on this page, please enable JavaScript. Acetylcholine receptor antibody is a protein found in the blood of ...

[Antibodies against TSH receptors (TRAb) as indicators in prognosing the effectiveness of Tiamazol therapy for Grave's Disease].

Science.gov (United States)

Bojarska-Szmygin, Anna; Ciechanek, Roman

2003-01-01

The aim of the study was to evaluate the usefulness of TRAb determinations in prognosing and monitoring the efficacy of conservative treatment in Graves' disease. The examinations were performed in 54 patients. During the 18-month observation all the patients were treated with Tiamazol. The control group consisted of 20 healthy volunteers. The TRAb levels were determined before as well as 12 and 18 months after thyrostatic treatment. Simultaneously, the levels of TSH and FT4 were analysed. Moreover, all the patients underwent ultrasound examinations to assess the size of the thyroid gland. The findings of the 18-month follow up showed that in 31 patients (57%) the thyroid function became normal (group I--euthyreosis), in 23 patients (43%) hyperactivity persisted (group II--hyperthyreosis). The TRAb levels were analysed in both groups of patients. An increased initial level of TRAb was found in the hyperactivity group mean -54.39 + 31.21 U/l which was statistically significantly different from the TRAb levels in the euthyreosis group mean -29.13 +/- 19.14 U/l and in controls mean -2.75 +/- 2.06 U/l (p Graves' disease. High initial levels of antibodies are the poor prognostic factors. The TRAb determinations are of some prognostic value not only before but also 12 months since the onset of therapy. The lack of antibody level normalization during treatment is connected with persisting hyperactivity. The TRAb concentration correlates with the thyroid size.

Incidence of radiation-induced Graves' disease in patients treated with radioiodine for thyroid autonomy before and after introduction of a high-sensitivity TSH receptor antibody assay

Energy Technology Data Exchange (ETDEWEB)

Dunkelmann, Simone; Wolf, Ricarda; Koch, Annedore; Kittner, Christian; Groth, Peter; Schuemichen, Carl [University of Rostock, Clinic of Nuclear Medicine, Rostock (Germany)

2004-10-01

Autoimmune hyperthyroidism may occur several months after radioiodine therapy (RIT) for functional thyroid autonomy. Exacerbation of pre-existing subclinical Graves' disease (GD) has been held responsible for this phenomenon. Determination of TSH receptor antibody using solubilised porcine epithelial cell membranes is insensitive and may have failed to diagnose GD in these patients before RIT. Following the introduction of a more sensitive assay, using the human TSH receptor as an antigen, it has been expected that the incidence of radiation-induced GD after RIT for functional thyroid autonomy will be reduced. In a first group of 1,428 patients treated between November 1993 and March 1997 (group I) we used the porcine TRAb assay to exclude GD, while in a second group comprising 1,408 patients treated between January 2000 and December 2001 (group II), GD was excluded using the human TRAb assay. A matched control group of 231 patients was derived from group II. In group I a total of 15 (1.05%) patients developed obvious or suspected radiation-induced GD, while in group II 17 (1.2%) did so; the interval until development of GD was 8.4 and 8.8 months, respectively, after RIT. Serum anti-thyroid peroxidase levels before RIT were elevated in 36.4% of group I patients and 47.1% of group II patients, but in only 5.6% of the control group. Other non-specific signs of mild immunopathy of the thyroid were seen retrospectively in 73.3%, 64.7% and 16.0% of the patients in these three groups, respectively. In conclusion, the introduction of a high-sensitivity TRAb assay did not reduce the incidence of autoimmune hyperthyroidism occurring late after RIT for functional thyroid autonomy, but mild immunopathy of the thyroid is seen more frequently in these patients and seems to be a predisposing factor in the development of radiation-induced GD. (orig.)

Maternal TSH level and TPOAb status in early pregnancy and their relationship to the risk of gestational diabetes mellitus.

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Ying, Hao; Tang, Yu-Ping; Bao, Yi-Rong; Su, Xiu-Juan; Cai, XueYa; Li, Yu-Hong; Wang, De-Fen

2016-12-01

Subclinical hypothyroidism is common in pregnant women and often related to adverse pregnancy outcomes, but its relationship with gestational diabetes remains controversial. In particular, the impact of thyroperoxidase antibodies status on the relationship between subclinical hypothyroidism and gestational diabetes is not clear. We investigated the association between combined thyroid stimulating hormone (TSH) level and thyroperoxidase antibodies status in early pregnancy (gestation) and gestational diabetes mellitus. A total of 7084 pregnant women met the inclusion criteria, which included thyroperoxidase antibodies-positive subclinical hypothyroidism [TSH(H)TPOAb(+)] (n = 78), thyroperoxidase antibodies-negative subclinical hypothyroidism [TSH(H)TPOAb(-)] (n = 281), thyroperoxidase antibodies-positive euthyroidism [TSH(N)TPOAb(+)] (n = 648), and thyroperoxidase antibodies-negative euthyroidism [TSH(N)TPOAb(-)] (n = 6077). Of the 7084 cases included in our study, 1141 cases were diagnosed with gestational diabetes mellitus at 24-28 weeks of pregnancy. The prevalence of gestational diabetes mellitus in TSH(N)TPOAb(-), TSH(H)TPOAb(-), TSH(N)TPOAb(+), and TSH(H)TPOAb(+) was 14.65, 19.57, 24.85, and 46.15 %, respectively. Compared with TSH(N)TPOAb(-) women, the risk of gestational diabetes mellitus was increased in all other groups of women in early pregnancy. After dividing early pregnancy into first and second trimesters, we found that TSH(H)TPOAb(-) women in the first trimester do not show this increase. Our study suggests that subclinical hypothyroidism and thyroperoxidase antibodies-positive euthyroidism in early pregnancy are associated with an increased risk of gestational diabetes mellitus.

Radioimmunoassay of TSH subunits in thyroid diseases and endocrine opthalmopahty

International Nuclear Information System (INIS)

Eder, W.

1982-01-01

Highly sensitive radioimmunoassays of hTSH sub-units were developed. The hormone preparations were labelled with 125-iodine according to a modified chloramine -T method, and purified by chromatography using biogel P6 and P60. Rabbit antisera were used as antibodies. Separation of the antibody-bound and of the free antigens was carried out via the double antibody method. The antiserum required for this purpose was obtained from a goat. The sensitivity of the assay was influenced by changing the protein content of the buffer, the incubation volume, the tracer amounts, the incubation time and the incubation temperature. For hTSH-α, the lowest detectable limit was found to be 50 pg/ml, for hTSH-#betta# 20 pg/ml. Thus, the sub-units could be determined for 98% of the patients under review. The #betta#-TSH radioimmunoassay is largely specific, TSH cross-reacts to a degree of 5%. The computerized evoluation was carried out by means of Spline approximation using the Siemens 4004 computer. Precision and accurateness are in compliance with generally accpted criteria. The serum levels of α and #betta# sub-units showed no discordancy with regard to TSH. In all groups of patients examined, the levels of the hormone-specific #betta#-chain were found to be exclusively dependent upon the actual thyroid activity. (orig.) [de

Antithyroid antibodies in hyperthyroidism - personal experience

International Nuclear Information System (INIS)

Dedoussis, H.

2003-01-01

Thyroid diseases of autoimmune type may be expressed by symptoms and signs of either hyperthyroidism or euthyroidism or even hypothyroidism. Common factor in these diseases is the presence in the serum of these patients of antithyroid or anti-TSN autoantibodies in various percentages. Since there is not always a positive correlation between the levels of these antibodies and the severity of thyroid disease we have studied in cases of Graves disease (GD), Multinodular toxic goiter (MTG) and Toxic adenoma (TA), the anti-microsomal antibody (antithyroid peroxidase-ATPO-Ab), the antithyroglobulin antibody (Tg-Ab) and the anti-TSH receptor antibody (TSH-Ab) in 260 patients with the three above forms of hyperthyroidism. In Group A, GD, 23 men and 44 women, in Group B MTG, 24 men and 71 women in Group C TA, 8 men and 25 women and in Group C patients with clinical hyperthyroidism without detectable goiter, 19 men and 46 women. thyroid status was assessed clinically by the so called thyroid index of hyperthyroidism, modified by the authors and by the laboratory tests of free thyroxine (FT4), free triiodothyronine (FT3), TSH and the I-131 uptake by the thyroid gland. Results showed that TPO-Ab were in the 4 Groups:75%, 36%,6%, and 66%. The Tg-Ab were:48%, 25%, 0% and 28%. The TSH-Ab were: 49%, 27%, 12% and 23% respectively. Results show that: a) the percentage of TPO-Ab an GD is high and is related to the duration and or the size of the goiter, since in Group D there was a lower percentage of positive TPO-Ab. b) TSH-Ab and Tg-Ab are of minor importance in differentiating different types of hyperthyroidism and may as well be omitted. c) in patients with GD the high levels of TPO-Ab are not synchronous but are related to the severity and/or the relapse of the disease. d) Tg-Ab although not expected are sometimes increased in hypothyroidism as well as in normal people. e) in order to realize the importance of TSH-Ab we should be able to test the number and the sensitivity of

B lymphocyte depletion with the monoclonal antibody rituximab in Graves' disease: a controlled pilot study

DEFF Research Database (Denmark)

El Fassi, Daniel; Nielsen, Claus H; Bonnema, Steen J

2007-01-01

Graves' disease (GD) is a common TSH receptor autoantibody (TRAb)-mediated disorder. Because B lymphocytes are important self-antigen presenting cells and precursors for antibody-secreting plasma cells, temporary B-lymphocyte depletion with the monoclonal antibody rituximab (RTX) might...

The impact of a TSH receptor gene polymorphism on thyroid-related phenotypes in a healthy Danish twin population

DEFF Research Database (Denmark)

Hansen, Pia Skov; van der Deure, Wendy M; Peeters, Robin P

2007-01-01

OBJECTIVES: The Asp727Glu polymorphism in the TSH receptor (TSHR) gene is associated with serum TSH levels. However, the proportion of genetic variation accounted for by this polymorphism is unknown. In this study, we (1) examined the association of the Asp727Glu polymorphism with thyroid size...... between the TSHR-Asp727Glu polymorphism and measures of thyroid homeostasis were assessed and the effect of the polymorphism on the trait's phenotypic variability was quantified by incorporating the genotype information in structural equation modelling. RESULTS: The genotype distribution was Asp/Asp 84.......9%; Asp/Glu 14.5% and Glu/Glu 0.6%. Carriers of the TSHR-Glu727 allele had lower TSH levels (noncarriers vs. carriers: 1.78 +/- 0.93 vs. 1.60 +/- 0.84 mU/l, P = 0.04). Regression analysis showed an association between the TSHR-Asp727Glu polymorphism and serum TSH (P = 0.007). The polymorphism accounted...

A Prospective Investigation of Graves' Disease and Selenium: Thyroid Hormones, Auto-Antibodies and Self-Rated Symptoms

DEFF Research Database (Denmark)

Calissendorff, Jan; Mikulski, Emil; Larsen, Erik Huusfeldt

2015-01-01

-stimulating hormone (TSH), free thyroxine (FT4), free triiodothyronine (FT3), thyroid receptor antibodies and thyroid peroxidase auto-antibodies before medication and at 6, 18 and 36 weeks after commencing treatment with methimazole and levo-thyroxine, with a randomized blinded oral administration of 200 µg Se...

Effect of Sulpirid on blood serum prolactin- and TSH-levels

International Nuclear Information System (INIS)

Foldes, J.; Gyertyanfi, G.; Borvendeg, J.

1979-01-01

Euthyreoid and hyperthyreoid women were subjected to examinations investigating the effect of a dopamine-antagonist (Sulpirid) on serum TSH and prolactin (LTH)-levels. For measurements of serum concentrations the following kits were used: prolactine: CIS; TSH: Ria-mat-TSH (Byk-Mallinkrodt); thyroxine: Tiopac T 4 (Amersham); triiodothyronine: Ria-mat-T 3 (Byk-Mallinkrodt). Sulpirid increased both the LTH and the TSH-levels. In case of hyperthyreosis the effect of Sulpirid on LTH-levels was less pronounced and it had no effect on serum-TSH at all. Pre-treatment with a dopamine-agonist (Bromocryptin) impeded the effect of Sulpirid. It is concluded that dopamine-receptors do have a role in the regulation of TSH-secretion in the hypophysis. (L.E.)

Radioimmunoassay of Human Thyrotropin - Part 1. Plasma TSH levels in various thyroid functions

International Nuclear Information System (INIS)

Koh, Chang Soon; Lee, Hong Kyu; Ro, Heung Kyu; Lee, Mun Ho

1972-01-01

The radioimmunoassay of human thyrotropin was performed in various thyroid states, utilizing the anti-h-T.S.H. antibody and purified human thyrotropin supplied from National Institute of Arthritis and Metabolic Diseases, Bethesda, Ma., U.S.A., and human thyrotropin standard-A obtained from National Institute for Biologic Standards, Mill Hill, London, England. 131 I labelled h-TSH was prepared after the Chloramine-T method of Greenwood et al. This double antibody system had a assay sensitivity of about l. 0 μU/ml of plasma HTS-A and could detect the plasma h-TSH level in the euthyroid patients. Plasma h-TSH level of the normal 26 Korean was l.1±0. 83 μU/ml, and that of the 8 hypothyroidisms were 8.3 to 67.5 μU/ml. In hyperthyroidisms, no cases showed the plasma h-TSH levels over l. 0 μU/ ml. Between the hypothyroidism and euthyroidism, no overlap is noticed on plasma h-TSH levels. A case of transient hypothyroid state identified by determination of plasma h-TSH level is presented. These results revealed that the radioimmunoassay of h-TSH in plasma could be a sensitive method to diagnose the hypothyroidism, if not caused by a pituitary disease.

Monoclonal Antibodies to the Thyrotropin Receptor

Directory of Open Access Journals (Sweden)

Takao Ando

2005-01-01

Full Text Available The thyrotropin receptor (TSHR is a seven transmembrane G-protein linked glycoprotein expressed on the thyroid cell surface and which, under the regulation of TSH, controls the production and secretion of thyroid hormone from the thyroid gland. This membrane protein is also a major target antigen in the autoimmune thyroid diseases. In Graves' disease, autoantibodies to the TSHR (TSHR-Abs stimulate the TSHR to produce thyroid hormone excessively. In autoimmune thyroid failure, some patients exhibit TSHR-Abs which block TSH action on the receptor. There have been many attempts to generate human stimulating TSHR-mAbs, but to date, only one pathologically relevant human stimulating TSHR-mAb has been isolated. Most mAbs to the TSHR have been derived from rodents immunized with TSHR antigen from bacteria or insect cells. These antigens lacked the native conformation of the TSHR and the resulting mAbs were exclusively blocking or neutral TSHR-mAbs. However, mAbs raised against intact native TSHR antigen have included stimulating mAbs. One such stimulating mAb has demonstrated a number of differences in its regulation of TSHR post-translational processing. These differences are likely to be reflective of TSHR-Abs seen in Graves' disease.

Indium-111 pentetreotide single-photon emission tomography in patients with TSH-secreting pituitary adenomas: correlation with the effect of a single administration of octreotide on serum TSH levels

Energy Technology Data Exchange (ETDEWEB)

Losa, M. [Department of Neurosurgery, IRCCS San Raffaele, University of Milan (Italy); Magnani, P. [INB-CNR Department of Nuclear Medicine, IRCCS San Raffaele, University of Milan (Italy); Mortini, P. [Department of Neurosurgery, IRCCS San Raffaele, University of Milan (Italy); Persani, L. [Centro Auxologico Italiano IRCCS, University of Milan (Italy); Acerno, S. [Department of Neurosurgery, IRCCS San Raffaele, University of Milan (Italy); Giugni, E. [Department of Neurosurgery, IRCCS San Raffaele, University of Milan (Italy); Songini, C. [INB-CNR Department of Nuclear Medicine, IRCCS San Raffaele, University of Milan (Italy); Fazio, F. [INB-CNR Department of Nuclear Medicine, IRCCS San Raffaele, University of Milan (Italy); Beck-Peccoz, P. [Institute of Endocrine Sciences, Istituto Clinico Humanitas, University of Milan (Italy); Giovanelli, M. [Department of Neurosurgery, IRCCS San Raffaele, University of Milan (Italy)

1997-07-01

Few data are available on the visualization of somatostatin receptors in vivo in patients with thyrotropin (TSH)-secreting adenoma. We studied five patients with TSH-secreting adenomas using single-photon emission tomography (SPET) after administration of indium-111 pentetreotide. The intensity of {sup 111}In-pentetreotide uptake by the tumours was correlated with the degree of TSH suppression after a single administration of 100 {mu}g octreotide s.c. Five patients (three women and two men) aged 27-46 years were investigated. Except for one patient with acromegaly, all had pure TSH-secreting tumours. One patient was previously untreated, while two had received octreotide, one antithyroid drugs, and one radioiodine. In all patients SPET demonstrated increased uptake of {sup 111}In-pentetreotide by the pituitary adenoma. The target to non-target ratio (T/nT) of {sup 111}In-pentetreotide uptake was higher than 10 in three patients. Administration of 100 {mu}g octreotide s.c. caused a significant reduction in TSH levels from 4.8{+-}1.4 mU/l to a nadir of 3.1{+-}1.1 mU/l after 6 h (P<0.001 by ANOVA). Suppression of TSH secretion ranged from 30% to 60% of the baseline value. The T/nT ratio showed a trend toward a direct relationship with the degree of TSH inhibition after acute octreotide administration (r=0.67; P=NS). Our study showed that {sup 111}In-pentetreotide scan visualized somatostatin receptors in all five of the patients with TSH-secreting pituitary adenomas, confirming the frequent presence of somatostatin receptors in these rare tumours, even though the correlation with the TSH inhibition after a single administration of octreotide did not reach significance. (orig.). With 1 fig., 1 tab.

Molecular cloning of a novel, putative G protein-coupled receptor from sea anemones structurally related to members of the FSH, TSH, LH/CG receptor family from mammals

DEFF Research Database (Denmark)

Nothacker, H P; Grimmelikhuijzen, C J

1993-01-01

hormone (FSH, TSH, LH/CG) receptor family from mammals, including a very large, extracellular N terminus (18-25% sequence identity) and a 7 transmembrane region (44-48% sequence identity). As with the mammalian glycoprotein hormone receptor genes, the sea anemone receptor gene yields transcripts which can...... be alternatively spliced, thereby yielding a shortened receptor variant only containing the large extracellular (soluble) N terminus. All this is strong evidence that the putative glycoprotein hormone receptor from sea anemones is evolutionarily related to those from mammals. This is the first report showing...

First results with a radioreceptor-assay (TRAK-Assay) for TSH-receptor-autoantibodies

International Nuclear Information System (INIS)

Becker, W.; Reiners, C.; Boerner, W.

1983-01-01

A new radioreceptor-assay (TRAK-assay) for autoantibodies against TSH-receptors was tested in 48 untreated thyrotoxic patients (26 regional autonomies, 22 toxic diffuse goiters). None of the 26 patients with regional autonomy showed positive autoantibody-titers. 4 patients with toxic diffuse goiter and thyrotoxic exophthalmos were TRAK-positive. Positive titers of microsomal and thyreoglobulin autoantibodies could be seen in 8 of 9 patients with positive TRAK-titers. In accordance with the conventional methods for detecting thyroid-stimulating immunoglobulins the new TRAK-assay seems to be suited for differentiating between immunogenic toxic diffuse goiter (Graves' disease) and goiter with disseminated autonomy as well as for prediction of relapse. (orig.) [de

Purification of bovine thyroid-stimulating hormone by a monoclonal antibody

International Nuclear Information System (INIS)

Lock, A.J.; van Denderen, J.; Aarden, L.A.

1988-01-01

A monoclonal antibody directed against bovine TSH was obtained by hybridoma technology. This antibody was specific for TSH and did not react with bovine LH and FSH. Affinity chromatography of crude TSH was performed on anti-TSH Sepharose. Bovine TSH was purified in a single step to near homogeneity by this technique, as shown by cation exchange chromatography and sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the purified TSH. The biological activity of the hormone was not affected during the purification, as determined by [ 3 H]thymidine incorporation of the TSH-dependent FRTL5 cell line. The results indicate that affinity purification of TSH by means of a monoclonal antibody is a simple one-step procedure for the production of biologically active, highly purified TSH

Production of antibodies which recognize opiate receptors on murine leukocytes

Energy Technology Data Exchange (ETDEWEB)

Carr, D.J.J.; Bost, K.L.; Blalock, J.E.

1988-01-01

An antibody has been developed which recognizes opiate receptors on cells of the immune system. This antibody blocks specific binding of the radiolabeled opiate receptor ligand, /sup 3/H-dihydromorphine, to receptors on murine splenocytes. Additionally, the anti-receptor antibody competes with ..beta..-endorphin, meta-enkephalin, and naloxone for the same binding site on the leukocytes. Moreover, the anti-receptor antibody possesses agonist activity similar to ..beta..-endorphin in suppressing cAMP production by lymphocytes. These results suggest the development of an antibody which recognizes classical opiate receptors on cells of the immune system.

Age and body composition influence TSH concentrations after administration of rhTSH.

Science.gov (United States)

Holthausen, F F; von Müller, F; Happel, C; Kranert, W T; Grünwald, F

2015-01-01

Previous studies listed body surface area (BSA), lean body mass (LBM), and age as modifying factors on the TSH concentrations after administration of recombinant human thyrotropin (rhTSH). The purpose of this study was to identify the main modifying factors on serum TSH levels and to compare the stimulation via single rhTSH injection after a short thyroid hormone withdrawal (THW) with that of the standard stimulating protocol. 106 patients with differentiated thyroid cancer (DTC) undergoing radioiodine therapy (RIT) after rhTSH administration were obtained through chart review. Two groups were evaluated: Group I was treated with a single rhTSH administration after two weeks of T3 therapy followed by one week of THW. Group II was stimulated according to the international standard protocol via rhTSH injections for two consecutive days. Serum TSH concentrations were documented prior to rhTSH administration (day 1 TSH), one day after (day 3 TSH) and 3-6 days after (mean 4.2 days, day 6 TSH) the last rhTSH injection. The following data was collected: age, gender, weight, height, BMI, LBM, BSA, residual thyroid tissue, CRP, creatinine, GFR, liver enzymes, alkaline phosphatase, cholesterol, and triglycerides. Group I: Age combined with anthropometric factors like BMI (TSH increase and day 6 TSH), BSA (TSH decrease), and gender (day 6 TSH) are the main modifying factors on serum TSH concentrations after rhTSH administration. Group II: Age and lean body mass (LBM) showed a significant impact on day 3 TSH, TSH increase (day 3-day 1), and TSH decrease (day 6-day 3). Day 6 TSH was found to be influenced by GFR (group II). Age and anthropometric parameters have significant independent influence on TSH concentrations after rhTSH injection in both groups. Anthropometric parameters (BSA, LBM) and demographic parameters (female gender) show strong influence on TSH concentrations. Further research should be conducted to examine the influence of body compartments on TSH levels

SEARCH FOR TARGET TISSUE IN THE EYE ORBIT FOR AUTOIMMUNE AGGRESSION OF THYROID ANTIBODIES IN ENDOCRINE OPHTHALMOPATHY

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V. G. Likhvantseva

2017-01-01

Full Text Available We searched for a possible target tissue in eye orbit for thyroid autoantibodies in endocrine ophthalmopathy (Graves’ disease, using correlation analysis method. We examined a group of 139 patients (278 eye orbits with thyroid-associated ophthalmopathy associated with diffuse toxic goiter. Serological parameters (antibodies to thyroid-stimulating hormone receptor; thyroglobulin, thyroid peroxidase were compared with instrumental diagnostic data (multi-layer CT, ultrasonography of eye orbit, and exophthalmometer, as well as clinical symptoms. Statistical correlation analysis enabled us to show different degrees of association between thyroid antibodies and clinical manifestations of Graves’ disease and eye orbit involvement. Especially, carriers of antibodies to TSH receptor and thyroglobulin (as compared to seronegative patients exhibited higher exophthalmos scores (19.16±0.26 mm, p < 0.001, and 19.41±0.40 mm, p < 0.05, respectively, and with total muscle index (2.42±0.05, p < 0.01, and 2.42±0.08, respectively. Meanwhile, eyelids in carriers of antibodies to TSH receptor and thyroid peroxidase proved to be more swollen (p < 0.001, p < 0.05, respectively. Carriage of antibodies to thyroglobulin was associated with synchronous involvement of two structures of the eye orbit: extraocular muscles and retrobulbar tissue, which is reflected by increase in the average ntegral exophthalmos index within the group.

TSH Isoforms: About a Case of Hypothyroidism in a Down's Syndrome Young Adult

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Anne-Sophie Gauchez

2010-01-01

Full Text Available Background. For unknown reasons, the prevalence of thyroid autoimmune disorders is higher in patients with Down's syndrome than in the general population. The present case strongly supports a recent evaluation of propagating screening for thyroid disease in this group of patients to assure early diagnosis of hypothyroidism. Methods. In a 25-year-old man diagnosed with Down's syndrome, clinical manifestations of hypothyroidism were lacking, but profound biochemical abnormalities were found with particularly high levels of thyroid stimulating hormone (TSH. Antigenic properties of TSH were characterized using a panel of anti-TSH antibodies. Results. Technical problems not infrequently associated with TSH measurements are convincingly ruled out. Antigenic characterization of the patient's circulating TSH revealed circulating forms of TSH different from pituitary TSH which closely resembled TSH recombinant human hormone. Conclusions. It appears counterintuitive that the bioactivity of TSH decreases in the hypothyroid state as higher bioactivity of TSH is anticipated in hypothyroidism promoted by an increased hypothalamic TRH drive. In contrast, diminished negative thyroid hormone feedback will enhance posttranslational glycosylation of TSH subunits and increase sialylation of the carbohydrate side chains. Both exert a negative effect on TSH bioactivity, only compensated by the very high levels of the hormone as in the present case.

Protocol for thyroid remnant ablation after recombinant TSH in thyroid carcinoma

International Nuclear Information System (INIS)

Pitoia, F.; Salvai, M.E.; Niepomniszcze, H.; Tamer, E. El

2009-01-01

In some countries, in order to perform rhTSH-aided thyroid remnant ablation (TRA) after surgery, it is generally necessary to confirm that thyroidectomy has been almost complete. Otherwise, the nuclear medicine specialist will not administer a high radioiodine dose because it might be hazardous due to the possibility of thyroid remnant actinic thyroiditis. Considering this, it would be necessary to use two rhTSH kits (one for diagnostic purposes and the other one to administer the 131 I dose). In this study, we used an alternative protocol for TRA with the use of one kit of rhTSH in twenty patients diagnosed with low risk papillary thyroid carcinoma. All patients had negative titers of anti-thyroglobulin antibodies. Successful thyroid remnant ablation was confirmed with an undetectable rhTSH stimulated thyroglobulin level ( [es

C4d-negative antibody-mediated rejection with high anti-angiotensin II type I receptor antibodies in absence of donor-specific antibodies.

Science.gov (United States)

Fuss, Alexander; Hope, Christopher M; Deayton, Susan; Bennett, Greg Donald; Holdsworth, Rhonda; Carroll, Robert P; Coates, P Toby H

2015-07-01

Acute antibody-mediated rejection can occur in absence of circulating donor-specific antibodies. Agonistic antibodies targeting the anti-angiotensin II type 1 receptor (anti-AT1 R) are emerging as important non-human leucocyte antigen (HLA) antibodies. Elevated levels of anti-angiotensin II receptor antibodies were first observed in kidney transplant recipients with malignant hypertension and allograft rejection. They have now been studied in three separate kidney transplant populations and associate to frequency of rejection, severity of rejection and graft failure. We report 11 cases of biopsy-proven, Complement 4 fragment d (C4d)-negative, acute rejection occurring without circulating donor-specific anti-HLA antibodies. In eight cases, anti-angiotensin receptor antibodies were retrospectively examined. The remaining three subjects were identified from our centre's newly instituted routine anti-angiotensin receptor antibody screening. All subjects fulfilled Banff 2013 criteria for antibody-mediated rejection and all responded to anti-rejection therapy, which included plasma exchange and angiotensin receptor blocker therapy. These cases support the routine assessment of anti-AT1 R antibodies in kidney transplant recipients to identify subjects at risk. Further studies will need to determine optimal assessment protocol and the effectiveness of pre-emptive treatment with angiotensin receptor blockers. © 2015 Asian Pacific Society of Nephrology.

KADAR ANTIBODI-TIROPEROKSIDASE DAN ANTIBODI-TIROGLOBULIN PADA WANITA USIA SUBUR DI DAERAH ENDEMlS GAKI

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Agus Wibowo

2012-10-01

Full Text Available Background: Thyroid hormones play a critical role in human. Disorders of the thyroid gland result primary from autoimmune processes that either stimulate the over production of thyroid hormones (hyperthyroid or causes glandular destruction and hormones deficiency (hypothyroid. Autoimmune Thyroid Disease (AITD a common organ specific autoimmune disorder is seen mostly in women. AITD are complex disease that are caused by an interaction between susceptibility genes and environmental trigger such dietary iodine. The development of antibodies to Thyroid peroxidase (TPO and Thyroglobulin (TG is the main hall mark of AITD. Method: 'Thirty respondents from were analyzed. The blood were collected for TSH, FreeT4, Tyroglobulin Antibody and Tyroperoxidase Antibody analyzed and DNA isolation. Circulating TSH, FreeT4, autoantibodies to TPO and TG are measured by ELISA. Result: 50% respondent in normal thyroid hormones and 50% in hypothyroid and hyperthyroid status. TPO antibodies  and thyroglobulin antibodies found in all of respondent with thyroid disorder. Conclusion: Antibodies to TPO and TG is seen in respondent with thyroid disorder   Keywords: AITD, TSH, FreeT4, TPO antibodies, TG antibodies.

Development of antibodies against the rat brain somatostatin receptor.

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Theveniau, M; Rens-Domiano, S; Law, S F; Rougon, G; Reisine, T

1992-05-15

Somatostatin (SRIF) is a neurotransmitter in the brain involved in the regulation of motor activity and cognition. It induces its physiological actions by interacting with receptors. We have developed antibodies against the receptor to investigate its structural properties. Rabbit polyclonal antibodies were generated against the rat brain SRIF receptor. These antibodies (F4) were able to immunoprecipitate solubilized SRIF receptors from rat brain and the cell line AtT-20. The specificity of the interaction of these antibodies with SRIF receptors was further demonstrated by immunoblotting. F4 detected SRIF receptors of 60 kDa from rat brain and adrenal cortex and the cell lines AtT-20, GH3, and NG-108, which express high densities of SRIF receptors. They did not detect immunoreactive material from rat liver or COS-1, HEPG, or CRL cells, which do not express functional SRIF receptors. In rat brain, 60-kDa immunoreactivity was detected by F4 in the hippocampus, cerebral cortex, and striatum, which have high densities of SRIF receptors. However, F4 did not interact with proteins from cerebellum and brain stem, which express few SRIF receptors. Immunoreactive material cannot be detected in rat pancreas or pituitary, which have been reported to express a 90-kDa SRIF receptor subtype. The selective detection of 60-kDa SRIF receptors by F4 indicates that the 60- and 90-kDa SRIF receptor subtypes are immunologically distinct. The availability of antibodies that selectively detect native and denatured brain SRIF receptors provides us with a feasible approach to clone the brain SRIF receptor gene(s).

Binding-site analysis of opioid receptors using monoclonal anti-idiotypic antibodies

International Nuclear Information System (INIS)

Conroy, W.G.

1988-01-01

Structural relatedness between the variable region of anti-ligand antibodies and opioid binding sites allowed the generation of anti-idiotypic antibodies which recognized opioid receptors. The IgG 3 k antibodies which bound to opioid receptors were obtained when an anti-morphine antiserum was the idiotype. Both antibodies bound to opioid receptors, but only one of these blocked the binding of [ 3 H]naloxone. The antibody which did not inhibit the binding of [ 3 H]naloxone was itself displaced from the receptor by opioid ligands. The unique binding properties displayed by this antibody indicated that anti-idiotypic antibodies are not always a perfect image of the original ligand, and therefore may be more useful than typical ligands as probes for the receptor. An auto-anti-idiotypic technique was successfully used to obtain anti-opioid receptor antibodies. Another IgG 3 k antibody that blocked the binding of [ 3 H]naloxone to rat brain opioid receptors was obtained when a mouse was immunized with naloxone conjugated to bovine serum albumin. These data confirmed that an idiotype-anti-idiotype network which can generate an anti-receptor antibody normally functions when an opioid ligand is introduced into an animal in an immunogenic form

A 'same day' TSH radioimmunoassay kit with acceptable precision and accuracy

International Nuclear Information System (INIS)

Wood, W.G.; Muenchen Univ.

1980-01-01

A new 'same-day' TSH-RIA kit has been tested against an 'in-house' TSH-RIA, using incubation schemes of 4, 22 and 23 h. The kit standards were made up in human TSH-free serum and the method used a preincubation step and separation of bound and free antigen using a double antibody method. The correlation between the 'in-house' method and the kit was very good. The results in sera from TRH-test patients, and also from a recovery test with MRC 68/38 in human serum covering the range 0-50 mU/l were good. A comparison of the new kit was made with its precedessor which had protein based standards highlighted the need for standards in human TSH-free serum seen by the poor correlation (r = 0.619, n = 93). (orig.) [de

Association between TSH-Receptor Autoimmunity, Hyperthyroidism, Goitre, and Orbitopathy in 208 Patients Included in the Remission Induction and Sustenance in Graves' Disease Study

DEFF Research Database (Denmark)

Laurberg, Peter; Nygaard, Birte; Andersen, Stig

2014-01-01

Background. Graves' disease may have a number of clinical manifestations with varying degrees of activity that may not always run in parallel. Objectives. To study associations between serum levels of TSH-receptor autoantibodies and the three main manifestations of Graves' disease (hyperthyroidism...... and Sustenance in Graves' Disease (RISG)." Patients were systematically tested for degree of biochemical hyperthyroidism, enlarged thyroid volume by ultrasonography, and the presence of orbitopathy. Results. Positive correlations were found between the levels of TSH-receptor autoantibodies in serum and the three...... manifestations of Graves' disease: severeness of hyperthyroidism, presence of enlarged thyroid, and presence of orbitopathy, as well as between the different types of manifestations. Only around half of patients had enlarged thyroid gland at the time of diagnosis of hyperthyroidism, whereas 25-30% had...

Non-hyperfunctioning nodules from multinodular goiters: a minor role in pathogenesis for somatic activating mutations in the TSH-receptor and Gsalpha subunit genes.

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Derrien, C; Sonnet, E; Gicquel, I; Le Gall, J Y; Poirier, J Y; David, V; Maugendre, D

2001-05-01

Constitutive activation of the cAMP pathway stimulates thyrocyte proliferation. Gain-of-function mutations in Gsalpha protein have already been identified in thyroid nodules which have lost the ability to trap iodine. In contrast, most of the studies failed to detect somatic activating mutations in the thyrotropin receptor (TSH-R) in non-hyperfunctioning thyroid tumors. The aim of this study was to screen for mutations TSH-R exon 10, encoding the whole intracytoplasmic area involved in signal transduction, and Gsalpha exons 8 and 9, containing the two hot-spot codons 201 and 227, in a subset of non-hyperfunctioning nodules from multinodular goiter. Identified by matching ultrasonography and scintiscan, 22 eufunctioning (normal 99Tc uptake) and 15 nonfunctioning (decreased 99Tc uptake) nodules from 27 non-toxic multinodular goiters were isolated. After DNA extraction, TSH-R exon 10 was analyzed by direct sequencing of the PCR products and Gsalpha exons 8 and 9 by Denaturing Gradient Gel Electrophoresis. No mutation of TSH-R or Gsalpha was detected in the 37 nodules analyzed. This absence of mutation, despite the use of two sensitive screening methods associated with the analysis of the TSH-R whole intracytoplasmic area and Gsalpha two hot-spot codons, suggests that TSH-R and Gsalpha play a minor role in the pathogenesis of non-toxic nodules from multinodular goiters.

Frequency and Clinical Implication of the R450H Mutation in the Thyrotropin Receptor Gene in the Japanese Population Detected by Smart Amplification Process 2

Science.gov (United States)

Yanagawa, Yoshimaro; Aoki, Tomoyuki; Morimura, Tadashi; Araki, Osamu; Kimura, Takao; Ogiwara, Takayuki; Kotajima, Nobuo; Yanagawa, Masumi; Murakami, Masami

2014-01-01

In Japanese pediatric patients with thyrotropin (TSH) resistance, the R450H mutation in TSH receptor gene (TSHR) is occasionally observed. We studied the frequency and clinical implication of the R450H mutation in TSHR in the general population of Japanese adults using smart amplification process 2 (SmartAmp2). We designed SmartAmp2 primer sets to detect this mutation using a drop of whole blood. We analyzed thyroid function, antithyroid antibodies, and this mutation in 429 Japanese participants who had not been found to have thyroid disease. Two cases without antithyroid antibodies were heterozygous for the R450H mutation in TSHR. Thus, the prevalence of this mutation was 0.47% in the general population and 0.63% among those without antithyroid antibodies. Their serum TSH concentrations were higher than the average TSH concentration not only in subjects without antithyroid antibodies but also in those with antithyroid antibodies. The R450H mutation in TSHR is relatively common in the Japanese population and potentially affects thyroid function. The present study demonstrates that the SmartAmp2 method is useful to detect the R450H mutation in TSHR, which is one of the common causes of TSH resistance in the Japanese population. PMID:24895636

Thyroid failure in the elderly: microsomal antibodies as discriminant for therapy

International Nuclear Information System (INIS)

Rosenthal, M.J.; Hunt, W.C.; Garry, P.J.; Goodwin, J.S.

1987-01-01

Thyrotropin (thyroid-stimulating hormone [TSH]) levels were elevated above 4.0 mU/L (μU/mL) in serum samples from 13.2% of 258 healthy elderly subjects. To investigate the natural history of progressive thyroid failure, serial thyroid functions were measured using radioimmunoassay for four years in 26 of these subjects with elevated TSH levels. In one third of these subjects, biochemical thyroid failure developed within the course of the study. All subjects with initial TSH levels above 20 mU/L (μU/mL), and 80% of those with high-titer thyroid antimicrosomal antibodies (regardless of initial TSH level), became overtly hypothyroid. Compared with subjects with high-titer antibody, those with antibody titer less than 1:1600 had lower TSH and higher thyroxine levels, and thyroid failure developed in none during the study. These results suggest that among older patients with isolated elevations of the TSH level, only those with markedly elevated TSH levels or high-titer antimicrosomal antibodies should be prophylactically treated with levothyroxine sodium replacement

An Enantiomer of an Oral Small-Molecule TSH Receptor Agonist Exhibits Improved Pharmacologic Properties.

Science.gov (United States)

Neumann, Susanne; Padia, Umesh; Cullen, Mary Jane; Eliseeva, Elena; Nir, Eshel A; Place, Robert F; Morgan, Sarah J; Gershengorn, Marvin C

2016-01-01

We are developing an orally available small-molecule, allosteric TSH receptor (TSHR) agonist for follow-up diagnostics of patients with thyroid cancer. The agonist C2 (NCGC00161870) that we have studied so far is a racemic mixture containing equal amounts of two enantiomers, E1 and E2. As enantiomers of many drugs exhibit different pharmacologic properties, we assessed the properties of E1 and E2. We separated the two enantiomers by chiral chromatography and determined E2 as the (S)-(+) isomer via crystal structure analysis. E1 and E2 were shown to bind differently to a homology model of the transmembrane domain of TSHR in which E2 was calculated to exhibit lower binding energy than E1 and was, therefore, predicted to be more potent than E1. In HEK293 cells expressing human TSHRs, C2, E1, and E2 were equally efficacious in stimulating cAMP production, but their potencies were different. E2 was more potent (EC50 = 18 nM) than C2 (EC50 = 46 nM), which was more potent than E1 (EC50 = 217 nM). In primary cultures of human thyrocytes, C2, E1, and E2 stimulated increases in thyroperoxidase mRNA of 92-, 55-, and 137-fold and in sodium-iodide symporter mRNA of 20-, 4-, and 121-fold above basal levels, respectively. In mice, C2 stimulated an increase in radioactive iodine uptake of 1.5-fold and E2 of 2.8-fold above basal level, whereas E1 did not have an effect. C2 stimulated an increase in serum T4 of 2.4-fold, E1 of 1.9-fold, and E2 of 5.6-fold above basal levels, and a 5-day oral dosing regimen of E2 increased serum T4 levels comparable to recombinant human TSH (rhTSH, Thyrogen(®)). Thus, E2 is more effective than either C2 or E1 in stimulating thyroid function and as efficacious as rhTSH in vivo. E2 represents the next step toward developing an oral drug for patients with thyroid cancer.

An Enantiomer of an Oral Small Molecule TSH Receptor Agonist Exhibits Improved Pharmacologic Properties

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Susanne Neumann

2016-07-01

Full Text Available We are developing an orally available small molecule, allosteric TSH receptor (TSHR agonist for follow up diagnostics of patients with thyroid cancer. The agonist C2 (NCGC00161870 that we have studied so far is a racemic mixture containing equal amounts of two enantiomers, E1 and E2. As enantiomers of many drugs exhibit different pharmacologic properties, we assessed the properties of E1 and E2. We separated the two enantiomers by chiral chromatography and determined E2 as the (S-(+ isomer via crystal structure analysis. E1 and E2 were shown to bind differently to a homology model of the transmembrane domain of TSHR in which E2 was calculated to exhibit lower binding energy than E1 and was therefore predicted to be more potent than E1. In HEK293 cells expressing human TSHRs, C2, E1, and E2 were equally efficacious in stimulating cAMP production, but their potencies were different. E2 was more potent (EC50 = 18 nM than C2 (EC50 = 46 nM which was more potent than E1 (EC50 = 217 nM. In primary cultures of human thyrocytes, C2, E1, and E2 stimulated increases in thyroperoxidase mRNA of 92-, 55-, and 137-fold and in sodium-iodide symporter mRNA of 20-fold, 4-fold and 121-fold above basal levels, respectively. In mice, C2 stimulated an increase in radioactive iodine uptake of 1.5-fold and E2 of 2.8-fold above basal level, whereas E1 did not have an effect. C2 stimulated an increase in serum T4 of 2.4-fold, E1 of 1.9-fold, and E2 of 5.6-fold above basal levels, and a 5 day oral dosing regimen of E2 increased serum T4 levels comparable to recombinant human TSH (rhTSH, Thyrogen®. Thus, E2 is more effective than either C2 or E1 in stimulating thyroid function and as efficacious as rhTSH in vivo. E2 represents the next step toward developing an oral drug for patients with thyroid cancer.

Apparent genetic difference between hypothyroid patients with blocking-type thyrotropin receptor antibody and those without, as shown by restriction fragement length polymorphism analyses of HLA-DP loci

Energy Technology Data Exchange (ETDEWEB)

Inoue, Daisuke; Sugawa, Hideo; Akamizu, Takashi; Mori, Toru (Kyoto Univ. School of Medicine, Kyoto (Japan)); Sato, Kaoru; Inoko, Hidetoshi; Tsuji, Kimiyoshi (Tokai Univ. School of Medicine, Kanagawa (Japan)); Maeda, Masahiro (Nichirei Corp., Tokyo (Japan))

1993-09-01

HLA types in Japanese patients with primary hypothyroidism were analyzed to see whether those with blocking-type TSH receptor antibody (TSH-R BAb M) differed genetically from those with idiopathic myxedema (IM). HLA typings of -A, -B, -C, -DR, and -DQ (73 antigens) were performed serologically, and those of -D and -DP (29 antigens) were analyzed by the restriction fragment length polymorphism method. Thirty patients were studied with TSH-R BAb M, and 28 with IM. The data were analyzed and compared with previous results from 88 Graves' patients, 46 Hashimoto patients, and 186 control subjects. Overall, 192 patients with 4 autoimmune thyroid disorders showed a decrease in -Aw19 and an increase in -DQw4 (corrected P < 0.05) and significant associations of -Aw33, -Bw46, -Cw3, -DRw8, -DR9, and -DQw3. In TSH-R BAb M patients, increases in -B35, -Bw60, and -Dw8 and decreases in -DR4 and -DPw2 were seen, whereas IM patients showed increased -DPw2, -Bw61, and -Dw23. In comparisons between TSH-R-BAb M and IM, the difference in -DPw2 was highly significant. HLA-B35 differed significantly in these 2 types of hypothyroidism. In conclusion, TSH-R BAb M patients have decreased frequency of -DPw2 and are genetically similar to Graves' disease, whereas IM patients are characterized by high frequency of -DPw2 and are genetically similar to Hashimoto's thyroiditis. 39 refs., 2 figs., 3 tabs.

Immunoassay of blood spot TSH; development of a rapid two-site immunoradiometric assay and comparison with radioimmunoassay as a screening method for neonatal hypothyroidism

International Nuclear Information System (INIS)

Sutherland, R.M.; Ratcliffe, J.G.; Chapman, R.S.

1982-01-01

The development of a two-site immunoradiometric assay (IRMA) for thyrotropin (TSH) eluted from dried blood filter paper discs is described and compared with a conventional TSH radioimmunoassay (RIA) as a screening procedure for neonatal hypothyroidism. The two-site IRMA involves a primary incubation of excess labelled TSH antibody and the blood disc for 16-18 h at pH 8 and a secondary 3 h incubation under agitation, with solid phase TSH antibody. Bound and free fractions are separated by a semi-automated washing procedure. It is concluded that the two-site TSH IRMA has advantages over conventional RIA in speed, sensitivity, precision and ruggedness and can be recommended as an efficient screening procedure for neonatal hypothyroidism. (Auth.)

Two-monoclonal-antibody sandwich-type assay for thyrotropin, with use of an avidin-biotin separation technique

International Nuclear Information System (INIS)

Odell, W.D.; Griffin, J.; Zahradnik, R.

1986-01-01

We have developed a sensitive, specific, noncompetitive, sandwich-type radioimmunoassay for human thyrotropin (hTSH), which can be performed in 30 min. The assay involves two monoclonal antibodies, selected for high affinity and specificity and also for reaction against antigenic sites on hTSH that are distal from each other. One of these antibodies is labeled with 125 I; the other is conjugated covalently to biotin. Polystyrene beads were also conjugated covalently to biotin. After conjugation, the beads were incubated with avidin. These beads represent a rapid, simple method for separating hTSH-bound antibody from free antibody. The biotin-antibody-hTSH- 125 I-labeled antibody complexes bind to the beads and hTSH concentration is directly related to counts per minute. This assay can detect hTSH at a concentration of 0.06 milli-unit/L in serum

Biological impact of the TSH-beta splice variant in health and disease

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John R. Klein

2014-04-01

Full Text Available Thyroid stimulating hormone (TSH, a glycoprotein hormone composed of alpha and beta chains, is produced by thryrotrope cells of the anterior pituitary. Within the conventional endocrine loop, pituitary-derived TSH binds to receptors in the thyroid, resulting in the release of the thyroid hormones thyroxine (T4 and triiodothyronine (T3. T4 and T3 in turn regulate nearly every aspect of mammalian physiology, including basal metabolism, growth and development, and mood and cognition. Although TSH-beta has been known for years to be produced by cells of the immune system, the significance of that has remained largely unclear. Recently, a splice variant of TSH-beta (TSH-beta-v, which consists of a truncated but biologically functional portion of the native form of TSH-beta, was shown to be produced by bone marrow cells and peripheral blood leukocytes, particularly cells of the myeloid/monocyte lineage. In contrast, full-length native TSH-beta is minimally produced by cells of the immune system. The present article will describe the discovery of the TSH-beta-v and will discuss its potential role in immunity and autoimmunity, inflammation, and bone remodeling.

Concomitant Graves' disease and Hashimoto's thyroiditis, presenting as primary hypothyroidism.

LENUS (Irish Health Repository)

Cronin, C C

2012-02-03

Hypothyroidism in patients with Graves\\' disease is usually the result of ablative treatment. We describe a 58 year old man with Graves\\' ophthalmopathy and pre-tibial myxoedema, who presented with spontaneous primary hypothyroidism. Circulating TSH receptor antibody activity was increased, while thyroid microsomal antibody was detectable in titres greater than one in one hundred thousand. It is likely that the TSH receptor antibody of Graves\\' disease was ineffective in stimulating hyperthyroidism because of concomitant thyroid destruction due to Hashimoto\\'s disease. Alternatively, primary hypothyroidism could have resulted from the effects of a circulating TSH receptor blocking antibody.

The development of T3-RIA, T4-RIA and TSH-IRMA for in vitro testing of thyroid function

International Nuclear Information System (INIS)

Borza, V.; Neacsu, G.; Chariton, Despina

1998-01-01

Thyroxine (T 4 ) and triiodothyronine (T 3 ) are two principal thyroid hormones; the release of this hormones and control of different stages of their synthesis are performed by thyrotropin (TSH), secreted by pituitary gland. Also, T 3 and T 4 exert negative feed-back on the pituitary, inhibiting the release of TSH. The measurement of T 3 , T 4 content in un-extracted serum, correlated with TSH values are useful results for investigating the pituitary-thyroid axis. This paper describes radioimmunological procedures for the measurement of T 3 and T 4 using as separation method of the bound and free radiolabeled antigen, the precipitation of antigen-antibody complex by polyethyleneglycol (PEG). Antisera against T 3 , T 4 were produced by immunizing sheep with conjugates of the hormones and bovine albumin; T 3 and T 4 standards were made in horse serum free of these hormones. Binding of T 3 and T 4 to TBG in serum was inhibited by addition of 8-aniline-1-naphthalene-sulfonic acid (ANS). The separation of antigen-antibody complex was carried out using 25.5% PEG 6000. In order to develop a simple T 3 solid phase radioimmunoassay, in this paper the immobilization of anti-T 3 antibodies on polystyrene tubes is presented. The best results were obtained with an exposure time of anti-T 3 antibodies (diluted in buffer solution, pH 8.4-8.6) of 40 h at 4 o C. Also, in this study the preparation of 125 I labeled monoclonal antibody (Mab)-anti-TSH is described, which will be used as a component of a TSH-IRMA kit; this kit is to be realized in our department. 125 I - Mab anti-TSH has the following characteristics: specific activity = 20 - 24 μCi/μg and radioactive concentration ≅ 25 μCi/ml; also, the immunological properties of tracer were verified. The major results of this activity is that the total dependence on important kits will be eliminated and also, the costs will be reduced. (authors)

Chemokine Receptor-Specific Antibodies in Cancer Immunotherapy: Achievements and Challenges

Science.gov (United States)

Vela, Maria; Aris, Mariana; Llorente, Mercedes; Garcia-Sanz, Jose A.; Kremer, Leonor

2015-01-01

The 1990s brought a burst of information regarding the structure, expression pattern, and role in leukocyte migration and adhesion of chemokines and their receptors. At that time, the FDA approved the first therapeutic antibodies for cancer treatment. A few years later, it was reported that the chemokine receptors CXCR4 and CCR7 were involved on directing metastases to liver, lung, bone marrow, or lymph nodes, and the over-expression of CCR4, CCR6, and CCR9 by certain tumors. The possibility of inhibiting the interaction of chemokine receptors present on the surface of tumor cells with their ligands emerged as a new therapeutic approach. Therefore, many research groups and companies began to develop small molecule antagonists and specific antibodies, aiming to neutralize signaling from these receptors. Despite great expectations, so far, only one anti-chemokine receptor antibody has been approved for its clinical use, mogamulizumab, an anti-CCR4 antibody, granted in Japan to treat refractory adult T-cell leukemia and lymphoma. Here, we review the main achievements obtained with anti-chemokine receptor antibodies for cancer immunotherapy, including discovery and clinical studies, proposed mechanisms of action, and therapeutic applications. PMID:25688243

Characterization of monoclonal antibodies directed against human thyroid stimulating hormone

International Nuclear Information System (INIS)

Soos, M.; Siddle, K.

1982-01-01

Monoclonal antibodies directed against human thyroid stimulating hormone (TSH) were obtained from hybrid myelomas, following fusion of mouse NSI myeloma cells with mouse spleen cells. Ten different antibodies were obtained from 4 separate fusions. Eight antibodies were of the IgG 1 subclass. Affinities of antibodies for TSH were in the range 2 x 10 8 -5 x 10 10 M -1 . Five of the antibodies were specific for TSH and did not react with LH, FSH or hCG. The remaining antibodies reacted with all these hormones and were assumed to recognise their common (α) subunit. The 5 specific antibodies fell into 3 subgroups recognising distinct antigenic determinants, whereas the 5 non-specific antibodies recognised a single determinant or closely related set of sites. It is concluded that these antibodies should be valuable reagents for use in sensitive and specific two-site immunoradiometric assays. (Auth.)

Definition of reference ranges for free T4, TSH, and thyroglobulin levels in healthy subjects of the Jaén Health District.

Science.gov (United States)

Olmedo Carrillo, Pablo; Santiago Fernández, Piedad; García Fuentes, Eduardo; Ureña Fernández, Tomás; Gutiérrez Alcántara, Carmen; Sánchez-Malo, Carolina; Gassó Campos, Manuela; Martínez Ramírez, María José

2017-10-01

The treatment guidelines for thyroid dysfunction recommend defining reference ranges for thyroid hormones in each area through assessment of local population data considering the iodine nutritional status. The aim of this study was to define the reference ranges of free thyroxine (FT4), TSH, and thyroglobulin levels in a general population from Jaen, an area of southern Spain with an adequate iodine nutritional status, and whether they were associated with urinary iodine levels. A cross-sectional study was conducted in 1,003 subjects of the general population of the Jaen Health District. Levels of urinary iodine, FT4, TSH, thyroglobulin, and thyroid peroxidase (TPO) antibodies were measured according to age and sex. Median and mean urinary iodine levels were 110.59μg/L and 130.11μg/L respectively. Median TSH level was 1.83μIU/mL (p2.5=0.56μIU/mL, p97.5=4.66μIU/mL). Median FT4 level was 0.84ng/dL (p2.5=0.62ng/dL, p97.5=1.18ng/dL). TPO antibodies were detected in 5.7% of subjects. There was no correlation between urinary iodine levels and FT4, TSH or TPO antibodies. Subjects with positive TPO antibodies had higher TSH levels (3.34μIU/L versus 2.14μIU/mL, P=.001; odds ratio=2.42). Urinary iodine levels in Jaen are optimal according to World Health Organization standards. Reference ranges of FT4, TSH, and thyroglobulin do not differ from those reported in the literature and are no associated to urinary iodine levels. The prevalence of positive TPO antibodies was similar to that reported in other Spanish areas. Copyright © 2017 SEEN y SED. Publicado por Elsevier España, S.L.U. All rights reserved.

Immunological Reactivity Using Monoclonal and Polyclonal Antibodies of Autoimmune Thyroid Target Sites with Dietary Proteins

Directory of Open Access Journals (Sweden)

Datis Kharrazian

2017-01-01

Full Text Available Many hypothyroid and autoimmune thyroid patients experience reactions with specific foods. Additionally, food interactions may play a role in a subset of individuals who have difficulty finding a suitable thyroid hormone dosage. Our study was designed to investigate the potential role of dietary protein immune reactivity with thyroid hormones and thyroid axis target sites. We identified immune reactivity between dietary proteins and target sites on the thyroid axis that includes thyroid hormones, thyroid receptors, enzymes, and transport proteins. We also measured immune reactivity of either target specific monoclonal or polyclonal antibodies for thyroid-stimulating hormone (TSH receptor, 5′deiodinase, thyroid peroxidase, thyroglobulin, thyroxine-binding globulin, thyroxine, and triiodothyronine against 204 purified dietary proteins commonly consumed in cooked and raw forms. Dietary protein determinants included unmodified (raw and modified (cooked and roasted foods, herbs, spices, food gums, brewed beverages, and additives. There were no dietary protein immune reactions with TSH receptor, thyroid peroxidase, and thyroxine-binding globulin. However, specific antigen-antibody immune reactivity was identified with several purified food proteins with triiodothyronine, thyroxine, thyroglobulin, and 5′deiodinase. Laboratory analysis of immunological cross-reactivity between thyroid target sites and dietary proteins is the initial step necessary in determining whether dietary proteins may play a potential immunoreactive role in autoimmune thyroid disease.

Thyrotropin-luteinizing hormone/chorionic gonadotropin receptor extracellular domain chimeras as probes for thyrotropin receptor function

International Nuclear Information System (INIS)

Nagayama, Yuji; Wadsworth, H.L.; Chazenbalk, G.D.; Russo, D.; Seto, Pui; Rapoport, B.

1991-01-01

To define the sites in the extracellular domain of the human thyrotropin (TSH) receptor that are involved in TSH binding and signal transduction the authors constructed chimeric thyrotropin-luteinizing hormone/chorionic gonadotropin (TSH-LH/CG) receptors. The extracellular domain of the human TSH receptor was divided into five regions that were replaced, either singly or in various combinations, with homologous regions of the rat LH/CG receptor. The chimeric receptors were stably expressed in Chinese hamster ovary cells. The data obtained suggest that the carboxyl region of the extracellular domain (amino acid residues 261-418) and particularly the middle region (residues 171-260) play a role in signal transduction. The possibility is also raised of an interaction between the amino and carboxyl regions of the extracellular domain in the process of signal transduction. In summary, these studies suggest that the middle region and carboxyl half of the extracellular domain of the TSH receptor are involved in signal transduction and that the TSH-binding region is likely to span the entire extracellular domain, with multiple discontinuous contact sites

Clinical experience of a sensitive immunoradiometric thyrotropin (TSH) assay kit (RIA-gnost hTSH)

International Nuclear Information System (INIS)

Nakamura, Saeko; Jibiki, Kazuko; Demura, Reiko; Koike, Sachiko; Kurihara, Shigeko; Odagiri, Emi; Demura, Hiroshi

1987-01-01

A commercially available immunoradiometric thyrotropin (TSH) assay kit (RIA-gnost hTSH) was used to study the concentration of TSH in serum in a series of 124 patients with thyroid dysfunction and 35 normal controls. Laboratory test for RIA-gnost hTSH showed a detection limit for TSH to be 0.03 μU/ml. The basal serum concentration of TSH in normal controls ranged from 0.17 to 3.21 μU/ml, with a mean of 0.74 μU/ml. It was less than 0.04 μU/ml in all 28 untreated patients with Graves' disease, indicating the discrimination between normal and hyperthyroid subjects. In the case of untreated 7 patients with hypothalamic hypopituitarism, the basal TSH concentration ranged from 0.80 to 13.5 μU/ml. There was no consistent tendency for changes in TSH levels with normalization of free thyroxine in 8 treated patients with Graves' disease. The basal serum concentration of TSH reflected the response of TSH to thyrotropin releasing hormone in 10 treated patients with Graves' disease. The use of the RIA-gnost hTSH would be of clinical significance in the diagnosis and management of patients with Graves' disease or hypopituitarism. (Namekawa, K.)

Thyroid disorders and the prevalence of antithyroid antibodies in Shiraz population.

Science.gov (United States)

Karimi, Fariba; Kalantarhormozi, Mohammad Reza; Dabbaghmanesh, Mohammad Hossein; Ranjbar Omrani, Gholamhossein

2014-05-01

Thyroid dysfunction is a common health problem affecting millions of patients worldwide. Autoimmune thyroid disorders are among the most common autoimmune disorders. In this population-based study, we assessed the prevalence of abnormal thyroid function, antithyroid antibodies and the probable relationship between them in Shiraz, southern Iran. Serum thyrotropin (TSH) was determined in 981 subjects (66.8% female and 33.2% male; mean age: 39.1 ± 14.3 years), who were selected with stratified random sampling. Because of the preponderance of females over males, we performed the statistical analyses using sex-weighted data (50% for each sex). Also, antithyroid peroxidase antibodies (TPOAb), and antithyroglobulin antibodies (TgAb) were measured in two random subgroups of 376 and 537 patients respectively). Thyromegaly detected on physical examination. In this cross-sectional study, 8.1% of participants had elevated serum TSH level and 3.4% had low serum TSH level. A statistically significant relationship was found between gender and thyromegaly and TSH values. Positive TPOAb and positive TgAb were detected in 17% and 5.1% of participants respectively. In addition, a significant relationship was observed between elevated TSH levels and positive results for both antibodies. Detectable levels of thyroid antibodies correlated with female sex, while no correlation was observed between detectable levels of thyroid antibodies and thyromegaly. Thyroid disorders, especially elevated TSH level, are common. It seems that autoimmune mechanisms are strongly involved in the etiology of hypothyroidism in this area.

Familial Longevity Is Associated With Higher TSH Secretion and Strong TSH-fT3 Relationship

DEFF Research Database (Denmark)

Jansen, Steffy W; Roelfsema, Ferdinand; van der Spoel, Evie

2015-01-01

and in their partners, ultradian and circadian rhythmicity of TSH, temporal relationship, and feedback and forward interplay between TSH and TH. METHODS: We collected blood samples every 10 minutes for 24 hours for TSH and TH profiles. We used a deconvolution analysis to estimate basal (nonpulsatile), pulsatile......, and other secretion parameters to characterize ultradian rhythmicity and locally weighted polynomial regression of TSH to assess circadian rhythmicity. A cross-correlation analysis was used to investigate the temporal relationship between TSH and TH and cross-approximate entropy to assess feedback...... TSH secretion and a strong temporal relationship between TSH and free T3 but not with differences in ultradian or circadian TSH rhythmicity or feedback and forward interplay between TSH and TH....

The appearance in thyroidectomized mice of immunoglobulins that bind TSH and stimulate FRTL-5 thyrocytes

International Nuclear Information System (INIS)

Gafny, M.; Ben-David, C.; Sirkis, N.; Gordon, A.; Gross, J.

1992-01-01

The model system chosen was the thyroidectomized mouse, exhibiting an elevated level of endogenous, circulating TSH. Mice were thyroidectomized by 131 I administration. Sera samples were drawn 1 to 14 months later. The following activities were measured in the immunoglobulin (Ig) fractions prepared: (a) TSH binding by elisa techniques, (b) iodide pump activity (as measured by 99m TcO 4 uptake) and (c) increased [ 3 H]thymidine incorporation into the DNA of FRTL-5 cells. TSH binding Igs were detected in 29/98 mice thyroidectomized for 7-14 months. Stimulation of technetium uptake was observed in 59/110 mice and stimulated labeled thymidine uptake in 37/102 mice, beginning eight and nine months after thyroidectomy, respectively. Of the positive animals, 51 showed a single stimulating activity. The incidence and the serum titers of Igs that stimulate technitium uptake increased significantly with time. Indeed, in the group tested 14 months post-thyroidectomy, 75% of the sera were positive for this antibody with a mean titer eightfold higher than the controls. Hybridomas were prepared from the spleen lymphocytes of thyroidectomized mice. Of these, 18 produced 99m TcO 4 uptake stimulating Igs, 12[ 3 H]thymidine-uptake stimulating Igs and 18 TSH binding Igs. Most of the hybridomas secreted Igs with a single bioactivity. One monoclonal antibody was isolated which neutralized the bioactivity of bTSH on FRTL-5 cells. 99m TcO 4 uptake was decreased by 50% and [ 3 H]thymidine uptake was virtually abolished. These results suggest that the hypothyroid mouse can develop anti-TSH antobodies and thyroid-stimulating antiidiotypic antiboides by an autoimmune process. (BN)

Serum TSH reference interval in healthy Finnish adults using the Abbott Architect 2000i Analyzer.

Science.gov (United States)

Schalin-Jäntti, Camilla; Tanner, Pirjo; Välimäki, Matti J; Hämäläinen, Esa

2011-07-01

Current serum TSH reference intervals have been criticized as they were established from unselected background populations. A special concern is that the upper limit, which defines subclinical hypothyroidism, is too high. The objective was to redefine the TSH reference interval in the adult Finnish population. The current reference interval for the widely used Abbott Architect method in Finland is 0.4-4.0 mU/L. Serum TSH and free T4 concentrations were derived from 606 healthy, non-pregnant, 18-91-year-old Finns from the Nordic Reference Interval Project (NORIP) and the possible effects of age, sex and thyroid peroxidase antibody (TPOAb) status were evaluated. After excluding TPOAb-positive subjects and outliers, a reference population of 511 subjects was obtained. In the reference population, no statistically significant gender- or age-specific differences in mean TSH (1.55 ± 3.30 mU/L) or TSH reference intervals were observed. The new reference interval was 0.5-3.6 mU/L (2.5th-97.5th percentiles). The current upper TSH reference limit is 10% too high. A TSH > 3.6 mU/L, confirmed with a repeat TSH sampling, may indicate subclinical hypothyroidism. Differences in ethnicity, regional iodine-intake and analytical methods underline the need for redefining the TSH reference interval in central laboratories in different countries.

Characterization of monoclonal antibodies against human thyrotropin and use in an immunoradiometric assay and immunohistochemistry

International Nuclear Information System (INIS)

Benkirane, M.; Bon, D.; Bellot, F.; Prince, P.; Delori, P.; Hassoun, J.; Carayon, P.

1987-01-01

Monoclonal antibodies were prepared against human thyrotropin. 13 different antibodies were characterized. Ten antibodies were of the IgG1 subclass. The affinities of the antibodies were in the range 10 9 -10 11 mol -1 .l. Four of them were specific for hTSH and did not react with hLH, hFSH, hCG or αhCG. Four reacted with these hormones and recognized the α subunit of hCG. One cross-reacted only with HFSH. The remaining four antibodies recognized the holo-hTSH only, and thus were designated as anti-conformational determinants. Monoclonal antibodies reacting with different antigenic determinants on the hTSH molecule defined seven clusters. Two of them were used to develop a simplified two-site sandwich radioimmunoassay in which one monoclonal antibody was immobilized on tubes (anti-βTSH) and another (anti-α) labelled with 125 I. This assay was highly specific and demonstrated a sensitivity level of 0.1 μIU/ml. Two monoclonal antibodies were used in immunohistochemistry and their quality and specificity was assessed in the detection of hTSH immunoreactivity in human pituitary biological sections. 20 refs.; 6 figs.; 2 tabs

Pendrin and NIS antibodies are absent in healthy individuals and are rare in autoimmune thyroid disease

DEFF Research Database (Denmark)

Brix, Thomas H; Hegedüs, Laszlo; Weetman, Anthony P

2014-01-01

prevalence than the controls: NISAb: 17% vs 0% (P Graves' disease (GD) and 14% (5/37) of patients with Hashimoto's thyroiditis (HT) had NISAb, (P ...OBJECTIVE: Antibodies against thyroglobulin, thyroid peroxidase and the TSH receptor are accepted as pathophysiological and diagnostic biomarkers in autoimmune thyroid disease (AITD). In contrast, the prevalence, aetiology and clinical relevance of autoantibodies against the human sodium...

[Harmonization of TSH Measurements.

Science.gov (United States)

Takeoka, Keiko; Hidaka, Yoh; Hishinuma, Akira; Ikeda, Katsuyoshi; Okubo, Shigeo; Tsuchiya, Tatsuyuki; Hashiguchi, Teruto; Furuta, Koh; Hotta, Taeko; Matsushita, Kazuyuki; Matsumoto, Hiroyuki; Murakami, Masami; Maekawa, Masato

2016-05-01

The measured concentration of thyroid stimulating hormone (TSH) differs depending on the reagents used. Harmonization of TSH is crucial because the decision limits are described in current clinical practice guide- lines as absolute values, e.g. 2.5 mIU/L in early pregnancy. In this study, we tried to harmonize the report- ed concentrations of TSH using the all-procedure trimmed mean. TSH was measured in 146 serum samples, with values ranging from 0.01 to 18.8 mIU/L, using 4 immunoassays. The concentration of TSH was highest with E test TOSOH and lowest with LUMIPULSE. The concentrations with each reagent were recalculated with the following formulas: E test TOSOH 0.855x-0.014; ECLusys 0.993x+0.079; ARCHITECT 1.041x- 0.010; and LUMIPULSE 1.096x-0.015. Recalculation eliminated the between-assay discrepancy. These formulas may be used until harmonization of TSH is achieved by the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC).

Netrin-1 receptor antibodies in thymoma-associated neuromyotonia with myasthenia gravis.

Science.gov (United States)

Torres-Vega, Estefanía; Mancheño, Nuria; Cebrián-Silla, Arantxa; Herranz-Pérez, Vicente; Chumillas, María J; Moris, Germán; Joubert, Bastien; Honnorat, Jérôme; Sevilla, Teresa; Vílchez, Juan J; Dalmau, Josep; Graus, Francesc; García-Verdugo, José Manuel; Bataller, Luis

2017-03-28

To identify cell-surface antibodies in patients with neuromyotonia and to describe the main clinical implications. Sera of 3 patients with thymoma-associated neuromyotonia and myasthenia gravis were used to immunoprecipitate and characterize neuronal cell-surface antigens using reported techniques. The clinical significance of antibodies against precipitated proteins was assessed with sera of 98 patients (neuromyotonia 46, myasthenia gravis 52, thymoma 42; 33 of them with overlapping syndromes) and 219 controls (other neurologic diseases, cancer, and healthy volunteers). Immunoprecipitation studies identified 3 targets, including the Netrin-1 receptors DCC (deleted in colorectal carcinoma) and UNC5A (uncoordinated-5A) as well as Caspr2 (contactin-associated protein-like 2). Cell-based assays with these antigens showed that among the indicated patients, 9 had antibodies against Netrin-1 receptors (7 with additional Caspr2 antibodies) and 5 had isolated Caspr2 antibodies. Only one of the 219 controls had isolated Caspr2 antibodies with relapsing myelitis episodes. Among patients with neuromyotonia and/or myasthenia gravis, the presence of Netrin-1 receptor or Caspr2 antibodies predicted thymoma ( p myasthenia gravis, and neuromyotonia, often with Morvan syndrome ( p = 0.009). Expression of DCC, UNC5A, and Caspr2 proteins was demonstrated in paraffin-embedded thymoma samples (3) and normal thymus. Antibodies against Netrin-1 receptors (DCC and UNC5a) and Caspr2 often coexist and associate with thymoma in patients with neuromyotonia and myasthenia gravis. This study provides Class III evidence that antibodies against Netrin-1 receptors can identify patients with thymoma (sensitivity 21.4%, specificity 100%). © 2017 American Academy of Neurology.

Diural TSH variations in hypothyroidism.

Science.gov (United States)

Weeke, J; Laurberg, P

1976-07-01

There is a circadian variation in serum TSH in euthyroid subjects. A similar diurnal variation has been demonstrated in patients with hypothyroidism. In the present study the 24-hour pattern of serum TSH was investigated in eight patients with hypothyroidism of varying severity and in five hypothyroid patients treated with thyroxine (T4). There was a circadian variation in serum TSH in patients with hypothyroidism of moderate degree, and in patients treated for severe hypothyrodism with thyroxine. The pattern was similar to that found in normal subjects, i.e., low TSH levels in the daytime and higher levels at night. In severely hypothyroid patients, no diurnal variation in serum TSH was observed. A practical consequence is that blood samples for TSH measurements in patients with moderately elevated TSH levels are best taken after 1100 h, when the low day levels are reached.

Detection of thyroid stimulating hormone receptor antibodies (TRAb) by radioreceptor assay (RRA) and enzyme-linked immunosorbent assay (ELISA)

International Nuclear Information System (INIS)

Dumrongpisutikul, S.; Tuchinda, S.

1990-01-01

Thyroid stimulating hormone receptor antibodies (TRAb) were determined in 100 patients using radioreceptor assay (RRA) and enzyme-linked immunosorbent assay (ELISA). The sensitivity of RRA and ELISA were found to be 70.6% and 88.2% respectively (n=51). The specificity of both assays were 100% (n=16). With RRA as the standard test the sensitivity and specificity of ELISA were 75.8% and 86.8%. In the untreated hyperthyroid the RRA result which expressed as % specific 125 I-TSH inhibition was 33.6% (n=51), decline to 26.9% in the treated hyperthyroid (n=33) and 14.1% in the euthyroid (n=16). The mean 0.D 492nm of TRAb-ELISA were 0.861 in untreated hyperthyroid, 0.437 in treated hyperthyroid and 0.135 in euthyroid Phi coefficient analysis show that the RRA was 60.4% correlated to hyperthyroidism where as TRAb-ELISA was 80.1%

Structural–Functional Features of the Thyrotropin Receptor: A Class A G-Protein-Coupled Receptor at Work

Directory of Open Access Journals (Sweden)

Gerd Krause

2017-04-01

Full Text Available The thyroid-stimulating hormone receptor (TSHR is a member of the glycoprotein hormone receptors, a sub-group of class A G-protein-coupled receptors (GPCRs. TSHR and its endogenous ligand thyrotropin (TSH are of essential importance for growth and function of the thyroid gland and proper function of the TSH/TSHR system is pivotal for production and release of thyroid hormones. This receptor is also important with respect to pathophysiology, such as autoimmune (including ophthalmopathy or non-autoimmune thyroid dysfunctions and cancer development. Pharmacological interventions directly targeting the TSHR should provide benefits to disease treatment compared to currently available therapies of dysfunctions associated with the TSHR or the thyroid gland. Upon TSHR activation, the molecular events conveying conformational changes from the extra- to the intracellular side of the cell across the membrane comprise reception, conversion, and amplification of the signal. These steps are highly dependent on structural features of this receptor and its intermolecular interaction partners, e.g., TSH, antibodies, small molecules, G-proteins, or arrestin. For better understanding of signal transduction, pathogenic mechanisms such as autoantibody action and mutational modifications or for developing new pharmacological strategies, it is essential to combine available structural data with functional information to generate homology models of the entire receptor. Although so far these insights are fragmental, in the past few decades essential contributions have been made to investigate in-depth the involved determinants, such as by structure determination via X-ray crystallography. This review summarizes available knowledge (as of December 2016 concerning the TSHR protein structure, associated functional aspects, and based on these insights we suggest several receptor complex models. Moreover, distinct TSHR properties will be highlighted in comparison to other

Structural-Functional Features of the Thyrotropin Receptor: A Class A G-Protein-Coupled Receptor at Work.

Science.gov (United States)

Kleinau, Gunnar; Worth, Catherine L; Kreuchwig, Annika; Biebermann, Heike; Marcinkowski, Patrick; Scheerer, Patrick; Krause, Gerd

2017-01-01

The thyroid-stimulating hormone receptor (TSHR) is a member of the glycoprotein hormone receptors, a sub-group of class A G-protein-coupled receptors (GPCRs). TSHR and its endogenous ligand thyrotropin (TSH) are of essential importance for growth and function of the thyroid gland and proper function of the TSH/TSHR system is pivotal for production and release of thyroid hormones. This receptor is also important with respect to pathophysiology, such as autoimmune (including ophthalmopathy) or non-autoimmune thyroid dysfunctions and cancer development. Pharmacological interventions directly targeting the TSHR should provide benefits to disease treatment compared to currently available therapies of dysfunctions associated with the TSHR or the thyroid gland. Upon TSHR activation, the molecular events conveying conformational changes from the extra- to the intracellular side of the cell across the membrane comprise reception, conversion, and amplification of the signal. These steps are highly dependent on structural features of this receptor and its intermolecular interaction partners, e.g., TSH, antibodies, small molecules, G-proteins, or arrestin. For better understanding of signal transduction, pathogenic mechanisms such as autoantibody action and mutational modifications or for developing new pharmacological strategies, it is essential to combine available structural data with functional information to generate homology models of the entire receptor. Although so far these insights are fragmental, in the past few decades essential contributions have been made to investigate in-depth the involved determinants, such as by structure determination via X-ray crystallography. This review summarizes available knowledge (as of December 2016) concerning the TSHR protein structure, associated functional aspects, and based on these insights we suggest several receptor complex models. Moreover, distinct TSHR properties will be highlighted in comparison to other class A GPCRs to

Structural–Functional Features of the Thyrotropin Receptor: A Class A G-Protein-Coupled Receptor at Work

Science.gov (United States)

Kleinau, Gunnar; Worth, Catherine L.; Kreuchwig, Annika; Biebermann, Heike; Marcinkowski, Patrick; Scheerer, Patrick; Krause, Gerd

2017-01-01

The thyroid-stimulating hormone receptor (TSHR) is a member of the glycoprotein hormone receptors, a sub-group of class A G-protein-coupled receptors (GPCRs). TSHR and its endogenous ligand thyrotropin (TSH) are of essential importance for growth and function of the thyroid gland and proper function of the TSH/TSHR system is pivotal for production and release of thyroid hormones. This receptor is also important with respect to pathophysiology, such as autoimmune (including ophthalmopathy) or non-autoimmune thyroid dysfunctions and cancer development. Pharmacological interventions directly targeting the TSHR should provide benefits to disease treatment compared to currently available therapies of dysfunctions associated with the TSHR or the thyroid gland. Upon TSHR activation, the molecular events conveying conformational changes from the extra- to the intracellular side of the cell across the membrane comprise reception, conversion, and amplification of the signal. These steps are highly dependent on structural features of this receptor and its intermolecular interaction partners, e.g., TSH, antibodies, small molecules, G-proteins, or arrestin. For better understanding of signal transduction, pathogenic mechanisms such as autoantibody action and mutational modifications or for developing new pharmacological strategies, it is essential to combine available structural data with functional information to generate homology models of the entire receptor. Although so far these insights are fragmental, in the past few decades essential contributions have been made to investigate in-depth the involved determinants, such as by structure determination via X-ray crystallography. This review summarizes available knowledge (as of December 2016) concerning the TSHR protein structure, associated functional aspects, and based on these insights we suggest several receptor complex models. Moreover, distinct TSHR properties will be highlighted in comparison to other class A GPCRs to

Changes of TSH-Stimulation Blocking Antibody (TSBAb and Thyroid Stimulating Antibody (TSAb Over 10 Years in 34 TSBAb-Positive Patients with Hypothyroidism and in 98 TSAb-Positive Graves’ Patients with Hyperthyroidism: Reevaluation of TSBAb and TSAb in TSH-Receptor-Antibody (TRAb-Positive Patients

Directory of Open Access Journals (Sweden)

Nobuyuki Takasu

2012-01-01

Full Text Available Two TRAbs: TSBAb and TSAb. TSBAb causes hypothyroidism. TSAb causes Graves’ hyperthyroidism. TSBAb and TSAb block TSH-binding to cells as TRAb, measured as TSH-binding inhibitory immunoglobulin (TBII. We reevaluate TSBAb and TSAb. We studied TSBAb, TSAb, and TBII over 10 years in 34 TSBAb-positives with hypothyroidism and in 98 TSAb-positives with hyperthyroidism. Half of the 34 TSBAb-positives with hypothyroidism continued to have persistently positive TSBAb, continued to have hypothyroidism, and did not recover from hypothyroidism. Ten of the 98 TSAb-positives with hyperthyroidism continued to have positive TSAb and continued to have hyperthyroidism. TSBAb had disappeared in 15 of the 34 TSBAb-positives with hypothyroidism. With the disappearance of TSBAb, recovery from hypothyroidism was noted in 13 (87% of the 15 patients. TSAb had disappeared in 73 of the 98 TSAb-positives with hyperthyroidism. With the disappearance of TSAb, remissions of hyperthyroidism were noted in 60 (82% of the 73. Two of the 34 TSBAb-positives with hypothyroidism developed TSAb-positive Graves’ hyperthyroidism. Two of the 98 TSAb-positive Graves’ patients with hyperthyroidism developed TSBAb-positive hypothyroidism. TSBAb and TSAb are TRAbs. TSBAb-hypothyroidism and TSAb-hyperthyroidism may be two aspects of one disease (TRAb disease. Two forms of autoimmune thyroiditis: atrophic and goitrous. We followed 34 TSBAb-positive patients with hypothyroidism (24 atrophic and 10 goitrous over 10 years. All of the 10 TSBAb-positive goitrous patients recovered from hypothyroidism and 19 (79% of the 24 TSBAb-positive atrophic patients continued to have hypothyroidism.

Changes of TSH-Stimulation Blocking Antibody (TSBAb) and Thyroid Stimulating Antibody (TSAb) Over 10 Years in 34 TSBAb-Positive Patients with Hypothyroidism and in 98 TSAb-Positive Graves' Patients with Hyperthyroidism: Reevaluation of TSBAb and TSAb in TSH-Receptor-Antibody (TRAb)-Positive Patients

Science.gov (United States)

Takasu, Nobuyuki; Matsushita, Mina

2012-01-01

Two TRAbs: TSBAb and TSAb. TSBAb causes hypothyroidism. TSAb causes Graves' hyperthyroidism. TSBAb and TSAb block TSH-binding to cells as TRAb, measured as TSH-binding inhibitory immunoglobulin (TBII). We reevaluate TSBAb and TSAb. We studied TSBAb, TSAb, and TBII over 10 years in 34 TSBAb-positives with hypothyroidism and in 98 TSAb-positives with hyperthyroidism. Half of the 34 TSBAb-positives with hypothyroidism continued to have persistently positive TSBAb, continued to have hypothyroidism, and did not recover from hypothyroidism. Ten of the 98 TSAb-positives with hyperthyroidism continued to have positive TSAb and continued to have hyperthyroidism. TSBAb had disappeared in 15 of the 34 TSBAb-positives with hypothyroidism. With the disappearance of TSBAb, recovery from hypothyroidism was noted in 13 (87%) of the 15 patients. TSAb had disappeared in 73 of the 98 TSAb-positives with hyperthyroidism. With the disappearance of TSAb, remissions of hyperthyroidism were noted in 60 (82%) of the 73. Two of the 34 TSBAb-positives with hypothyroidism developed TSAb-positive Graves' hyperthyroidism. Two of the 98 TSAb-positive Graves' patients with hyperthyroidism developed TSBAb-positive hypothyroidism. TSBAb and TSAb are TRAbs. TSBAb-hypothyroidism and TSAb-hyperthyroidism may be two aspects of one disease (TRAb disease). Two forms of autoimmune thyroiditis: atrophic and goitrous. We followed 34 TSBAb-positive patients with hypothyroidism (24 atrophic and 10 goitrous) over 10 years. All of the 10 TSBAb-positive goitrous patients recovered from hypothyroidism and 19 (79%) of the 24 TSBAb-positive atrophic patients continued to have hypothyroidism. PMID:22655217

Production of monoclonal antibodies for use in immunoassays based on the magnetizable solid phase separation technique

International Nuclear Information System (INIS)

Charoensiriwatana, W.; Janejai, N.; Krasao, P.

1996-01-01

Monoclonal antibodies to TSH were produced by using mouse-ascites techniques. Various methods for purifying the antibody from the ascetic fluid have been tried in order to obtain an appropriate TSH kit production protocol. The purified antibodies were then immobilized on magnetizable cellulose for developing an IRMA for TSH. A detailed study of the assay system, including the stability of the magnetic adsorbent was made, which showed that the SCIPAc magnetizable cellulose is suitable for the production of TSH - Blood spot IRMA kits for use in the Neonatal hypothyroid screening programme to be launched in Thailand in the near future. (author). 4 refs, 12 figs, 2 tabs

Effect of thyroid auto-antibodies on hypothyroidism of adolescents with graves disease after 131I treatment

International Nuclear Information System (INIS)

Feng Xuemin; Wang Junqi; Qin Lan

2011-01-01

To investigate the effect of TSH receptor antibody (TRAb) and thyroid peroxidase antibody (TPOAb) levels in adolescents with Graves disease (GD) before 131 I treatment on the incidence of hypothyroidism after 131 I therapy. The total 264 adolescent with GD were treated with 131 I. All patients before the treatment were divided into A, B, C, D, E and F groups in accordance with the levels of TRAb and TPOAb in various combinations. The serum TSH, FT 3 , FT 4 , TRAb and TPOAb levels in all patients were measured after 131 I treatment. The incidence of hypothyroidism within three years were observed in each group. The results showed that the incidence of hypothyroidism in TRAb negative group was higher than that of positive group (χ 2 =4.67, P 2 =4.10, 4.34, 5.66, P 131 I therapy. It could be cautious in treatment of GD adolescents of TRAb negative and TPOAb positive with 131 I. (authors)

The TSH levels and risk of hypothyroidism: Results from a population based prospective cohort study in an Iranian adult's population.

Science.gov (United States)

Aminorroaya, Ashraf; Meamar, Rokhsareh; Amini, Massoud; Feizi, Awat; Nasri, Maryam; Tabatabaei, Azamosadat; Faghihimani, Elham

2017-06-01

The aim of current study was to assess the relationship between serum TSH levels and hypothyroidism risk in the euthyroid population. In a population-based cohort study, a total of 615 individuals with a normal baseline TSH, from of total population (n=2254) in 2006, were followed up for 6years. TSH, total T4, thyroid peroxidase antibody (TPOAb), and thyroglobulin antibody (TgAb) were measured. The relative risk (RR) and 95% confidence interval (95%CI) were calculated based on logistic regression. The Receiver Operating Characteristic (ROC) analysis along with area under the curve (AUC) was used to prediction of future hypothyroidism. TSH level in 2006 was a significant predictor for overt hypothyroidism, in the total population (RR=3.5) and female (RR=1.37) (all, P valuehypothyroidism from euthyroid. However, this cut off was not observed when we included only negative TPO and TgAbs people in 2006. The RR of hypothyroidism increased gradually when TSH level increased from 2.06-3.6mIU/L to >3.6mIU/L in the total population and both sexes. In women, the risk of overt hypothyroidism was significantly higher in subjects with TSH above 3.6 than those subject with THS levels≤2.05 [RR: (CI95 %), 20.57(2.-207.04), P valuehypothyroidism in future. However, it was not applicable for people with negative TPOAb and negative TgAb. Copyright © 2016 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

Agonistic effects of a monoclonal antibody specific for the interleukin-2 receptor

International Nuclear Information System (INIS)

Eardley, D.D.; Makrides, V.

1986-01-01

Interleukin-2 (IL-2) mediated immune responses can be blocked by monoclonal antibodies to the IL-2 receptor. The monoclonal antibody, M720, is defined as specific for the IL-2 receptor because it blocks 35 S-IL-2 binding to Con A blasts, reacts with lymphoblasts but not resting splenocytes, and inhibits IL-2 induced proliferation to mitogen, antigen, or allogeneic stimuli. Under appropriate culture conditions, the IL-2 receptor-specific antibody can act like IL-2 in that it will induce proliferation in T cells in the absence of additional antigen or mitogen. This agonistic effect is dependent on time, dose of antibody, and requires fetal calf serum (FCS) in the media. Because the FCS is not mitogenic by itself, the authors propose that the FCS components act as incomplete mitogen to induce appearance of IL-2 receptors but lack a factor which would push the majority of the cells into the S phase of the cell cycle. This factor is usually IL-2, but in the authors experiments, the IL-2 receptor-specific antibody can provide the same stimulus. These data indicate that factors like FCS can induce IL-2 receptors, but without additional IL-2 or receptor triggering, the cells will not proceed through the synthetic and proliferative phases of cell growth

Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies.

Science.gov (United States)

Dalmau, Josep; Gleichman, Amy J; Hughes, Ethan G; Rossi, Jeffrey E; Peng, Xiaoyu; Lai, Meizan; Dessain, Scott K; Rosenfeld, Myrna R; Balice-Gordon, Rita; Lynch, David R

2008-12-01

A severe form of encephalitis associated with antibodies against NR1-NR2 heteromers of the NMDA receptor was recently identified. We aimed to analyse the clinical and immunological features of patients with the disorder and examine the effects of antibodies against NMDA receptors in neuronal cultures. We describe the clinical characteristics of 100 patients with encephalitis and NR1-NR2 antibodies. HEK293 cells ectopically expressing single or assembled NR1-NR2 subunits were used to determine the epitope targeted by the antibodies. Antibody titres were measured with ELISA. The effect of antibodies on neuronal cultures was determined by quantitative analysis of NMDA-receptor clusters. Median age of patients was 23 years (range 5-76 years); 91 were women. All patients presented with psychiatric symptoms or memory problems; 76 had seizures, 88 unresponsiveness (decreased consciousness), 86 dyskinesias, 69 autonomic instability, and 66 hypoventilation. 58 (59%) of 98 patients for whom results of oncological assessments were available had tumours, most commonly ovarian teratoma. Patients who received early tumour treatment (usually with immunotherapy) had better outcome (p=0.004) and fewer neurological relapses (p=0.009) than the rest of the patients. 75 patients recovered or had mild deficits and 25 had severe deficits or died. Improvement was associated with a decrease of serum antibody titres. The main epitope targeted by the antibodies is in the extracellular N-terminal domain of the NR1 subunit. Patients' antibodies decreased the numbers of cell-surface NMDA receptors and NMDA-receptor clusters in postsynaptic dendrites, an effect that could be reversed by antibody removal. A well-defined set of clinical characteristics are associated with anti-NMDA-receptor encephalitis. The pathogenesis of the disorder seems to be mediated by antibodies.

Measurement of anti- acetylcholine receptor auto-antibodies in ...

African Journals Online (AJOL)

auto-antibodies in myasthenia gravis. K. J. Steenkamp, W. Duim, M. s. Myer,. S. C. K. Malfeld, R. Anderson. Two different acetylcholine receptor (AChR) preparations derived from ... the detection of AChR auto-antibodies in serum specimens from 20 ... 4°C. Thereafter, 1 ml of washing solution (phosphate- buffered saline ...

Extended and structurally supported insights into extracellular hormone binding, signal transduction and organization of the thyrotropin receptor.

Directory of Open Access Journals (Sweden)

Gerd Krause

Full Text Available The hormone thyrotropin (TSH and its receptor (TSHR are crucial for the growth and function of the thyroid gland. The TSHR is evolutionary linked with the receptors of follitropin (FSHR and lutropin/choriogonadotropin (LHR and their sequences and structures are similar. The extracellular region of TSHR contains more than 350 amino acids and binds hormone and antibodies. Several important questions related to functions and mechanisms of TSHR are still not comprehensively understood. One major reason for these open questions is the lack of any structural information about the extracellular segment of TSHR that connects the N-terminal leucine-rich repeat domain (LRRD with the transmembrane helix (TMH 1, the hinge region. It has been shown experimentally that this segment is important for fine tuning of signaling and ligand interactions. A new crystal structure containing most of the extracellular hFSHR region in complex with hFSH has recently been published. Now, we have applied these new structural insights to the homologous TSHR and have generated a structural model of the TSHR LRRD/hinge-region/TSH complex. This structural model is combined and evaluated with experimental data including hormone binding (bTSH, hTSH, thyrostimulin, super-agonistic effects, antibody interactions and signaling regulation. These studies and consideration of significant and non-significant amino acids have led to a new description of mechanisms at the TSHR, including ligand-induced displacements of specific hinge region fragments. This event triggers conformational changes at a convergent center of the LRRD and the hinge region, activating an "intramolecular agonistic unit" close to the transmembrane domain.

Extended and structurally supported insights into extracellular hormone binding, signal transduction and organization of the thyrotropin receptor.

Science.gov (United States)

Krause, Gerd; Kreuchwig, Annika; Kleinau, Gunnar

2012-01-01

The hormone thyrotropin (TSH) and its receptor (TSHR) are crucial for the growth and function of the thyroid gland. The TSHR is evolutionary linked with the receptors of follitropin (FSHR) and lutropin/choriogonadotropin (LHR) and their sequences and structures are similar. The extracellular region of TSHR contains more than 350 amino acids and binds hormone and antibodies. Several important questions related to functions and mechanisms of TSHR are still not comprehensively understood. One major reason for these open questions is the lack of any structural information about the extracellular segment of TSHR that connects the N-terminal leucine-rich repeat domain (LRRD) with the transmembrane helix (TMH) 1, the hinge region. It has been shown experimentally that this segment is important for fine tuning of signaling and ligand interactions. A new crystal structure containing most of the extracellular hFSHR region in complex with hFSH has recently been published. Now, we have applied these new structural insights to the homologous TSHR and have generated a structural model of the TSHR LRRD/hinge-region/TSH complex. This structural model is combined and evaluated with experimental data including hormone binding (bTSH, hTSH, thyrostimulin), super-agonistic effects, antibody interactions and signaling regulation. These studies and consideration of significant and non-significant amino acids have led to a new description of mechanisms at the TSHR, including ligand-induced displacements of specific hinge region fragments. This event triggers conformational changes at a convergent center of the LRRD and the hinge region, activating an "intramolecular agonistic unit" close to the transmembrane domain.

Fall in thyroid stimulating hormone (TSH) may be an early marker of ipilimumab-induced hypophysitis.

Science.gov (United States)

De Sousa, Sunita M C; Sheriff, Nisa; Tran, Chau H; Menzies, Alexander M; Tsang, Venessa H M; Long, Georgina V; Tonks, Katherine T T

2018-06-01

Hypophysitis develops in up to 19% of melanoma patients treated with ipilimumab, a cytotoxic T-lymphocyte antigen-4 antibody. Early detection may avert life-threatening hypopituitarism. We aimed to assess the incidence of ipilimumab-induced hypophysitis (IH) at a quaternary melanoma referral centre, and to determine whether cortisol or thyroid stimulating hormone (TSH) monitoring could predict IH onset. We performed a retrospective cohort study of ipilimumab-treated patients at a quaternary melanoma referral centre in Australia. The inclusion criteria were patients with metastatic or unresectable melanoma treated with ipilimumab monotherapy, and cortisol and TSH measurements prior to ≥ 2 infusions. The main outcomes were IH incidence and TSH and cortisol patterns in patients who did and did not develop IH. Of 78 ipilimumab-treated patients, 46 met the study criteria and 9/46 (20%) developed IH at a median duration of 13.0 weeks (range 7.7-18.1) following ipilimumab initiation. All patients whose TSH fell ≥ 80% compared to baseline developed IH, and, in 5/9 patients with IH, TSH fell prior to cortisol fall and IH diagnosis. Pre-cycle-4 TSH was significantly lower in those who developed IH (0.31 vs. 1.73 mIU/L, P = 0.006). TSH fall was detected at a median time of 9.2 (range 7.7-16.4) weeks after commencing ipilimumab, and a median of 3.6 (range of - 1.4 to 9.7) weeks before IH diagnosis. There was no difference in TSH between the groups before cycles 1-3 or in cortisol before cycles 1-4. TSH fall ≥ 80% may be an early marker of IH. Serial TSH measurement during ipilimumab therapy may be an inexpensive tool to expedite IH diagnosis.

Antibodies to the α-subunit of insulin receptor from eggs of immunized hens

International Nuclear Information System (INIS)

Song, C.; Yu, J.; Bai, D.H.; Hester, P.Y.; Kim, K.

1985-01-01

Simple methods for the generation, purification, and assay of antibodies to the α-subunit of insulin receptor from eggs of immunized hen have been described. Chicken antibodies against the α-subunit inhibit insulin binding to the receptor and stimulate glucose oxidation as well as autophosphorylation of the β-subunit. Thus the properties of chicken antibodies are very similar to those of antibodies found in human autoimmune diseases and different from rabbit antibodies obtained against the same antigen

A RNA transcript (Heg) in mononuclear cells is negatively correlated with CD14 mRNA and TSH receptor autoantibodies

DEFF Research Database (Denmark)

Habekost, G.; Bratholm, P.; Christensen, Niels Juel

2008-01-01

of the poly A(-) transcript (designated Heg) in mononuclear cells was correlated with CD14 mRNA in normal subjects and with CD14 mRNA and TSH receptor autoantibodies in patients with acute and untreated Graves' disease. mRNA was expressed in amol/mu g DNA. The main study groups were: (i) normal subjects; (ii......) patients with early and untreated Graves' disease; and (iii) patients with Graves' disease studied after treatment. In 18 normal subjects and in 20 patients with treated Graves' disease CD14 mRNA was negatively correlated with Heg (P Graves' disease Heg and thyroid...

Ion channels in EEG: isolating channel dysfunction in NMDA receptor antibody encephalitis.

Science.gov (United States)

Symmonds, Mkael; Moran, Catherine H; Leite, M Isabel; Buckley, Camilla; Irani, Sarosh R; Stephan, Klaas Enno; Friston, Karl J; Moran, Rosalyn J

2018-04-30

Neurological and psychiatric practice frequently lack diagnostic probes that can assess mechanisms of neuronal communication non-invasively in humans. In N-methyl-d-aspartate (NMDA) receptor antibody encephalitis, functional molecular assays are particularly important given the presence of NMDA antibodies in healthy populations, the multifarious symptomology and the lack of radiological signs. Recent advances in biophysical modelling techniques suggest that inferring cellular-level properties of neural circuits from macroscopic measures of brain activity is possible. Here, we estimated receptor function from EEG in patients with NMDA receptor antibody encephalitis (n = 29) as well as from encephalopathic and neurological patient controls (n = 36). We show that the autoimmune patients exhibit distinct fronto-parietal network changes from which ion channel estimates can be obtained using a microcircuit model. Specifically, a dynamic causal model of EEG data applied to spontaneous brain responses identifies a selective deficit in signalling at NMDA receptors in patients with NMDA receptor antibody encephalitis but not at other ionotropic receptors. Moreover, though these changes are observed across brain regions, these effects predominate at the NMDA receptors of excitatory neurons rather than at inhibitory interneurons. Given that EEG is a ubiquitously available clinical method, our findings suggest a unique re-purposing of EEG data as an assay of brain network dysfunction at the molecular level.

Multinodular goiter treatment with radioiodine aided by recombinant human TSH in different doses: a randomized, double-blind, placebo-controlled study;Administracao previa do TSH humano recombinante, em diferentes doses, no tratamento do bocio multinodular com iodo radioativo: um estudo randomizado, duplo cego, controlado com placebo

Energy Technology Data Exchange (ETDEWEB)

Albino, Claudio Cordeiro

2009-07-01

Background: There is not an optimal treatment for multinodular goiter (MNG). Surgery is the main therapeutic option because it decreases thyroid volume, reduces compression symptoms and provide histological diagnosis. Radioiodine ({sup 131}I) is an efficient therapeutic option for the treatment of MNG mainly when surgery is not indicated or when the patient refused it. However, high activities of {sup 131}I are frequently required for clinically significant results. This procedure increases the body radiation exposure and the hospitalization costs. Recombinant human TSH (rh TSH) allows a reduction in the administered activity of {sup 131}I with effective thyroid volume (TV) reduction. However, this combination therapeutic can increase collateral effects. Objective: To evaluate the efficacy and safety of low and intermediate doses of rh TSH compared to placebo, associated with a fixed activity of {sup 131}I in MNG treatment. Patients and Methods: Thirty patients with MNG received 0.1 mg of rh TSH (group I, n=10), 0.01 mg of rh TSH (group II, n=10), or placebo (control group, n=10). After 24 hours, 30 mCi of {sup 131}I was given to all patients. Radioactive iodine uptake (RAIU) was determined before and 24 hours after rh TSH. Before and 2, 7, 180 and 360 days after the TV was measured by magnetic resonance image (MRI). The smallest cross-sectional area of tracheal lumen (Scat) was also measured with MRI before, 2 and 7 days after treatment. Antithyroid antibodies, TSH, T3 and free T4 were assessed regularly. Results: After 6 months, the decrease in TV was more significant in groups I (30.3 +- 16.5%) and II (22.6 +- 14.5%), than in control group (5.0 +- 14.6%; p=0.01). After 12 months, TV decreased more in group I (39.2 +- 16.9%) and group II (38.8 +- 24.4%) than in group III (23.4 +- 23.59%) but it was not statistically significant (p=0.205). During the first 30 days,total T3 and free T4 increased, without reaching thyrotoxic levels and TSH decreased. After 12 months

The main immunogenic region of acetylcholine receptors does not provoke the formation of antibodies of a predominant idiotype.

Science.gov (United States)

Killen, J A; Hochschwender, S M; Lindstrom, J M

1985-08-01

Anti-idiotype antibodies were induced in rats by immunization with rat monoclonal antibodies to the main immunogenic region of acetylcholine receptors. These anti-idiotype antibodies showed very little crossreaction with other rat monoclonal antibodies which bind to the same region of the receptor. When the rats producing these anti-idiotype antibodies were immunized with receptor, they showed no net decrease in anti-receptor antibody production. These data indicate that, although more than half of the antibodies produced by rats immunized with receptor are directed at a small region, many anti-receptor idiotypes are involved in this response and anti-idiotype therapy is not beneficial.

Evaluation of the 2. generation radio-receptional assay for anti-TSH receptor antibodies (TRAb) in autoimmune thyroid diseases. Comparison with 1. generation and anti-thyroperoxidae antibodies (AbTPO)

International Nuclear Information System (INIS)

Giovanella, L.; Ceriani, L.; Garacini, S.

2001-01-01

The detection of autoantibodies to the TSH-receptor (TRAb) by radio-receptor assays (RRA) is widely requested in clinical practice for the diagnostic work-up of Graves' disease and its differentiation from diffuse thyroid autonomy. Additionally, TRAb measurement can be useful during antithyroid drug treatment of Graves' disease to evaluate the risk of relapse after therapy discontinuation. Nevertheless, some patients affected by Graves' disease are TRAb-negative when 1. generation assay is used. In this study the diagnostic performance of a newly developed 2. generation TRAb assay (TRAK human DYNOtest(R), BRAHMS Diagnostica GmbH, Berlin, Germany) was evaluated in 74 untreated patients affected by Graves' disease, in 53 untreated patients affected by Hashimoto's thyroiditis and in 88 patients affected by euthyroid nodular goiter. It was also compared the new TRAb assay with the 1. generation test (TRAK(R) Assay, BRAHMS Diagnostica GmbH, Berlin, Germany) and anti-thyroperoxidase assay (AbTPO DYNOtest(R), BRAHMS GmbH, Berlin). The 2. generation TRAb assay showed the better diagnostic sensitivity in Graves' disease (97%) with respect to the 1. generation assay (85%) and AbTPO assay (64%). The AbTPO assay was positive in 50 of 53 (94%) patients affected by autoimmune thyroiditis. The 1. and 2. generation TRAb assays were positive in 4 (7%) and 7 (13%) of 53 patients affected by autoimmune thyroiditis, respectively. No patients affected by nodular goiter showed positive 1. and 2. generation TRAb assay while AbTPO levels were positive in 8 of 88 patients (specificity 91%). In conclusion, the 2. generation TRAb assay is clearly more sensitive than the 1. generation test and should be used in clinical practice to minimize the incidence of TRAb-negative Graves' disease. Long term prospective studies are needed to evaluate the prognostic role of 2. generation TRAb assay in Graves' disease. The assay of AbTPO is the best marker for autoimmune thyroiditis but is clearly less

Evaluation of the 2. generation radio-receptional assay for anti-TSH receptor antibodies (TRAb) in autoimmune thyroid diseases. Comparison with 1. generation and anti-thyroperoxidae antibodies (AbTPO)

Energy Technology Data Exchange (ETDEWEB)

Giovanella, L.; Ceriani, L.; Garacini, S. [University Hospital Ospedale di Circolo e Fondazione Macchi, Dept. of Nuclear Medicine, Lab. of Endocrinology and Thyroid Unit, Varese (Italy)

2001-03-01

The detection of autoantibodies to the TSH-receptor (TRAb) by radio-receptor assays (RRA) is widely requested in clinical practice for the diagnostic work-up of Graves' disease and its differentiation from diffuse thyroid autonomy. Additionally, TRAb measurement can be useful during antithyroid drug treatment of Graves' disease to evaluate the risk of relapse after therapy discontinuation. Nevertheless, some patients affected by Graves' disease are TRAb-negative when 1. generation assay is used. In this study the diagnostic performance of a newly developed 2. generation TRAb assay (TRAK human DYNOtest(R), BRAHMS Diagnostica GmbH, Berlin, Germany) was evaluated in 74 untreated patients affected by Graves' disease, in 53 untreated patients affected by Hashimoto's thyroiditis and in 88 patients affected by euthyroid nodular goiter. It was also compared the new TRAb assay with the 1. generation test (TRAK(R) Assay, BRAHMS Diagnostica GmbH, Berlin, Germany) and anti-thyroperoxidase assay (AbTPO DYNOtest(R), BRAHMS GmbH, Berlin). The 2. generation TRAb assay showed the better diagnostic sensitivity in Graves' disease (97%) with respect to the 1. generation assay (85%) and AbTPO assay (64%). The AbTPO assay was positive in 50 of 53 (94%) patients affected by autoimmune thyroiditis. The 1. and 2. generation TRAb assays were positive in 4 (7%) and 7 (13%) of 53 patients affected by autoimmune thyroiditis, respectively. No patients affected by nodular goiter showed positive 1. and 2. generation TRAb assay while AbTPO levels were positive in 8 of 88 patients (specificity 91%). In conclusion, the 2. generation TRAb assay is clearly more sensitive than the 1. generation test and should be used in clinical practice to minimize the incidence of TRAb-negative Graves' disease. Long term prospective studies are needed to evaluate the prognostic role of 2. generation TRAb assay in Graves' disease. The assay of AbTPO is the best marker for

Improved radioimmunoassay for human TSH

International Nuclear Information System (INIS)

Spencer, C.A.; Nicoloff, J.T.

1980-01-01

This study concerns the optimization of the human TSH (h-TSH) radioimmunoassay with special emphasis on reducing the heterogeneity of the 125 I h-TSH tracer. Enzymatic iodination of h-TSH with glucose oxidase/lactoperoxidase was shown to be superior to either low or high dose chloramine-T procedures, producing a high specific activity reagent (70-150 μCi/μg) with minimal evidence of damage. Tracer purification procedures not only affected initial immunoactivity but also storage stability and heterogeneity of the resulting 125 I h-TSH. The assay developed using these technical approaches shows a sensitivity limit of 0.005+-0.001 (S.E.M.) μU/tube; 50% displacement at 0.18+-0.08 (S.E.M.) μU/tube and complete delineation between euthyroid (n=49, 2.44+-0.18 (S.E.M.) mU/l, range 1.00-6.08) and hyperthyroid (n=62, 0.34+-0.02 (S.E.M.) mU/l, range 0.10-0.85), serum h-TSH levels. (Auth.)

Characterization of thyroid function and antithyroid antibody tests among Saudis

Science.gov (United States)

Jammah, Anwar A.; Alshehri, Anwar S.; Alrakhis, Afaf A.; Alhedaithy, Asma S.; Almadhi, Asma M.; Alkwai, Hala M.; Alhamad, Maram M.; Alzahrani, Saad H.

2015-01-01

Objective: To determine the reference intervals for thyroid function tests and the prevalence of thyroid autoimmunity in the Saudi population. Methods: A cross-sectional prospective study was conducted in King Khalid University Hospital, Riyadh, Saudi Arabia from January to June 2013. History and physical examination were obtained. Thyroid-stimulating hormone (TSH), free thyroxine (FT4), and free triiodothyronine (FT3) were measured by Electro-chemiluminescence Immunoassay system-assay. Anti-thyroperoxidase, and anti-thyroglobulin antibodies were measured using enzyme-linked immunosorbent-assay. Subjects with previous or a family history of thyroid disorders, those taking medications affecting thyroid function, pregnant or lactating women, and those with goiter were excluded. Individuals with positive antibodies were excluded from the final analysis of the TSH reference range, but were used to determine the prevalence of thyroid autoimmunity. Results: Out of 337 Saudi subjects initially screened, 132 (aged 13-60 years) were candidates for reference calculation, the mean±standard deviation, and (2.5th-97.5th) percentile of TSH (mIU/L) was 1.96±0.9 (0.59-4.37), for FT4 (pmol/L) was 15.47±1.83 (12.04-19.13), and for FT3 (pmol/L) was 5.22±0.7 (4.07-6.76). The TSH was higher in the antibodies positive group (2.5±1.17 mIU/L) compared with the negative one (1.96±0.9 mIU/L) (pantithyroid antibodies. Conclusion: The TSH reference range was similar to laboratory references. Thyroid antibodies were prevalent in Saudis, necessitating further work in larger scale studies. PMID:25987111

TSH IRMA of dried blood spots

International Nuclear Information System (INIS)

Tojinda, N.; Pattanachak, C.; Chongchirasiri, S.; Pattanachak, S.; Putrasreni, N.; Pleehachinda, R.; Suwanik, R.

1990-01-01

TSH determination is most useful for screening of neonatal hypothyroid in the population in iodine deficient areas. The NETRIA IRMA method for serum TSH was applied for blood-spot TSH. Cord blood on SS No. 903 filter paper was left dry overnight. The spot of 6 mm diameter, one/tube, was mixed with an assay buffer, diluted labelled m-anti-TSH, and diluted anti-TSH-solid phase. The mixture was rotated for 22-24 hours. After washing twice with wash buffer, it was counted for 1 minute. The standard curve with 0, 5, 10, 25, 50, 100, and 150 mIU/L whole blood was obtained with the maximum binding of 25%. The precision profile was satisfactory with %CV of 0 C) or 4 0 C or -20 0 C. The correlation between serum and blood-spot TSH values (n=120) showed r of 0.9541 and y=1.6123 (BS-TSH) +1.382. The mean of normal cord blood spot TSH (n=142) was 5.27 mIU/L. The technique was found to be precise, sensitive and easy to perform. Mass screening with this developed method is underway

Antibodies immobilized on magnetic particles for RIA and IRMA of thyroid related hormones

International Nuclear Information System (INIS)

Wayan, R.S.; Djayusman, D.S.

1996-01-01

In Indonesia radioimmunoassay kits on the magnetic method of separation need to be imported and are very expensive. Local production of these kits would be economical. Different types of magnetic particles have been used for immobilizing antibodies for use in RIA of T 3 , T 4 , IRMA-TSH as well as neonatal IRMA-TSH. The particles studied here include magnetic cellulose (SCIPAC, U.K.), magnetite (Hungary), Silanized Iron Oxide (China) and Latex-M. Various parameters have been studied in order to optimize the antibody immobilization procedures as well as the assays based on these immunoadsorbents. The assays developed by us have been compared with those obtained with commercial kits from Amersham, NETRIA and DPC. The study done in this work includes immobilization of second antibodies for RIA of T 4 and immobilization of anti-TSH for IRMA-TSH. Among several different magnetic particles studied in this work, magnetite and silanized iron oxide were found to be satisfactory on account of the simplicity of immobilization, high binding capacity and the low non specific binding. A good assay performance in the case of RIA T 3 and T 4 was obtained using second antibodies immobilized magnetic particles. However, the quality of first antibodies is found to play an important role on the sensitivity and precision of the assay. Good correlation has been obtained with Amersham kit (y = 1.06x - 0.12 and r = 0.987). Assay performance of IRMA-TSH using in-house prepared anti-TSH immobilized magnetic particles is also found to be comparable with Amersham, NETRIA and DPC kits. (author). 4 refs, 6 figs, 1 tab

Dose-dependent acute effects of recombinant human TSH (rhTSH) on thyroid size and function. Comparison of 0.1, 0.3 and 0.9 mg of rhTSH

DEFF Research Database (Denmark)

Fast, Søren; Nielsen, Viveque Egsgaard; Bonnema, Steen Joop

2009-01-01

Context: Recombinant human TSH (rhTSH) is used to augment the effect of radioiodine therapy for nontoxic multinodular goitre. Reports of acute thyroid swelling and hyperthyroidism warrant safety studies evaluating whether these side-effects are dose-dependent. Objective: To determine the effects...... on thyroid size and function of various doses of rhTSH. Design: In nine healthy male volunteers the effect of placebo, 0.1, 0.3 and 0.9 mg of rhTSH was examined in a paired design including four consecutive study rounds. Main outcome measures: Were evaluated at baseline, 24h, 48h, 96h, 7 days and 28 days...... after rhTSH and included: Thyroid volume (TV) estimation by planimetric ultrasound, and thyroid function by serum TSH, freeT3, freeT4 and Tg levels. Results: Following placebo or 0.1 mg rhTSH the TV did not change significantly from baseline at any time. At 24 and 48 hours after administration of 0.3 mg...

Clinical relevancy of a sensitive TSH-RIA

International Nuclear Information System (INIS)

Seidel, C.; Ziegelitz, D.; Weber, A.; Dittmer, T.; Gerl, H.; Knappe, G.; Correns, H.J.

1982-01-01

Based on a sensitive TSH-RIA (measuring range 0.2-25 mU/l, 50%-intercept 2 mU/l, coefficients of between-assay-variation 5-10%) and on nearly 1200 cases, it is demonstrated that clinical results can be received by determination of basal serum TSH alone. Values above 0.5 mU TSH/l indicate positive TRH tests in a good correlation between increasing basal concentrations and pituitary TSH reserve. TSH levels below 0.3 mU/l proceed with negative TRH tests. In selected healthy subjects, we found all TSH values between 0.7 and nearly 5 mU/l (x-bar = 1.99). In euthyroid goiters TSH levels are normally in the same range, but in nodular goiters, subnormal values were found accumulated. TSH levels below 0.3 mU/l are helpful to discover non-suppressibility. Hormone treatment of goiters is successful above all in case of high-normal pretherapeutic TSH values. 'Fine-tuning' of hormone dosage (goiter treatment, postoperative prophylaxis, suppression therapy in thyroid carcinoma) as well as monitoring of thyrotoxicosis treatment is recommended to be performed by means of basal TSH determination. In pituitary disorders, thyroid hormone treatment seems to be necessary only at TSH levels below 0.5 mU/l. Combination of basal TSH and total T 3 is economical and describes nearly all functional situations in diagnosis and treatment of thyroid diseases. (author)

T3 Regulates a Human Macrophage-Derived TSH-β Splice Variant: Implications for Human Bone Biology.

Science.gov (United States)

Baliram, R; Latif, R; Morshed, S A; Zaidi, M; Davies, T F

2016-09-01

TSH and thyroid hormones (T3 and T4) are intimately involved in bone biology. We have previously reported the presence of a murine TSH-β splice variant (TSH-βv) expressed specifically in bone marrow-derived macrophages and that exerted an osteoprotective effect by inducing osteoblastogenesis. To extend this observation and its relevance to human bone biology, we set out to identify and characterize a TSH-β variant in human macrophages. Real-time PCR analyses using human TSH-β-specific primers identified a 364-bp product in macrophages, bone marrow, and peripheral blood mononuclear cells that was sequence verified and was homologous to a human TSH-βv previously reported. We then examined TSH-βv regulation using the THP-1 human monocyte cell line matured into macrophages. After 4 days, 46.1% of the THP-1 cells expressed the macrophage markers CD-14 and macrophage colony-stimulating factor and exhibited typical morphological characteristics of macrophages. Real-time PCR analyses of these cells treated in a dose-dependent manner with T3 showed a 14-fold induction of human TSH-βv mRNA and variant protein. Furthermore, these human TSH-βv-positive cells, induced by T3 exposure, had categorized into both M1 and M2 macrophage phenotypes as evidenced by the expression of macrophage colony-stimulating factor for M1 and CCL-22 for M2. These data indicate that in hyperthyroidism, bone marrow resident macrophages have the potential to exert enhanced osteoprotective effects by oversecreting human TSH-βv, which may exert its local osteoprotective role via osteoblast and osteoclast TSH receptors.

The Presence of Thyroid-Stimulation Blocking Antibody Prevents High Bone Turnover in Untreated Premenopausal Patients with Graves' Disease.

Science.gov (United States)

Cho, Sun Wook; Bae, Jae Hyun; Noh, Gyeong Woon; Kim, Ye An; Moon, Min Kyong; Park, Kyoung Un; Song, Junghan; Yi, Ka Hee; Park, Do Joon; Chung, June-Key; Cho, Bo Youn; Park, Young Joo

2015-01-01

Osteoporosis-related fractures are one of the complications of Graves' disease. This study hypothesized that the different actions of thyroid-stimulating hormone receptor (TSHR) antibodies, both stimulating and blocking activities in Graves' disease patients might oppositely impact bone turnover. Newly diagnosed premenopausal Graves' disease patients were enrolled (n = 93) and divided into two groups: patients with TSHR antibodies with thyroid-stimulating activity (stimulating activity group, n = 83) and patients with TSHR antibodies with thyroid-stimulating activity combined with blocking activity (blocking activity group, n = 10). From the stimulating activity group, patients who had matched values for free T4 and TSH binding inhibitor immunoglobulin (TBII) to the blocking activity group were further classified as stimulating activity-matched control (n = 11). Bone turnover markers BS-ALP, Osteocalcin, and C-telopeptide were significantly lower in the blocking activity group than in the stimulating activity or stimulating activity-matched control groups. The TBII level showed positive correlations with BS-ALP and osteocalcin levels in the stimulating activity group, while it had a negative correlation with the osteocalcin level in the blocking activity group. In conclusion, the activation of TSHR antibody-activated TSH signaling contributes to high bone turnover, independent of the actions of thyroid hormone, and thyroid-stimulation blocking antibody has protective effects against bone metabolism in Graves' disease.

The Presence of Thyroid-Stimulation Blocking Antibody Prevents High Bone Turnover in Untreated Premenopausal Patients with Graves' Disease.

Directory of Open Access Journals (Sweden)

Sun Wook Cho

Full Text Available Osteoporosis-related fractures are one of the complications of Graves' disease. This study hypothesized that the different actions of thyroid-stimulating hormone receptor (TSHR antibodies, both stimulating and blocking activities in Graves' disease patients might oppositely impact bone turnover. Newly diagnosed premenopausal Graves' disease patients were enrolled (n = 93 and divided into two groups: patients with TSHR antibodies with thyroid-stimulating activity (stimulating activity group, n = 83 and patients with TSHR antibodies with thyroid-stimulating activity combined with blocking activity (blocking activity group, n = 10. From the stimulating activity group, patients who had matched values for free T4 and TSH binding inhibitor immunoglobulin (TBII to the blocking activity group were further classified as stimulating activity-matched control (n = 11. Bone turnover markers BS-ALP, Osteocalcin, and C-telopeptide were significantly lower in the blocking activity group than in the stimulating activity or stimulating activity-matched control groups. The TBII level showed positive correlations with BS-ALP and osteocalcin levels in the stimulating activity group, while it had a negative correlation with the osteocalcin level in the blocking activity group. In conclusion, the activation of TSHR antibody-activated TSH signaling contributes to high bone turnover, independent of the actions of thyroid hormone, and thyroid-stimulation blocking antibody has protective effects against bone metabolism in Graves' disease.

Antibody-induced dimerization activates the epidermal growth factor receptor tyrosine kinase

NARCIS (Netherlands)

Spaargaren, M.; Defize, L. H.; Boonstra, J.; de Laat, S. W.

1991-01-01

The relationship between epidermal growth factor receptor (EGF-R) protein tyrosine kinase activation and ligand-induced receptor dimerization was investigated using several bivalent anti-EGF-R antibodies directed against various receptor epitopes. In A431 membrane preparations and permeabilized

Thymus cells in myasthenia gravis selectively enhance production of anti-acetylcholine-receptor antibody by autologous blood lymphocytes

International Nuclear Information System (INIS)

Newsom-Davis, J.; Willcox, N.; Calder, L.

1981-01-01

We investigated the role of the thymus in 16 patients with myasthenia gravis without thymoma by studying the production of anti-acetylcholine-receptor antibody by thymic and blood lymphocytes cultured alone or together. In 10 responders (with the highest receptor-antibody titers in their plasma), cultured thymic cells spontaneously produced measurable receptor antibody. Receptor-antibody production by autologous blood lymphocytes was enhanced by the addition of responder's thymic cells, irradiated to abrogate antibody production and suppression (P<0.01). This enhancement was greater and more consistent than that by pokeweed mitogen; it depended on viable thymic cells, appeared to be selective for receptor antibody, and correlated with the ratio of thymic helper (OKT4-positive or OKT4+) to suppressor (OKT8+) T cells (P<0.01). These results suggest that myasthenic thymus contains cell-bound acetylcholine-receptor-like material or specific T cells (or both) that can aid receptor-antibody production. This may be relevant to the benefits of thymectomy in myasthenia and to the breakdown in self-tolerance in this and other autoimmune diseases

Thymus cells in myasthenia gravis selectively enhance production of anti-acetylcholine-receptor antibody by autologous blood lymphocytes

Energy Technology Data Exchange (ETDEWEB)

Newsom-Davis, J.; Willcox, N.; Calder, L.

1981-11-26

We investigated the role of the thymus in 16 patients with myasthenia gravis without thymoma by studying the production of anti-acetylcholine-receptor antibody by thymic and blood lymphocytes cultured alone or together. In 10 responders (with the highest receptor-antibody titers in their plasma), cultured thymic cells spontaneously produced measurable receptor antibody. Receptor-antibody production by autologous blood lymphocytes was enhanced by the addition of responder's thymic cells, irradiated to abrogate antibody production and suppression (P<0.01). This enhancement was greater and more consistent than that by pokeweed mitogen; it depended on viable thymic cells, appeared to be selective for receptor antibody, and correlated with the ratio of thymic helper (OKT4-positive or OKT4+) to suppressor (OKT8+) T cells (P<0.01). These results suggest that myasthenic thymus contains cell-bound acetylcholine-receptor-like material or specific T cells (or both) that can aid receptor-antibody production. This may be relevant to the benefits of thymectomy in myasthenia and to the breakdown in self-tolerance in this and other autoimmune diseases.

Characterization of 125ITSH binding to its receptor in thyroid hyperplasies

International Nuclear Information System (INIS)

Bianco, A.C.; Nunes, M.T.

1985-01-01

An unpredictable and unbalanced response to a stimulus like TSH is indeed a striking characteristic of the follicles of the simple goiter. Since it is known that the first step for TSH action on its target cell is binding to specific TSH plasma membrane receptors, the binding of 125 ITSH to these receptors was studied in normal and ''cold'' hyperplastic thyroid fragments obtained at surgery. Through the Scatchard analysis it was verified that there are no differences with regard to the binding capacity of TSH receptors between normal and hyperplastic tissues. On the other hand, a significant decrease of the dissociation constant (Kd) was observed in hyperplastic tissue indicating higher affinity for TSH binding. It is known that intracellular iodine content can interfere with the TSH induced modifications on the thyroid folicular cells. It is supposed that this is mediated by interference on TSH binding to its receptor and/or activation of adenylate cyclase. Due to impaired organification capacity of ''cold'' tissue it is assumed that these cells present decreased intracellular iodine content. Therefore it is proposed that alterations of TSH binding to its receptors detected in the present investigation are consequent of the low iodine content of the hyperplastic folicular cell. (author) [pt

Highly sensitive determination of TSH in the follow-up of TSH-suppressive therapy of patients with differentiated thyroid cancer

International Nuclear Information System (INIS)

Mann, K.; Saller, B.; Mehl, U.; Hoermann, R.; Moser, E.

1988-01-01

Basal and TRH-stimulated TSH levels were determined in 72 patients with differentiated thyroid cancer on hormonal treatment, using a highly sensitive immunoradiometric assay (IRMAclon, Henning). 43 patients were under treatment with levothyroxine (T 4 ), 29 patients with triiodothyronine (T 3 ). In 33/43 patients (77%) under T 4 - and in 18/29 patients (62%) under T 3 -treatment basal TSH levels were below 0.1 mU/l. 3 patients showed a significant response (to above 0.5 mU/l) in the TRH test despite basal values of less than 0.1 mU/l. In 2 patients with elevated basal TSH levels (0.23 and 0.60 mU/l, resp.) in the IRMAclon, total suppression of TSH secretion was suggested by a failure of TSH to rise after TRH. By retesting these samples in an own TSH IRMA, basal and stimulated TSH values were below 0.1 mU/l. In conclusion, basal and TRH-stimulated TSH levels are well correlated in most patients with thyroid cancer under hormonal treatment. However, in some cases (5/72) determination of basal TSH could not clearly define the degree of thyrotropic suppression. Thus, TRH testing is still necessary to establish definitely complete TSH suppression in patients with thyroid carcinoma under suppressive treatment. (orig.) [de

Adult celiac disease with acetylcholine receptor antibody positive myasthenia gravis

Institute of Scientific and Technical Information of China (English)

Hugh J Freeman; Helen R Gillett; Peter M Gillett; Joel Oger

2009-01-01

Celiac disease has been associated with some autoimmune disorders. A 40-year-old competitive strongman with celiac disease responded to a glutenfree diet, but developed profound and generalized motor weakness with acetylcholine receptor antibody positive myasthenia gravis, a disorder reported to occur in about 1 in 5000. This possible relationship between myasthenia gravis and celiac disease was further explored in serological studies. Frozen stored serum samples from 23 acetylcholine receptor antibody positive myasthenia gravis patients with no intestinal symptoms were used to screen for celiac disease. Both endomysial and tissue transglutaminase antibodies were examined. One of 23 (or, about 4.3%) was positive for both IgA-endomysial and IgA tissue transglutaminase antibodies. Endoscopic studies subsequently showed duodenal mucosal scalloping and biopsies confirmed the histopathological changes of celiac disease. Celiac disease and myasthenia gravis may occur together more often than is currently appreciated. The presence of motor weakness in celiac disease may be a clue to occult myasthenia gravis, even in the absence of intestinal symptoms.

Measurement of antiacetylcholine receptor auto-antibodies in ...

African Journals Online (AJOL)

Two different acetylcholine receptor (AChR) preparations derived from amputated human muscle (AChRAMP) and from the human rhabdomyosarcoma cell line TE671 (AChRTE67,) were compared in radio-immunoprecipitation assays for the detection of AChR auto-antibodies in serum specimens from 20 patients with ...

Anti-idiotypic antibody: A new strategy for the development of a growth hormone receptor antagonist.

Science.gov (United States)

Lan, Hainan; Zheng, Xin; Khan, Muhammad Akram; Li, Steven

2015-11-01

In general, traditional growth hormone receptor antagonist can be divided into two major classes: growth hormone (GH) analogues and anti-growth hormone receptor (GHR) antibodies. Herein, we tried to explore a new class of growth hormone receptor (GHR) antagonist that may have potential advantages over the traditional antagonists. For this, we developed a monoclonal anti-idiotypic antibody growth hormone, termed CG-86. A series of experiments were conducted to characterize and evaluate this antibody, and the results from a competitive receptor-binding assay, Enzyme Linked Immunosorbent Assays (ELISA) and epitope mapping demonstrate that CG-86 behaved as a typical Ab2β. Next, we examined its antagonistic activity using in vitro cell models, and the results showed that CG-86 could effectively inhibit growth hormone receptor-mediated signalling and effectively inhibit growth hormone-induced Ba/F3-GHR638 proliferation. In summary, these studies show that an anti-idiotypic antibody (CG-86) has promise as a novel growth hormone receptor antagonist. Furthermore, the current findings also suggest that anti-idiotypic antibody may represent a novel strategy to produce a new class of growth hormone receptor antagonist, and this strategy may be applied with other cytokines or growth factors. Copyright © 2015 Elsevier Ltd. All rights reserved.

Mechanisms and regulation of TSH glycosylation

International Nuclear Information System (INIS)

Gesundheit, N.; Weintraub, B.D.

1986-01-01

Some differences in carbohydrate composition of secreted TSH-alpha, TSH-beta, and free alpha-subunits are examined. In order to explore whether each of the secreted TSH subunits has a distinctive carbohydrate composition, the authors incubated hypothyroid mouse tritiated sugar precursors: tritium-glucosamine; tritium-mannose; tritium-l-fucose; and tritium-N-acetylmannosamine, a specific precursor of the sialic acid tritium-N-acetylneuraminic acid. It was shown that although the two TSH subunits, alpha and beta, combine soon after synthesis and are secreted as a dimeric protein, there are notable differences in the carbohydrate processing of the two subunits

Clinical Association of Thyroid Stimulating Hormone Receptor Antibody Levels with Disease Severity in the Chronic Inactive Stage of Graves' Orbitopathy.

Science.gov (United States)

Woo, Young Jae; Jang, Sun Young; Lim, Tyler Hyung Taek; Yoon, Jin Sook

2015-08-01

To investigate associations between serum thyroid stimulating hormone (TSH) receptor antibody (TRAb) levels and Graves' orbitopathy (GO) activity/severity in chronic-stage GO and compare the performance of two newly-developed TRAb assays (third-generation TSH-binding inhibition immunoglobulin [TBII] assay versus Mc4 thyroid-stimulating immunoglobulin [TSI] bioassay). This study is a retrospective review of medical charts and blood tests from Korean GO patients who first visited the departments of ophthalmology and endocrinology, Yonsei University College of Medicine from January 2008 to December 2011, were diagnosed with GO and Graves' hyperthyroidism, and were followed up for ≥18 months. Third-generation M22-TBII and Mc4-TSI assays were performed in the chronic-inactive GO patients in whom euthyroidism status was restored. Patients' GO activity/severity clinical activity scores (CAS), and modified NOSPECS scores were examined for a correlation with TRAb assays. Fifty patients (mean age, 41.3 years; 41 females) were analyzed. The mean duration of Graves' hyperthyroidism symptom was 63 months (range, 18 to 401 months) and that of GO was 46 months (range, 18 to 240 months). All patients had been treated previously with anti-thyroid drugs for a median period of 52.3 months, and two patients underwent either radioiodine therapy or total thyroidectomy. Mean CAS and NOSPECS scores were 0.5 ± 0.9 (standard deviation) and 4.8 ± 3.1, respectively. Mean M22-TBII and Mc4-TSI values were 7.5 ± 10.2 IL/L and 325.9 ± 210.1 specimen-to-reference control ratio. TSI was significantly correlated with NOSPECS score (R = 0.479, p 0.05), because GO inflammatory activity subsided in the chronic stages of GO. In chronic-inactive GO after euthyroid restoration, GO activity score did not associate with serum levels of TRAb or TBII. However, levels of the functional antibody Mc4-TSI did correlate with GO severity. Therefore, the TSI bioassay is a clinically relevant measure of disease

Sole validity of the radioimmunological TSH-estimate

International Nuclear Information System (INIS)

Mahlstedt, J.

1982-01-01

TSH-measurements in plasma as a single parameter for the evaluation of thyroid status need a highly sensitive radioimmunoassay, hitherto not available from commercial sources. The results, however, of such an assay allow to distinguish satisfactorily between suppressed, partially suppressed and normal regulation as well as overstimulation of the thyroid. For several indications, the TRH-test could be replaced by a basal TSH-value. Suppressed regulation without measurable TSH-levels is not to be identified automatically with clearcut hyperthyroidism because of several disturbing factors to be considered in clinical circumstances. Normally the positive TRH-test includes basal TSH-levels between 0.5 and 5 μU/ml thereby excluding significant hormone excess as a possible cause of clinical signs of hyperthyroidism; however, some exceptions do exist (TSH-secreting pineal tumors; partial TSH-resistance of the hypophysis; crossreacting immunoglobulins after microbial vaccination) and should be considered in case of conflicting results. From a clinical point of view a highly sensitive TSH-RIA would be very interesting but would require the use of most recent technologies. (orig.) [de

Anti-transferrin receptor antibody and antibody-drug conjugates cross the blood-brain barrier

International Nuclear Information System (INIS)

Friden, P.M.; Walus, L.R.; Musso, G.F.; Taylor, M.A.; Malfroy, B.; Starzyk, R.M.

1991-01-01

Delivery of nonlipophilic drugs to the brain is hindered by the tightly apposed capillary endothelial cells that make up the blood-brain barrier. The authors have examined the ability of a monoclonal antibody (OX-26), which recognizes the rat transferrin receptor, to function as a carrier for the delivery of drugs across the blood-brain barrier. This antibody, which was previously shown to bind preferentially to capillary endothelial cells in the brain after intravenous administration, labels the entire cerebrovascular bed in a dose-dependent manner. The initially uniform labeling of brain capillaries becomes extremely punctate ∼ 4 hr after injection, suggesting a time-dependent sequestering of the antibody. Capillary-depletion experiments, in which the brain is separated into capillary and parenchymal fractions, show a time-dependent migration of radiolabeled antibody from the capillaries into the brain parenchyma, which is consistent with the transcytosis of compounds across the blood-brain barrier. Antibody-methotrexate conjugates were tested in vivo to assess the carrier ability of this antibody. Immunohistochemical staining for either component of an OX-26-methotrexate conjugate revealed patterns of cerebrovascular labeling identical to those observed with the unaltered antibody. Accumulation of radiolabeled methotrexate in the brain parenchyma is greatly enhanced when the drug is conjugated to OX-26

Thyroid-Stimulating Hormone Receptor Antibodies in Pregnancy: Clinical Relevance

Science.gov (United States)

Bucci, Ines; Giuliani, Cesidio; Napolitano, Giorgio

2017-01-01

Graves’ disease is the most common cause of thyrotoxicosis in women of childbearing age. Approximately 1% of pregnant women been treated before, or are being treated during pregnancy for Graves’ hyperthyroidism. In pregnancy, as in not pregnant state, thyroid-stimulating hormone (TSH) receptor (TSHR) antibodies (TRAbs) are the pathogenetic hallmark of Graves’ disease. TRAbs are heterogeneous for molecular and functional properties and are subdivided into activating (TSAbs), blocking (TBAbs), or neutral (N-TRAbs) depending on their effect on TSHR. The typical clinical features of Graves’ disease (goiter, hyperthyroidism, ophthalmopathy, dermopathy) occur when TSAbs predominate. Graves’ disease shows some peculiarities in pregnancy. The TRAbs disturb the maternal as well as the fetal thyroid function given their ability to cross the placental barrier. The pregnancy-related immunosuppression reduces the levels of TRAbs in most cases although they persist in women with active disease as well as in women who received definitive therapy (radioiodine or surgery) before pregnancy. Changes of functional properties from stimulating to blocking the TSHR could occur during gestation. Drug therapy is the treatment of choice for hyperthyroidism during gestation. Antithyroid drugs also cross the placenta and therefore decrease both the maternal and the fetal thyroid hormone production. The management of Graves’ disease in pregnancy should be aimed at maintaining euthyroidism in the mother as well as in the fetus. Maternal and fetal thyroid dysfunction (hyperthyroidism as well as hypothyroidism) are in fact associated with several morbidities. Monitoring of the maternal thyroid function, TRAbs measurement, and fetal surveillance are the mainstay for the management of Graves’ disease in pregnancy. This review summarizes the biochemical, immunological, and therapeutic aspects of Graves’ disease in pregnancy focusing on the role of the TRAbs in maternal and fetal

Thyroid-Stimulating Hormone Receptor Antibodies in Pregnancy: Clinical Relevance

Directory of Open Access Journals (Sweden)

Ines Bucci

2017-06-01

Full Text Available Graves’ disease is the most common cause of thyrotoxicosis in women of childbearing age. Approximately 1% of pregnant women been treated before, or are being treated during pregnancy for Graves’ hyperthyroidism. In pregnancy, as in not pregnant state, thyroid-stimulating hormone (TSH receptor (TSHR antibodies (TRAbs are the pathogenetic hallmark of Graves’ disease. TRAbs are heterogeneous for molecular and functional properties and are subdivided into activating (TSAbs, blocking (TBAbs, or neutral (N-TRAbs depending on their effect on TSHR. The typical clinical features of Graves’ disease (goiter, hyperthyroidism, ophthalmopathy, dermopathy occur when TSAbs predominate. Graves’ disease shows some peculiarities in pregnancy. The TRAbs disturb the maternal as well as the fetal thyroid function given their ability to cross the placental barrier. The pregnancy-related immunosuppression reduces the levels of TRAbs in most cases although they persist in women with active disease as well as in women who received definitive therapy (radioiodine or surgery before pregnancy. Changes of functional properties from stimulating to blocking the TSHR could occur during gestation. Drug therapy is the treatment of choice for hyperthyroidism during gestation. Antithyroid drugs also cross the placenta and therefore decrease both the maternal and the fetal thyroid hormone production. The management of Graves’ disease in pregnancy should be aimed at maintaining euthyroidism in the mother as well as in the fetus. Maternal and fetal thyroid dysfunction (hyperthyroidism as well as hypothyroidism are in fact associated with several morbidities. Monitoring of the maternal thyroid function, TRAbs measurement, and fetal surveillance are the mainstay for the management of Graves’ disease in pregnancy. This review summarizes the biochemical, immunological, and therapeutic aspects of Graves’ disease in pregnancy focusing on the role of the TRAbs in maternal and

Rat TSH: Radioimmunological verification and secretion in vitro

International Nuclear Information System (INIS)

Rief-Mohs, G.

1983-01-01

The rat TSH radioimmunoassay with 125 I was worked up and validated. Measurement area: 300-10 4 ng TSH/ml, lower detection limit 200 ng/ml, intra-assay variance 3-5%, inter-assay variance 11-18%. For the study of TSH secretion in dispersed anterior pituitary cells, these cells were subjected to an one-hour incubation with a changing TRH concentration. This system, however, did not prove to be sensitive enough for a TRH-in vitro-bioassay. A culture of vital, functioning cells in micro-titer plates up to 30 days was possible. After stimulation with 10 -11 to 10 -6 M TRH over 2 hours a linear dose-dependent increased secretion of TSH with a maximum TSH response of 300% was shown. After fractionation of the anterior pituitary cells after a sedimentation over an albumin gradient it was shown that after fraction 40 there was an increase in the TSH content with a massive increase in TSH cells around fraction 60. The TSH content lay here around the factor 200 above that of the original suspension. A culture of pure TSH cells is therefore possible and for further studies accessible. (orig.) [de

Anti-idiotypes against a monoclonal anti-haloperidol antibody bind to dopamine receptor

International Nuclear Information System (INIS)

Elazar, Z.; Kanety, H.; Schreiber, M.; Fuchs, S.

1988-01-01

Anti-idiotypic antibodies were raised in rabbits by immunization with a monoclonal anti-haloperidol antibody. Some of these anti-idiotypic antibodies bind in a concentration dependent manner to bovine striatal membranes. Following affinity purification, these antibodies inhibit haloperidol binding to striatal membranes and deplete [ 3 H]-spiperone binding sites from a solubilized preparation of striatal membranes. It is thus concluded that these anti-idiotypic antibodies are an internal image of haloperidol and as such can interact with D 2 -dopamine receptors

Growth inhibition of tumor cells in vitro by using monoclonal antibodies against gonadotropin-releasing hormone receptor.

Science.gov (United States)

Lee, Gregory; Ge, Bixia

2010-07-01

As the continuation of a previous study, synthetic peptides corresponding to the extracellular domains of human gonadotropin-releasing hormone (GnRH) receptor were used to generate additional monoclonal antibodies which were further characterized biochemically and immunologically. Among those identified to recognize GnRH receptor, monoclonal antibodies designated as GHR-103, GHR-106 and GHR-114 were found to exhibit high affinity (Kd L37), when cancer cells were incubated with GnRH or GHR-106. The widespread expressions of GnRH receptor in almost all of the studied human cancer cell lines were also demonstrated by RT-PCR and Western blot assay, as well as indirect immunofluorescence assay with either of these monoclonal antibodies as the primary antibody. In view of the longer half life of antibodies as compared to that of GnRH or its analogs, anti-GnRH receptor monoclonal antibodies in humanized forms could function as GnRH analogs and serve as an ideal candidate of anti-cancer drugs for therapeutic treatments of various cancers in humans as well as for fertility regulations.

Study of antibody immobilization on different magnetic particles utilized for the radioimmunoassay (RIA) and immunoradiometric assay (IRMA) of hormones

International Nuclear Information System (INIS)

Ribela, M.T.C.P.; Peroni, C.N.; Bartolini, P.

1996-01-01

A study was carried out on antibody immobilization on three different types of magnetic particles: plain magnetite (Institute of Isotopes, Hungary), silanized magnetite (Institute of Atomic Energy, China) and Magnetizable cellulose (SCIPAC, UK). For radioimmunoassay (RIA) applications an efficient 2 nd antibody (AB)-coupled magnetic solid phase, utilizing plain magnetite and a purified anti-rabbit IgG antibody (Trilab, Brazil), was prepared. A consistent bias, detected in comparison with a well known commercial magnetic solid phase kit, was practically eliminated by modifying the coupling and saturation procedure. Concerning two-site IRMA application, an extensive study was carried out on the matching and selection of anti-hTSH antibodies that could be used for capture and detection. Very satisfactory results were obtained with the three types of magnetic particles using different monoclonal and polyclonal antibodies and in particular, two partners anti-hTSH mABs from the National Institute of Health of Thailand. Utilizing also a recombinant hTSH standard preparation, calibrated and distributed by our laboratory (IPEN-CNEN/SP, Brazil), it was possible to obtain a complete set of in-house reagents for hTSH IRMA, prepared and tested under IAEA support. (author). 11 refs, 4 figs, 12 tabs

Potentiated antibodies to mu-opiate receptors: effect on integrative activity of the brain.

Science.gov (United States)

Geiko, V V; Vorob'eva, T M; Berchenko, O G; Epstein, O I

2003-01-01

The effect of homeopathically potentiated antibodies to mu-receptors (10(-100) wt %) on integrative activity of rat brain was studied using the models of self-stimulation of the lateral hypothalamus and convulsions produced by electric current. Electric current was delivered through electrodes implanted into the ventromedial hypothalamus. Single treatment with potentiated antibodies to mu-receptors increased the rate of self-stimulation and decreased the threshold of convulsive seizures. Administration of these antibodies for 7 days led to further activation of the positive reinforcement system and decrease in seizure thresholds. Distilled water did not change the rate of self-stimulation and seizure threshold.

Functional diagnostics for thyrotropin hormone receptor autoantibodies: bioassays prevail over binding assays.

Science.gov (United States)

Lytton, Simon David; Schluter, Anke; Banga, Paul J

2018-06-01

Autoantibodies to the thyrotropin hormone receptor (TSH-R) are directly responsible for the hyperthyroidism in Graves' disease and mediate orbital manifestations in Graves' orbitopathy (otherwise known as thyroid eye disease). These autoantibodies are heterogeneous in their function and collectively referred to as TRAbs. Measurement of TRAbs is clinically important for diagnosis of a variety of conditions and different commercial assays with high sensitivity and specificity are available for diagnostic purposes. This review provides overwhelming evidence that the TRAbs detected in binding assays by mainly the automated electrochemical luminescence immunoassays (ECLIA) do not distinguish TRAbs that stimulate the TSH-R (called TSIs or TSAbs) and TRAbs that just inhibit the binding of TSH without stimulating the TSH-R (called TBAbs). However, TSAbs and TBAbs have divergent pathogenic roles, and depending which fraction predominates cause different clinical symptoms and engender different therapeutic regimen. Therefore, diagnostic distinction of TSAbs and TBAbs is of paramount clinical importance. To date, only bioassays such as the Mc4 TSH-R bioassay (Thyretain TM , Quidel) and the Bridge assay (Immulite 2000, Siemens) can measure TSAbs, with only the former being able to distinguish between TSAbs and TBAbs. On this note, it is strongly recommended to only use the term TSI or TSAb when reporting the results of bioassays, whereas the results of automated TRAb binding assays should be reported as TRAbs (of undetermined functional significance). This review aims to present a technical and analytical account of leading commercial diagnostic methods of anti-TSH-R antibodies, a metaanalysis of their clinical performance and a perspective for the use of cell based TSH-R bioassays in the clinical diagnostics of Graves' disease.

Preconceptional antithyroid peroxidase antibodies, but not thyroid-stimulating hormone, are associated with decreased live birth rates in infertile women.

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Seungdamrong, Aimee; Steiner, Anne Z; Gracia, Clarisa R; Legro, Richard S; Diamond, Michael P; Coutifaris, Christos; Schlaff, William D; Casson, Peter; Christman, Gregory M; Robinson, Randal D; Huang, Hao; Alvero, Ruben; Hansen, Karl R; Jin, Susan; Eisenberg, Esther; Zhang, Heping; Santoro, Nanette

2017-10-25

To study whether preconceptual thyroid-stimulating hormone (TSH) and antithyroid peroxidase (TPO) antibodies are associated with poor reproductive outcomes in infertile women. Secondary analysis of data from two multicenter, randomized, controlled trials conducted by the Reproductive Medicine Network of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Multivariable logistic regression analyses were performed to assess the association between preconceptual TSH levels and anti-TPO antibodies. Not applicable. Serum samples from 1,468 infertile women were utilized. None. Cumulative conception, clinical pregnancy, miscarriage, and live birth rates were calculated. Conception, clinical pregnancy, miscarriage, and live birth rates did not differ between patients with TSH ≥2.5 mIU/L vs. TSH < 2.5 mIU/L. Women with anti-TPO antibodies had similar conception rates (33.3% vs. 36.3%) but higher miscarriage rates (43.9% vs. 25.3%) and lower live birth rates (17.1% vs. 25.4%) than those without anti-TPO antibodies. Adjusted, multivariable logistic regression models confirmed elevated odds of miscarriage (odds ratio 2.17, 95% confidence interval 1.12-4.22) and lower odds of live birth (oddr ratio 0.58, 95% confidence interval 0.35-0.96) in patients with anti-TPO antibodies. In infertile women, preconceptional TSH ≥2.5 mIU/L is not associated with adverse reproductive outcomes; however, anti-TPO antibodies are associated with increased risk of miscarriage and decreased probability of live birth. PPCOS II NCT00719186; AMIGOS NCT01044862. Copyright © 2017. Published by Elsevier Inc.

Development of cell-penetrating bispecific antibodies targeting the N-terminal domain of androgen receptor for prostate cancer therapy.

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Goicochea, Nancy L; Garnovskaya, Maria; Blanton, Mary G; Chan, Grace; Weisbart, Richard; Lilly, Michael B

2017-12-01

Castration-resistant prostate cancer cells exhibit continued androgen receptor signaling in spite of low levels of ligand. Current therapies to block androgen receptor signaling act by inhibiting ligand production or binding. We developed bispecific antibodies capable of penetrating cells and binding androgen receptor outside of the ligand-binding domain. Half of the bispecific antibody molecule consists of a single-chain variable fragment of 3E10, an anti-DNA antibody that enters cells. The other half is a single-chain variable fragment version of AR441, an anti-AR antibody. The resulting 3E10-AR441 bispecific antibody enters human LNCaP prostate cells and accumulates in the nucleus. The antibody binds to wild-type, mutant and splice variant androgen receptor. Binding affinity of 3E10-AR441 to androgen receptor (284 nM) was lower than that of the parental AR441 mAb (4.6 nM), but could be improved (45 nM) through alternative placement of the affinity tags, and ordering of the VH and VK domains. The 3E10-AR441 bispecific antibody blocked genomic signaling by wild-type or splice variant androgen receptor in LNCaP cells. It also blocked non-genomic signaling by the wild-type receptor. Furthermore, bispecific antibody inhibited the growth of C4-2 prostate cancer cells under androgen-stimulated conditions. The 3E10-AR441 biAb can enter prostate cancer cells and inhibits androgen receptor function in a ligand-independent manner. It may be an attractive prototype agent for prostate cancer therapy. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Retrieval of estradiol receptor in paraffin sections of resting porcine uteri by microwave treatment. Immunostaining patterns obtained with different primary antibodies.

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Sierralta, W D; Thole, H H

1996-05-01

The unmasking of estradiol receptor in paraffin sections of Bouin's-fixed uterine tissue from ovariectomized gilts was attained with microwave treatment. Immunocytochemistry of the receptor was performed using a polyclonal or five monoclonal antibodies, two of which are commercially available, reacting with different domains of the protein and an amplified-peroxidase system for detection. With five of the antibodies, a predominance of nuclear staining was observed in cells of endometrial glands, while one monoclonal antibody (13H2), reacting with the receptor's domain E, showed a preference for the cytoplasmic receptor. In stroma, all antibodies detected more receptor in nuclei than in cytoplasm. In epithelium, the commercially available antibody H222, our monoclonals 13H2 and HT65, and the polyclonal antibody 402 demonstrated more receptor in cytoplasmic than in nuclear areas. In myometrium, the nuclei from longitudinal and ring muscles were definitely stained with the antibodies. We conclude that the accessibilities of the antibody epitopes of the receptor differ according to the functional uterine cell type.

Glutamate receptor antibodies in neurological diseases: anti-AMPA-GluR3 antibodies, anti-NMDA-NR1 antibodies, anti-NMDA-NR2A/B antibodies, anti-mGluR1 antibodies or anti-mGluR5 antibodies are present in subpopulations of patients with either: epilepsy, encephalitis, cerebellar ataxia, systemic lupus erythematosus (SLE) and neuropsychiatric SLE, Sjogren's syndrome, schizophrenia, mania or stroke. These autoimmune anti-glutamate receptor antibodies can bind neurons in few brain regions, activate glutamate receptors, decrease glutamate receptor's expression, impair glutamate-induced signaling and function, activate blood brain barrier endothelial cells, kill neurons, damage the brain, induce behavioral/psychiatric/cognitive abnormalities and ataxia in animal models, and can be removed or silenced in some patients by immunotherapy.

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Levite, Mia

2014-08-01

Glutamate is the major excitatory neurotransmitter of the Central Nervous System (CNS), and it is crucially needed for numerous key neuronal functions. Yet, excess glutamate causes massive neuronal death and brain damage by excitotoxicity--detrimental over activation of glutamate receptors. Glutamate-mediated excitotoxicity is the main pathological process taking place in many types of acute and chronic CNS diseases and injuries. In recent years, it became clear that not only excess glutamate can cause massive brain damage, but that several types of anti-glutamate receptor antibodies, that are present in the serum and CSF of subpopulations of patients with a kaleidoscope of human neurological diseases, can undoubtedly do so too, by inducing several very potent pathological effects in the CNS. Collectively, the family of anti-glutamate receptor autoimmune antibodies seem to be the most widespread, potent, dangerous and interesting anti-brain autoimmune antibodies discovered up to now. This impression stems from taking together the presence of various types of anti-glutamate receptor antibodies in a kaleidoscope of human neurological and autoimmune diseases, their high levels in the CNS due to intrathecal production, their multiple pathological effects in the brain, and the unique and diverse mechanisms of action by which they can affect glutamate receptors, signaling and effects, and subsequently impair neuronal signaling and induce brain damage. The two main families of autoimmune anti-glutamate receptor antibodies that were already found in patients with neurological and/or autoimmune diseases, and that were already shown to be detrimental to the CNS, include the antibodies directed against ionotorpic glutamate receptors: the anti-AMPA-GluR3 antibodies, anti-NMDA-NR1 antibodies and anti-NMDA-NR2 antibodies, and the antibodies directed against Metabotropic glutamate receptors: the anti-mGluR1 antibodies and the anti-mGluR5 antibodies. Each type of these anti

Clinical Value of Thyrotropin Receptor Antibodies for the Differential Diagnosis of Interferon Induced Thyroiditis.

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Benaiges, D; Garcia-Retortillo, M; Mas, A; Cañete, N; Broquetas, T; Puigvehi, M; Chillarón, J J; Flores-Le Roux, J A; Sagarra, E; Cabrero, B; Zaffalon, D; Solà, R; Pedro-Botet, J; Carrión, J A

2016-01-01

The clinical value of thyrotropin receptor antibodies for the differential diagnosis of thyrotoxicosis induced by pegylated interferon-alpha remains unknown. We analyzed the diagnostic accuracy of thyrotropin receptor antibodies in the differential diagnosis of thyrotoxicosis in patients with chronic hepatitis C (CHC) receiving pegylated interferon-alpha plus ribavirin. Retrospective analysis of 274 patients with CHC receiving pegylated interferon-alpha plus ribavirin. Interferon-induced thyrotoxicosis was classified according to clinical guidelines as Graves disease, autoimmune and non- autoimmune destructive thyroiditis. 48 (17.5%) patients developed hypothyroidism, 17 (6.2%) thyrotoxicosis (6 non- autoimmune destructive thyroiditis, 8 autoimmune destructive thyroiditis and 3 Graves disease) and 22 "de novo" thyrotropin receptor antibodies (all Graves disease, 2 of the 8 autoimmune destructive thyroiditis and 17 with normal thyroid function). The sensitivity and specificity of thyrotropin receptor antibodies for Graves disease diagnosis in patients with thyrotoxicosis were 100 and 85%, respectively. Patients with destructive thyroiditis developed hypothyroidism in 87.5% of autoimmune cases and in none of those with a non- autoimmune etiology (pthyroid scintigraphy for the differential diagnosis of thyrotoxicosis in CHC patients treated with pegylated interferon. © Georg Thieme Verlag KG Stuttgart · New York.

Synthesis and characterization of human recombinant thyrotropin (rec-hTSH) with a chimeric {beta}-subunit (rec-hTSH{beta}-CTPE hCG{beta}); Sintese e caracterizacao do hormonio tireotrofico humano recombinante (rec-hTSH) contendo uma subunidade {beta} quimerica (rec-hTSH{beta}-CTPE hCG{beta})

Energy Technology Data Exchange (ETDEWEB)

Murata, Yoko

1995-12-31

Recombinant hTSH is now successfully being used in clinical studies of thyroid cancer. Because of its therapeutic potential, we have constructed a longer acting analog of hTSH by fusing the carboxy terminal extension peptide (CTEP) of hCG{beta} onto hTSH{beta}. When coexpressed either with {alpha}-subunit complementary DNA or {alpha}-minigene in African green monkey (Cos-7) and human embryonic kidney (293) cells, the chimera was fully bioactive in vitro and exhibited enhanced in vivo potency associated with a prolonged plasma half-life. The addition of 29 amino acids with 4 O-linked oligosaccharide chains did not affect the assembly and secretion of chimeric TSH. Wild type (WT) and chimeric hTSH secreted by Cos-7 and 293 cells displayed wide differences in their plasma half-lives, presumably due to the difference in the terminal sialic acid and sulfate of their oligosaccharide chains. Chimeric and WT hTSH secreted by both cell lines demonstrated similar bioactivity in cAMP production, with some differences in [{sup 3} H]-thymidine incorporation. Chimeric hTSH secreted by Cos-7 appears to be more active than that secreted by 293 cells, as judged by growth assay. Cos-7 produced chimeric hTSH showed the maximum increase in half-life, indicating the importance of sialic acid in prolonging half-life and in vivo potency. Sulfation of both subunits, predominantly {beta} and to a lesser extent {alpha}, appears to be responsible, at least in part, for the increased metabolic clearance of WT and chimeric TSH secreted by 293 cells. Apart from its therapeutic potential, chimeric TSH produced in various cell lines can be used as a tool to delineate the roles of sulfate and sialic acid in the in vivo clearance and, thereby in the in vivo bioactivity. (author). 104 refs., 23 figs., 3 tabs.

Recombinant TSH in follow-up and therapy of differentiated thyroid carcinoma; Rekombinantes TSH in der Nachsorge und Therapie des differenzierten Schilddruesenkarzinoms

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Luster, M.; Reiners, C. [Wuerzburg Univ. (Germany). Klinik und Poliklinik fuer Nuklearmedizin

2000-03-01

I-131-scintigraphy and serum thyroglobulin testing - if possible under stimulation of thyrotropin - are besides physical examination and ultrasonography crucial for the optimal follow-up of patients with well-differentiated thyroid carcinoma. This required physicians to withdraw patients from thyroid hormone suppression therapy (THST) for several weeks in order to raise endogenous TSH-levels. Clinical hypothyroidism often results in substantial patient discomfort, with sometimes major psychic alterations; the subsequent disability to work is occasionally an unpleasant consequence from an economical point of view. The temporary use of bovine, and for a short period of time human TSH is obsolete today because of a high risk of allergic reactions or the potential transmission of the Creutzfeldt-Jakob disease, respectively. Lately recombinant human TSH (rhTSH, Thyrogen {sup trademark}), a hormone that was developed with the help of genetic engineering techniques, is available; its pharmacological safety has been demonstrated in previous phase-I/II-studies. The results of a phase-III-study showed in the majority of patients a marked rise in thyroglobulin levels after rhTSH. In all cases an adequate TSH level (>100 mU/l) was achieved after i.m. injection of recombinant TSH. Wholebody-scans showed a high level of accordance (>90%) in addition to a substantially lower background-activity. A tumour-background-ratio corresponding to conventional imaging could be demonstrated. (orig.) [German] Neben der klinischen Untersuchung und der Sonographie stellen die I-131-Szintigraphie sowie der Tumormarker Thyreoglobulin (Tg) - die Bestimmung von Tg moeglichst unter Stimulationsbedingungen - die Saeulen des Nachsorgekonzeptes beim differenzierten Schilddruesenkarzinom dar. Zur Induktion der endogenen TSH-Stimulation war es bislang erforderlich, eine mehrwoechige Phase des Absetzens der suppressiven Schilddruesenhormongabe mit konsekutiver Hypothyreose herbeizufuehren. Die

Determinants of Extraocular Muscle Volume in Patients with Graves' Disease

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Samer El-Kaissi

2012-01-01

Full Text Available Background. To examine factors contributing to extraocular muscle (EOM volume enlargement in patients with Graves’ hyperthyroidism. Methods. EOM volumes were measured with orbital magnetic resonance imaging (MRI in 39 patients with recently diagnosed Graves’ disease, and compared to EOM volumes of 13 normal volunteers. Thyroid function tests, uptake on thyroid scintigraphy, anti-TSH-receptor antibody positivity and other parameters were then evaluated in patients with EOM enlargement. Results. 31/39 patients had one or more enlarged EOM, of whom only 2 patients had clinical EOM dysfunction. Compared to Graves’ disease patients with normal EOM volumes, those with EOM enlargement had significantly higher mean serum TSH (0.020±0.005 versus 0.007±0.002 mIU/L; P value 0.012, free-T4 (52.9±3.3 versus 41.2±1.7 pmol/L; P value 0.003 and technetium uptake on thyroid scintigraphy (13.51±1.7% versus 8.55±1.6%; P value 0.045. There were no differences between the 2 groups in anti-TSH-receptor antibody positivity, the proportion of males, tobacco smokers, or those with active ophthalmopathy. Conclusions. Patients with recently diagnosed Graves’ disease and EOM volume enlargement have higher serum TSH and more severe hyperthyroidism than patients with normal EOM volumes, with no difference in anti-TSH-receptor antibody positivity between the two groups.

Antibody Selection for Cancer Target Validation of FSH-Receptor in Immunohistochemical Settings

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Nina Moeker

2017-10-01

Full Text Available Background: The follicle-stimulating hormone (FSH-receptor (FSHR has been reported to be an attractive target for antibody therapy in human cancer. However, divergent immunohistochemical (IHC findings have been reported for FSHR expression in tumor tissues, which could be due to the specificity of the antibodies used. Methods: Three frequently used antibodies (sc-7798, sc-13935, and FSHR323 were validated for their suitability in an immunohistochemical study for FSHR expression in different tissues. As quality control, two potential therapeutic anti-hFSHR Ylanthia® antibodies (Y010913, Y010916 were used. The specificity criteria for selection of antibodies were binding to native hFSHR of different sources, and no binding to non-related proteins. The ability of antibodies to stain the paraffin-embedded Flp-In Chinese hamster ovary (CHO/FSHR cells was tested after application of different epitope retrieval methods. Results: From the five tested anti-hFSHR antibodies, only Y010913, Y010916, and FSHR323 showed specific binding to native, cell-presented hFSHR. Since Ylanthia® antibodies were selected to specifically recognize native FSHR, as required for a potential therapeutic antibody candidate, FSHR323 was the only antibody to detect the receptor in IHC/histochemical settings on transfected cells, and at markedly lower, physiological concentrations (ex., in Sertoli cells of human testes. The pattern of FSH323 staining noticed for ovarian, prostatic, and renal adenocarcinomas indicated that FSHR was expressed mainly in the peripheral tumor blood vessels. Conclusion: Of all published IHC antibodies tested, only antibody FSHR323 proved suitable for target validation of hFSHR in an IHC setting for cancer. Our studies could not confirm the previously reported FSHR overexpression in ovarian and prostate cancer cells. Instead, specific overexpression in peripheral tumor blood vessels could be confirmed after thorough validation of the antibodies used.

Methimazole, but not betamethasone, prevents 131I treatment-induced rises in thyrotropin receptor autoantibodies in hyperthyroid Graves' disease

International Nuclear Information System (INIS)

Gamstedt, A.; Wadman, B.; Karlsson, A.

1986-01-01

The effects of methimazole or betamethasone therapy on the TSH receptor antibody response to radioiodine therapy were compared in a prospective randomized study of 60 patients with hyperthyroidism due to Graves' disease. The patients were followed for 1 yr after treatment with 131I. Twenty-three patients received 131I alone, 17 were treated with methimazole for 2 months before and 3 months after 131I therapy, and 20 patients were treated with betamethasone for 3 weeks before and 4 weeks after 131I therapy. 131I induced a transient rise in the mean serum level of TSH receptor autoantibodies, measured as TSH binding inhibitory immunoglobulin (TBII), but in patients receiving methimazole treatment, no such rise occurred. In the betamethasone-treated patients, TBII increased similarly to that in patients treated with 131I alone. In addition, in patients given betamethasone, there was an early decrease in total serum immunoglobulin G, which persisted throughout the follow-up period. In the other 2 groups, no changes in total immunoglobulin G were found. The results demonstrate that in hyperthyroid Graves' disease, TBII production is influenced by therapy. Methimazole abolished the 131I-induced increase in TBII, whereas betamethasone did not have such an inhibitory effect

Thyroid function and thyroid antibodies in recurrent miscarriage women

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Zahran, A. B. H.

2010-01-01

The aim of this study is to determine thyroid status in recurrent miscarriage Sudanese women and to determine the association between thyroid antibodies and miscarriage. The study included patients attending obstetrics and gynecology unit at Khartoum teaching hospital and Omdurman New hospital since June 2008 to Jan 2009, these patients were complaining of vaginal bleeding. Sixty, apparently healthy pregnant women with history of unexplained recurrent miscarriages during the first trimester, their ages ranged between 20 and 45 years were selected as target group. Forty healthy, normal pregnant women of the same gestational age and known to reach term and had healthy labor, patients with age ranged between 17 and 41 years were selected from (SAEC), referral clinic center at Khartoum Teaching and Omdurman New Hospitals as control group. The two groups were physically examined and their thyroid glands were seen by the physician. Questionnaires were completed for all the subjects. Patients with metabolic or endocrinologic disorders, genital organ anamoly, uterine myoma, mal nourishment or exposed to toxic substances were excluded from the study. Five ml of venous blood samples were collected from the target and control subjects. Thyroid function test and thyroid antibodies (TT 4 , TT 3 , FT 4 , FT 3 , TSH, TPO-Ab and Tg-Ab) were measured for the two groups (target and control ) using RIA technique. The results of this study showed that there was a significant decrease decrease in the concentrations of thyroid hormones (TT 4 and TT 3 ) in the target group (p-value = 0.0001 and 0.004 respectively) compared with the control group. Moreover, there was a significant elevation in the concentration of TSH in the target group (p- value = 0.0001). The free T-4 concentration was lower but not significant in the target group (p-value=0.075), FT 3 level was similar in both groups (p-value = 0.591). The presence of abnormal high concentrations of TT 4 in control and target groups

Is routine measurement of TSH in hospitalized patients necessary?

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Amir Bashkin

2018-04-01

Full Text Available TSH routine testing in hospitalized patients has low efficacy, but may be beneficial in a selected subgroup of patients. Our aim was to evaluate the efficacy of routine thyroid function tests among patients admitted to internal medicine departments. It is a retrospective study. A randomly selected cohort of hospitalized patients with abnormal thyroid-stimulating hormone (TSH blood tests drawn as part of admission protocol. Patient data were collected from the electronic medical files and analyzed for its efficacy. TSH as a screening test was proven unnecessary in 75% (174 of the study population. Leading causes were non-thyroidal illness syndrome, drugs affecting the test results and subclinical disorders. TSH testing was found to be clinically helpful in only 9 patients; however, all of them had other clinical need for TSH testing. We found a clinically abnormal TSH in 20 patients, hypothyroidism in 11 patients and thyrotoxicosis in 9 patients. Low efficacy ascribed to TSH screening test by this study correlates with recent recommendations that indicate TSH screening in admitted patients only with accompanying clinical suspicion. Most probably, the majority of patients found by screening to have thyrotoxicosis have non-thyroidal illness or drug effects so the threshold for FT4 to diagnose overt thyrotoxicosis should be higher than that in ambulatory patients. In elderly patients, clinically relevant TSH disturbances are more frequent and are harder to diagnose, therefore, TSH screening in this group of patients might be beneficial.

Immediate and Catastrophic Antibody-Mediated Rejection in a Lung Transplant Recipient With Anti-Angiotensin II Receptor Type 1 and Anti-Endothelin-1 Receptor Type A Antibodies.

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Cozzi, E; Calabrese, F; Schiavon, M; Feltracco, P; Seveso, M; Carollo, C; Loy, M; Cardillo, M; Rea, F

2017-02-01

Preexisting donor-specific anti-HLA antibodies (DSAs) have been associated with reduced survival of lung allografts. However, antibodies with specificities other than HLA may have a detrimental role on the lung transplant outcome. A young man with cystic fibrosis underwent lung transplantation with organs from a suitable deceased donor. At the time of transplantation, there were no anti-HLA DSAs. During surgery, the patient developed a severe and intractable pulmonary hypertension associated with right ventriular dysfunction, which required arteriovenous extracorporeal membrane oxygenation. After a brief period of clinical improvement, a rapid deterioration in hemodynamics led to the patient's death on postoperative day 5. Postmortem studies showed that lung specimens taken at the end of surgery were compatible with antibody-mediated rejection (AMR), while terminal samples evidenced diffuse capillaritis, blood extravasation, edema, and microthrombi, with foci of acute cellular rejection (A3). Immunological investigations demonstrated the presence of preexisting antibodies against the endothelin-1 receptor type A (ET A R) and the angiotensin II receptor type 1 (AT 1 R), two of the most potent vasoconstrictors reported to date, whose levels slightly rose after transplantation. These data suggest that preexisting anti-ET A R and anti-AT 1 R antibodies may have contributed to the onset of AMR and to the catastrophic clinical course of this patient. © Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.

Dual Mechanism of Interleukin-3 Receptor Blockade by an Anti-Cancer Antibody

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Sophie E. Broughton

2014-07-01

Full Text Available Interleukin-3 (IL-3 is an activated T cell product that bridges innate and adaptive immunity and contributes to several immunopathologies. Here, we report the crystal structure of the IL-3 receptor α chain (IL3Rα in complex with the anti-leukemia antibody CSL362 that reveals the N-terminal domain (NTD, a domain also present in the granulocyte-macrophage colony-stimulating factor (GM-CSF, IL-5, and IL-13 receptors, adopting unique “open” and classical “closed” conformations. Although extensive mutational analyses of the NTD epitope of CSL362 show minor overlap with the IL-3 binding site, CSL362 only inhibits IL-3 binding to the closed conformation, indicating alternative mechanisms for blocking IL-3 signaling. Significantly, whereas “open-like” IL3Rα mutants can simultaneously bind IL-3 and CSL362, CSL362 still prevents the assembly of a higher-order IL-3 receptor-signaling complex. The discovery of open forms of cytokine receptors provides the framework for development of potent antibodies that can achieve a “double hit” cytokine receptor blockade.

Clinical application and evaluation of TSH(IRMA) determination

International Nuclear Information System (INIS)

Yuan Jimin; Zhu Cuiying; Cui Wenru

1993-01-01

The serum TSH level of 303 healthy persons ranged from 0.3-5.6 mU/l and 205 cases of hyperthyroidism, 56 cases of early stage hyperthyroidism, 67 cases of subclinical hyperthyroidism ranged 3 as far as the sensitivity for the diagnosis and prognostic monitoring of thyrotoxicosis is concerned. Comparison of TSH(64 cases) and TSH stimulating test was highly correlated, therefore the application of latter test can be greatly reduced. And also the establishment and application of TSH(IRMA) gives a strategic change of the diagnostic procedure of thyroid function test

Alterações do TSH em pacientes com síndrome de Down: uma interpretação nem sempre fácil Alterations of TSH in Down's syndrome patients: a hard interpretation

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Renato M. Nisihara

2006-10-01

Full Text Available OBJETIVO: Determinar as concentrações de hormônio estimulante da tireóide (TSH e a presença de anticorpos antitireoperoxidase (anti-TPO em pacientes com síndrome de Down (SD atendidos no ambulatório do Hospital de Clínicas da Universidade Federal do Paraná. MÉTODOS: Foram incluídos no estudo 72 pacientes com SD, não aparentados e selecionados consecutivamente, com média de idade de 6,15 anos. Oitenta crianças sadias, pareadas com os pacientes, foram utilizadas como controles. Em todas as amostras foram determinadas as concentrações séricas de TSH e de anti-TPO, através do método de dosagem imunométrica. RESULTADOS: Trinta pacientes com SD (42,9% apresentaram alterações nas concentrações de TSH, sendo que 4,3% tinham valores menores que 0,5µUI/ml e 38,6%, valores superiores a 5µUI/ml (5,1 a 22 (média de 5,56 ± 4,18µUI/ml. Nos controles, a concentração média de TSH foi 2,76µUI/ml (± 1,14, evidenciando-se um aumento significativo nos níveis de TSH nos pacientes com SD (p OBJECTIVE: To evaluate the thyroid stimulating hormone (TSH levels and the presence of antithyroperoxidase antibody (anti-TPO in Down’s syndrome (DS patients from Hospital de Clínicas of Universidade Federal do Paraná (HC/UFPR. METHODS: Seventy-two DS patients, non-related and consecutively selected (mean age 6.15 were included in the study. Eighty matched healthy children were used as controls. The TSH measurement and the anti-TPO were determined by immunometric assay in all samples. RESULTS: Thirty patients with DS (42.9% presented abnormal levels of TSH; 4.3% showed values below 0.5µIU/ml and 38.6% presented values higher than 5µIU/ml (range 5.1-22; mean 5.56 ± 4.18µIU/ml. The mean concentration of TSH in the controls was 2.76 ± 1.14µIU/ml, indicating a significant increase in TSH levels in the DS patients (p < 0.001. Similarly, a significant difference was observed in the anti-TPO positivity in the patients’ group (15.4% when

Surveillance for Intracellular Antibody by Cytosolic Fc Receptor TRIM21

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William A. McEwan

2016-11-01

Full Text Available TRIM21 has emerged as an atypical Fc receptor that is broadly conserved and widely expressed in the cytoplasm of mammalian cells. Viruses that traffic surface-bound antibodies into the cell during infection recruit TRIM21 via a high affinity interaction between Fc and TRIM21 PRYSPRY domain. Following binding of intracellular antibody, TRIM21 acts as both antiviral effector and sensor for innate immune signalling. These activities serve to reduce viral replication by orders of magnitude in vitro and contribute to host survival during in vivo infection. Neutralization occurs rapidly after detection and requires the activity of the ubiquitin-proteasome system. The microbial targets of this arm of intracellular immunity are still being identified: TRIM21 activity has been reported following infection by several non-enveloped viruses and intracellular bacteria. These findings extend the sphere of influence of antibodies to the intracellular domain and have broad implications for immunity. TRIM21 has been implicated in the chronic auto-immune condition systemic lupus erythematosus and is itself an auto-antigen in Sjögren’s syndrome. This review summarises our current understanding of TRIM21’s role as a cytosolic Fc receptor and briefly discusses pathological circumstances where intracellular antibodies have been described, or are hypothesized to occur, and may benefit from further investigations of the role of TRIM21.

Focal status epilepticus and progressive dyskinesia: A novel phenotype for glycine receptor antibody-mediated neurological disease in children.

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Chan, D W S; Thomas, T; Lim, M; Ling, S; Woodhall, M; Vincent, A

2017-03-01

Antibody-associated disorders of the central nervous system are increasingly recognised in adults and children. Some are known to be paraneoplastic, whereas in others an infective trigger is postulated. They include disorders associated with antibodies to N-methyl-d-aspartate receptor (NMDAR), voltage-gated potassium channel-complexes (VGKC-complex), GABA B receptor or glycine receptor (GlyR). With antibodies to NMDAR or VGKC-complexes, distinct clinical patterns are well characterised, but as more antibodies are discovered, the spectra of associated disorders are evolving. GlyR antibodies have been detected in patients with progressive encephalopathy with rigidity and myoclonus (PERM), or stiff man syndrome, both rare but disabling conditions. We report a case of a young child with focal seizures and progressive dyskinesia in whom GlyR antibodies were detected. Anticonvulsants and immunotherapy were effective in treating both the seizures and movement disorder with good neurological outcome and with a decline in the patient's serum GlyR-Ab titres. Glycine receptor antibodies are associated with focal status epilepticus and seizures, encephalopathy and progressive dyskinesia and should be evaluated in autoimmune encephalitis. Copyright © 2016 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Monoclonal antibody to the rat glucocorticoid receptor. Relationship between the immunoreactive and DNA-binding domain

International Nuclear Information System (INIS)

Eisen, L.P.; Reichman, M.E.; Thompson, E.B.; Gametchu, B.; Harrison, R.W.; Eisen, H.J.

1985-01-01

The region of the glucocorticoid receptor that reacted with a monoclonal antibody (BUGR-1) was identified. In order to identify the immunoreactive region, the rat liver glucocorticoid receptor was subjected to limited proteolysis; immunoreactive fragments were identified by Western blotting. The monoclonal antibody reacted with both the undigested Mr approximately 97,000 receptor subunit and a Mr approximately 45,000 fragment containing the steroid-binding and DNA-binding domains. Digestion by trypsin also produced two steroid-binding fragments of Mr approximately 27,000 and 31,000 which did not react with the antibody and an immunoreactive Mr approximately 16,000 fragment. This Mr approximately 16,000 fragment was shown to bind to DNA-cellulose, indicating that it contained a DNA-binding domain of the receptor. The undigested receptor must have steroid associated with it to undergo activation to a DNA-binding form. However, the Mr approximately 16,000 immunoreactive fragment binds to DNA-cellulose even if it is obtained by digestion of the steroid-free holoreceptor which does not itself bind to DNA

Fc receptors for mouse IgG1 on human monocytes: polymorphism and role in antibody-induced T cell proliferation.

Science.gov (United States)

Tax, W J; Hermes, F F; Willems, R W; Capel, P J; Koene, R A

1984-09-01

In previous studies, it was shown that there is polymorphism in the mitogenic effect of mouse IgG1 monoclonal antibodies against the T3 antigen of human T cells. This polymorphism implies that IgG1 anti-T3 antibodies are not mitogenic for T cells from 30% of healthy individuals. The present results demonstrate that this polymorphism is caused by polymorphism of an Fc receptor for mouse IgG1, present on human monocytes. The Fc receptor for murine IgG1 could be detected by a newly developed rosetting assay on monocytes from all individuals responsive to the mitogenic effect of IgG1 anti-T3 antibodies. This Fc receptor was not detectable on monocytes from those individuals exhibiting no mitogenic responses to IgG1 anti-T3 monoclonal antibodies. Cross-linking of T3 antigens appears to be essential for antibody-induced mitosis of T cells, because mononuclear cells that did not proliferate in response to WT 31 (an IgG1 antibody against T3 antigen) showed a proliferative response to Sepharose beads coated with WT 31. The Fc receptor--if functionally present--may be involved in the cross-linking of T3 antigens through anti-T3 antibodies. Further evidence for the involvement of this Fc receptor in antibody-induced T cell proliferation was provided by inhibition studies. Immune complexes containing IgG1 antibodies were able to inhibit the proliferative response to IgG1 anti-T3 antibodies. This inhibition by immune complexes appears to be mediated through the monocyte Fc receptor for mouse IgG1. These findings are important for the interpretation of previously described inhibitory effects of anti-T cell monoclonal antibodies on T cell proliferation, and show that such inhibitory effects may be monocyte-mediated (via immune complexes) rather than caused by a direct involvement of the respective T cell antigens in T cell mitosis. The Fc receptor for mouse IgG1 plays a role in antibody-induced T cell proliferation. Its polymorphism may have important implications for the

Blockade of human P2X7 receptor function with a monoclonal antibody.

Science.gov (United States)

Buell, G; Chessell, I P; Michel, A D; Collo, G; Salazzo, M; Herren, S; Gretener, D; Grahames, C; Kaur, R; Kosco-Vilbois, M H; Humphrey, P P

1998-11-15

A monoclonal antibody (MoAb) specific for the human P2X7 receptor was generated in mice. As assessed by flow cytometry, the MoAb labeled human blood-derived macrophage cells natively expressing P2X7 receptors and cells transfected with human P2X7 but not other P2X receptor types. The MoAb was used to immunoprecipitate the human P2X7 receptor protein, and in immunohistochemical studies on human lymphoid tissue, P2X7 receptor labeling was observed within discrete areas of the marginal zone of human tonsil sections. The antibody also acted as a selective antagonist of human P2X7 receptors in several functional studies. Thus, whole cell currents, elicited by the brief application of 2',3'-(4-benzoyl)-benzoyl-ATP in cells expressing human P2X7, were reduced in amplitude by the presence of the MoAb. Furthermore, preincubation of human monocytic THP-1 cells with the MoAb antagonized the ability of P2X7 agonists to induce the release of interleukin-1beta.

Anti-N-methyl-D-aspartate receptor encephalitis with serum anti-thyroid antibodies and IgM antibodies against Epstein-Barr virus viral capsid antigen: a case report and one year follow-up

Directory of Open Access Journals (Sweden)

Xu Chun-Ling

2011-11-01

Full Text Available Abstract Background Anti-N-methyl-D-aspartate receptor encephalitis is an increasingly common autoimmune disorder mediated by antibodies to certain subunit of the N-methyl-D-aspartate receptor. Recent literatures have described anti-thyroid and infectious serology in this encephalitis but without follow-up. Case presentation A 17-year-old Chinese female patient presented with psychiatric symptoms, memory deficits, behavioral problems and seizures. She then progressed through unresponsiveness, dyskinesias, autonomic instability and central hypoventilation during treatment. Her conventional blood work on admission showed high titers of IgG antibodies to thyroglobulin, thyroid peroxidase and IgM antibodies to Epstein-Barr virus viral capsid antigen. An immature ovarian teratoma was found and removal of the tumor resulted in a full recovery. The final diagnosis of anti-N-methyl-D-aspartate receptor encephalitis was made by the identification of anti-N-methyl-D-aspartate receptor antibodies in her cerebral spinal fluid. Pathology studies of the teratoma revealed N-methyl-D-aspartate receptor subunit 1 positive ectopic immature nervous tissue and Epstein-Barr virus latent infection. She was discharged with symptoms free, but titers of anti-thyroid peroxidase and anti-thyroglobulin antibodies remained elevated. One year after discharge, her serum remained positive for anti-thyroid peroxidase and anti-N-methyl-D-aspartate receptor antibodies, but negative for anti-thyroglobulin antibodies and IgM against Epstein-Barr virus viral capsid antigen. Conclusions Persistent high titers of anti-thyroid peroxidase antibodies from admission to discharge and until one year later in this patient may suggest a propensity to autoimmunity in anti- N-methyl-D-aspartate receptor encephalitis and support the idea that neuronal and thyroid autoimmunities represent a pathogenic spectrum. Enduring anti-N-methyl-D-aspartate receptor antibodies from admission to one year

Hyperfunctioning thyroid nodules in toxic multinodular goiter share activating thyrotropin receptor mutations with solitary toxic adenoma.

Science.gov (United States)

Tonacchera, M; Chiovato, L; Pinchera, A; Agretti, P; Fiore, E; Cetani, F; Rocchi, R; Viacava, P; Miccoli, P; Vitti, P

1998-02-01

Toxic multinodular goiter is a cause of nonautoimmune hyperthyroidism and is believed to differ in its nature and pathogenesis from toxic adenoma. Gain-of-function mutations of the TSH receptor gene have been identified as a cause of toxic adenoma. The pathogenesis at the molecular level of hyperfunctioning nodules in toxic multinodular goiter has yet not been reported. Six patients with a single hot nodule within a multinodular goiter and 11 patients with toxic thyroid adenoma were enrolled in our study. At histology five hyperfunctioning nodules in multinodular goiters showed the features of adenomas, and one was identified as a hyperplastic nodule. The entire exon 10 of the TSH receptor gene was directly sequenced after PCR amplification from genomic DNA obtained from surgical specimens. Functional studies of mutated receptors were performed in COS-7 cells. Five out of 6 (83%) hyperfunctioning nodules within toxic multinodular goiters harbored a TSH receptor mutation. A TSH receptor mutation was also evident in the hyperfunctioning nodule that at histology had the features of noncapsulated hyperplastic nodule. Among toxic adenomas, 8 out of 11 (72%) nodules harbored a TSH receptor mutation. All the mutations were heterozygotic and somatic. Nonfunctioning nodules, whether adenomas or hyperplastic nodules present in association with hyperfunctioning nodules in the same multinodular goiters, had no TSH receptor mutation. All the mutations identified had constitutive activity as assessed by cAMP production after expression in COS-7 cells. Hyperfunctioning thyroid nodules in multinodular goiters recognize the same pathogenetic event (TSH receptor mutation) as toxic adenoma. Other mechanisms are implicated in the growth of nonfunctioning thyroid nodules coexistent in the same gland.

Thyrotropin Receptor and Membrane Interactions in FRTL-5 Thyroid Cell Strain in Microgravity

Science.gov (United States)

Albi, E.; Ambesi-Impiombato, F. S.; Peverini, M.; Damaskopoulou, E.; Fontanini, E.; Lazzarini, R.; Curcio, F.; Perrella, G.

2011-01-01

The aim of this work was to analyze the possible alteration of thyrotropin (TSH) receptors in microgravity, which could explain the absence of thyroid cell proliferation in the space environment. Several forms of the TSH receptor are localized on the plasma membrane associated with caveolae and lipid rafts. The TSH regulates the fluidity of the cell membrane and the presence of its receptors in microdomains that are rich in sphingomyelin and cholesterol. TSH also stimulates cyclic adenosine monophosphate (cAMP) accumulation and cell proliferation. Reported here are the results of an experiment in which the FRTL-5 thyroid cell line was exposed to microgravity during the Texus-44 mission (launched February 7, 2008, from Kiruna, Sweden). When the parabolic flight brought the sounding rocket to an altitude of 264km, the culture media were injected with or without TSH in the different samples, and weightlessness prevailed on board for 6 minutes and 19 seconds. Control experiments were performed, in parallel, in an onboard 1g centrifuge and on the ground in Kiruna laboratory. Cell morphology and function were analyzed. Results show that in microgravity conditions the cells do not respond to TSH treatment and present an irregular shape with condensed chromatin, a modification of the cell membrane with shedding of the TSH receptor in the culture medium, and an increase of sphingomyelin-synthase and Bax proteins. It is possible that real microgravity induces a rearrangement of specific sections of the cell membrane, which act as platforms for molecular receptors, thus influencing thyroid cell function in astronauts during space missions.

The effects of human TSH receptor gene transfection on iodide uptake and thyroid-specific gene expression in poorly differentiated thyroid carcinoma cell line

International Nuclear Information System (INIS)

Hou Shasha; Wang Hui; Feng Fang; Lin Ning; Fu Hongliang; Du Xueliang; Wu Jingchuan

2011-01-01

Objective: To investigate the changes of iodide uptake and the expression of thyroid-specific genes in poorly differentiated follicular thyroid carcinoma (FTC) cells after transfection of human TSH receptor (hTSHR) gene in vitro. Methods: The recombinant eukaryotic expression plasmid PcDNA3.1/hTSHR-cDNA was transformed into DH 5a bacterial for amplification and then the recombinant plasmid was extracted. The recombinant was identified with PCR amplifying, restriction enzyme digestion analysis and DNA sequencing. The recombinant plasmid pcDNA3.1/hTSHR was transfected into FTC-133 cell line by lipofectin method in vitro. Immunofluorescence, iodide uptake studies and real time-PCR were applied to detect target protein expression. Statistical analysis was performed with t-test using SPSS 13.0 software. Results: Kpn I and Xba I restriction enzyme digestion, PCR amplifying and DNA sequencing confirmed that pcDNA3.1/hTSHR was successfully constructed. After transfection of the recombinant plasmid pcDNA3.1/hTSHR-cDNA and the stimulation of hTSH, the tumor cells displayed the expression of hTSHR protein at cell surface and cytoplasm. The iodine uptake in pcDNA3.1/hTSHR transfected cells was 2.9 times higher than that of control(pcDNA3.1(+) transfected cells) group(t = 28.63, P<0.01). The expression of TSHR, NIS, TPO and Tg (mRNA levels) in pcDNA3.1/hTSHR transfected cells were also significantly elevated by 1.74 (t =5.959, P<0.01), 7.2 (t =3.807, P<0.05), 2.88 (t=4.769, P<0.01) and 2.67 times (t=6.388, P<0.01) respectively compared to those of the control group. Conclusion: The study demonstrates that iodide uptake may be reactivated by hTSHR receptor gene transfection in poorly differentiated FTC cell. (authors)

Ability of the rhTSH stimulation test to predict relapse in patients with differentiated thyroid carcinoma, after long-term follow-up

Science.gov (United States)

MARCELINO, MAFALDA; LOPES, ANA FILIPA; MADUREIRA, DEOLINDA; FERREIRA, TERESA C.; LIMBERT, EDWARD; LEITE, VALERIANO

2015-01-01

The analysis of serum thyroglobulin (Tg) following thyroid-stimulating hormone (TSH) stimulation (sTg) has been recommended in the follow-up of differentiated thyroid carcinoma (DTC) patients, however, its routine use remains controversial. The aim of the current study was to evaluate the accuracy of sTg testing following recombinant human (rh) TSH stimulation in DTC patients, with a follow-up of 12.4 years. Retrospective studies were conducted of 125 DTC patients, who underwent rhTSH stimulation testing between 1999 and 2002. The exclusion criteria were: Patients with anti-Tg antibodies, Tg levels >1 ng/ml under TSH suppression and the absence of radioactive iodine (RAI) ablation therapy following surgery. In total, 49 patients were included in the study and all had been previously treated with total or near total thyroidectomy (with or without central neck dissection) and RAI, postoperatively. The Tg functional sensitivity was 1.0 ng/ml. The follow-up for patients was performed annually. During the median follow-up of 12.4 years after the rhTSH stimulation test, nine patients exhibited recurrence (18.4%). Of the nine patients, six exhibited sTg levels >2 ng/ml (positive result) and three exhibited levels <2 ng/ml (negative result). Relapse occurred at a mean of 5.9 years following the rhTSH stimulation test. The positive predictive value and negative predictive value (NPV) of positive sTg were 50 and 91.9%, respectively, with a sensitivity of 66.6% and a specificity of 85.0%. The rhTSH-stimulated Tg levels have a high NPV, allowing the identification of the patients who are free of the tumour. These results are consistent with the previously published data; however, to the best of our knowledge, this is the study with the longest follow-up duration after rhTSH stimulation. PMID:25663898

Functional Evaluation of TSH Secretory Reserve Capacity in Hypothalamo pituitary Disorders

Energy Technology Data Exchange (ETDEWEB)

Kim, Sun Yong; Choi, Kyoo Ok; Park, Chang Yun; Huh, Kab Bum; Ryu, Kyung Ja [Yonsei University College of Medicine, Seoul (Korea, Republic of)

1979-03-15

The TRH stimulation test was known as a highly diagnostic method in hypothalamo pituitary disorders. To evaluate the location and the extension of the lesion, we estimated TSH response to TRH test in 27 patients. Correlation between volume of sella and TSH response was also studied. The results obtained were 25 follows: 1) In Sheehan's syndrome, TSH response after TRH test were not observed in all of 12 patients. 2) All 2 acromegaly patients showed normal TSH response. 3) In 4 cases of chromophobe adenoma, 2 cases showed no TSH response. In 2 responded cases, one patient whose tumor mass extended to suprasella region was hypothyroid state. 4) In craniopharyingioma 3 cases, the tumor which extended to intrasella showed hypothyroid and no TSH response. 5) Correlation between volume of sella and TSH response were valuable in 2 cases, but no diagnostic significance. 6) In diabetes inspidus, TSH response were all absent. 7) In primary amenorrhea, TSH response observed in 1 case, which conformed with isolated FSH deficiency.

Functional Evaluation of TSH Secretory Reserve Capacity in Hypothalamo pituitary Disorders

International Nuclear Information System (INIS)

Kim, Sun Yong; Choi, Kyoo Ok; Park, Chang Yun; Huh, Kab Bum; Ryu, Kyung Ja

1979-01-01

The TRH stimulation test was known as a highly diagnostic method in hypothalamo pituitary disorders. To evaluate the location and the extension of the lesion, we estimated TSH response to TRH test in 27 patients. Correlation between volume of sella and TSH response was also studied. The results obtained were 25 follows: 1) In Sheehan's syndrome, TSH response after TRH test were not observed in all of 12 patients. 2) All 2 acromegaly patients showed normal TSH response. 3) In 4 cases of chromophobe adenoma, 2 cases showed no TSH response. In 2 responded cases, one patient whose tumor mass extended to suprasella region was hypothyroid state. 4) In craniopharyingioma 3 cases, the tumor which extended to intrasella showed hypothyroid and no TSH response. 5) Correlation between volume of sella and TSH response were valuable in 2 cases, but no diagnostic significance. 6) In diabetes inspidus, TSH response were all absent. 7) In primary amenorrhea, TSH response observed in 1 case, which conformed with isolated FSH deficiency.

Nongoitrous autoimmune thyroiditis with facial palsy

Directory of Open Access Journals (Sweden)

Hyung Jik Lee

2013-12-01

Full Text Available We report a case of severe hypothyroidism with nongoitrous, autoimmune thyroiditis and pituitary hyperplasia in a 13-year-old boy, who presented with sudden palsy on the left side of his face. Prednisolone and antiviral medication was administered. However, the facial palsy did not improve completely. The medications were replaced with thyroxine, and the facial palsy recovered. Endocrinological testing showed severe hypothyroidism as follows: thyroid stimulating hormone (TSH level >100 µIU/mL, T4 of 1.04 µg/dL, T3 of 0.31 ng/mL, and free T4 of 0.07 ng/dL. Level of serum antithyroid peroxidase antibodies was 1,933.39 IU/mL, and that of antithyroglobulin antibodies was 848.16 IU/mL. Level of TSH receptor antibodies was >40 IU/L. Bioassay result for TSH receptor stimulating antibodies was negative. Thyroid sonography revealed no increase in the size or vascularity of the bilateral gland. Thyroid scintigraphy with 99mTc showed decreased uptake, and magnetic resonance imaging demonstrated an enlarged pituitary gland.

[A case of GH and TSH secreting pituitary macroadenoma].

Science.gov (United States)

Gołkowski, Filip; Buziak-Bereza, Monika; Stefańska, Agnieszka; Trofimiuk, Małgorzata; Pantofliński, Jacek; Huszno, Bohdan; Czepko, Ryszard; Adamek, Dariusz

2006-01-01

A case of GH and TSH secreting pituitary macroadenoma is reported. A 45-year-old female presented clinical features of acromegaly (the abnormal growth of the hands and feet, with lower jaw protrusion), diabetes mellitus, hypertension, nodular goiter and hyperthyroidism of unclear origin. NMR pituitary imaging revealed intra and extrasellar tumor. The laboratory examinations showed very high plasma levels of GH and IGF-1 and normal level of TSH coexisting with high plasma levels of free thyroid hormones. Pharmacological pretreatment with somatostatin analogues caused the substantial reduction of GH and TSH plasma levels. Histological and immunohistochemical examination of the tissue obtained at transsphenoidal surgery showed GH and TSH secreting adenoma. The laboratory examinations after surgery showed normal GH and IGF-1 plasma levels and reduced insulin requirement, what indicates radical operation. The very low plasma levels of TSH and free thyroid hormones after surgery and immunohistochemical examination suggest central hyperthyroidism due to TSH secreting pituitary tumor (thyrotropinoma).

Single-domain antibodies that compete with the natural ligand fibroblast growth factor block the internalization of the fibroblast growth factor receptor 1

Energy Technology Data Exchange (ETDEWEB)

Veggiani, Gianluca; Ossolengo, Giuseppe; Aliprandi, Marisa; Cavallaro, Ugo [IFOM-IEO Campus, Via Adamello 16, 20139 Milano (Italy); Marco, Ario de, E-mail: ario.demarco@ung.si [IFOM-IEO Campus, Via Adamello 16, 20139 Milano (Italy); Dept. Environmental Sciences, University of Nova Gorica (UNG), Vipavska 13, P.O. Box 301-SI-5000, Rozna Dolina, Nova Gorica (Slovenia)

2011-05-20

Highlights: {yields} Recombinant antibodies for FGFR1 were isolated from a llama naive library in VHH format. {yields} These antibodies compete with the natural ligand FGF-2 for the same epitope on FGFR1. {yields} The antibody competition inhibits the FGF-2-dependent internalization of FGFR1. -- Abstract: Single-domain antibodies in VHH format specific for fibroblast growth factor receptor 1 (FGFR1) were isolated from a phage-display llama naive library. In particular, phage elution in the presence of the natural receptor ligand fibroblast growth factor (FGF) allowed for the identification of recombinant antibodies that compete with FGF for the same region on the receptor surface. These antibodies posses a relatively low affinity for FGFR1 and were never identified when unspecific elution conditions favoring highly affine binders were applied to panning procedures. Two populations of competitive antibodies were identified that labeled specifically the receptor-expressing cells in immunofluorescence and recognize distinct epitopes. Antibodies from both populations effectively prevented FGF-dependent internalization and nuclear accumulation of the receptor in cultured cells. This achievement indicates that these antibodies have a capacity to modulate the receptor physiology and, therefore, constitute powerful reagents for basic research and a potential lead for therapeutic applications.

Single-domain antibodies that compete with the natural ligand fibroblast growth factor block the internalization of the fibroblast growth factor receptor 1

International Nuclear Information System (INIS)

Veggiani, Gianluca; Ossolengo, Giuseppe; Aliprandi, Marisa; Cavallaro, Ugo; Marco, Ario de

2011-01-01

Highlights: → Recombinant antibodies for FGFR1 were isolated from a llama naive library in VHH format. → These antibodies compete with the natural ligand FGF-2 for the same epitope on FGFR1. → The antibody competition inhibits the FGF-2-dependent internalization of FGFR1. -- Abstract: Single-domain antibodies in VHH format specific for fibroblast growth factor receptor 1 (FGFR1) were isolated from a phage-display llama naive library. In particular, phage elution in the presence of the natural receptor ligand fibroblast growth factor (FGF) allowed for the identification of recombinant antibodies that compete with FGF for the same region on the receptor surface. These antibodies posses a relatively low affinity for FGFR1 and were never identified when unspecific elution conditions favoring highly affine binders were applied to panning procedures. Two populations of competitive antibodies were identified that labeled specifically the receptor-expressing cells in immunofluorescence and recognize distinct epitopes. Antibodies from both populations effectively prevented FGF-dependent internalization and nuclear accumulation of the receptor in cultured cells. This achievement indicates that these antibodies have a capacity to modulate the receptor physiology and, therefore, constitute powerful reagents for basic research and a potential lead for therapeutic applications.

TSH elevations as the first laboratory evidence for pseudohypoparathyroidism type Ib (PHP-Ib)†

OpenAIRE

Molinaro, Angelo; Tiosano, Dov; Takatani, Rieko; Chrysis, Dionisios; Russell, William; Koscielniak, Nikolas; Kottler, Marie-Laure; Agretti, Patrizia; De Marco, Giuseppina; Ahtiainen, Petteri; Christov, Marta; Mäkitie, Outi; Tonacchera, Massimo; Jüppner, Harald

2015-01-01

Hypocalcemia and hyperphosphatemia because of resistance towards parathyroid hormone (PTH) in the proximal renal tubules are the most prominent abnormalities in patients affected by pseudohypoparathyroidism type Ib (PHP-Ib). In this rare disorder that is caused by GNAS methylation changes, resistance can occur towards other hormones, such as thyroid-stimulating hormone (TSH), that mediate their actions through G protein-coupled receptors. However, these additional laboratory abnormalities are...

Functional Evaluation of TSH Secretory Reserve Capacity in Hypothalamo pituitary Disorders

Energy Technology Data Exchange (ETDEWEB)

Kim, Sun Yong; Choi, Kyoo Ok; Park, Chang Yun; Huh, Kab Bum; Ryu, Kyung Ja [Yonsei University College of Medicine, Seoul (Korea, Republic of)

1979-03-15

The TRH stimulation test was known as a highly diagnostic method in hypothalamo pituitary disorders. To evaluate the location and the extension of the lesion, we estimated TSH response to TRH test in 27 patients. Correlation between volume of sella and TSH response was also studied. The results obtained were 25 follows: 1) In Sheehan's syndrome, TSH response after TRH test were not observed in all of 12 patients. 2) All 2 acromegaly patients showed normal TSH response. 3) In 4 cases of chromophobe adenoma, 2 cases showed no TSH response. In 2 responded cases, one patient whose tumor mass extended to suprasella region was hypothyroid state. 4) In craniopharyingioma 3 cases, the tumor which extended to intrasella showed hypothyroid and no TSH response. 5) Correlation between volume of sella and TSH response were valuable in 2 cases, but no diagnostic significance. 6) In diabetes inspidus, TSH response were all absent. 7) In primary amenorrhea, TSH response observed in 1 case, which conformed with isolated FSH deficiency.

HER2 monoclonal antibodies that do not interfere with receptor heterodimerization-mediated signaling induce effective internalization and represent valuable components for rational antibody-drug conjugate design.

Science.gov (United States)

de Goeij, Bart E C G; Peipp, Matthias; de Haij, Simone; van den Brink, Edward N; Kellner, Christian; Riedl, Thilo; de Jong, Rob; Vink, Tom; Strumane, Kristin; Bleeker, Wim K; Parren, Paul W H I

2014-01-01

The human epidermal growth factor receptor (HER)2 provides an excellent target for selective delivery of cytotoxic drugs to tumor cells by antibody-drug conjugates (ADC) as has been clinically validated by ado-trastuzumab emtansine (Kadcyla(TM)). While selecting a suitable antibody for an ADC approach often takes specificity and efficient antibody-target complex internalization into account, the characteristics of the optimal antibody candidate remain poorly understood. We studied a large panel of human HER2 antibodies to identify the characteristics that make them most suitable for an ADC approach. As a model toxin, amenable to in vitro high-throughput screening, we employed Pseudomonas exotoxin A (ETA') fused to an anti-kappa light chain domain antibody. Cytotoxicity induced by HER2 antibodies, which were thus non-covalently linked to ETA', was assessed for high and low HER2 expressing tumor cell lines and correlated with internalization and downmodulation of HER2 antibody-target complexes. Our results demonstrate that HER2 antibodies that do not inhibit heterodimerization of HER2 with related ErbB receptors internalize more efficiently and show greater ETA'-mediated cytotoxicity than antibodies that do inhibit such heterodimerization. Moreover, stimulation with ErbB ligand significantly enhanced ADC-mediated tumor kill by antibodies that do not inhibit HER2 heterodimerization. This suggests that the formation of HER2/ErbB-heterodimers enhances ADC internalization and subsequent killing of tumor cells. Our study indicates that selecting HER2 ADCs that allow piggybacking of HER2 onto other ErbB receptors provides an attractive strategy for increasing ADC delivery and tumor cell killing capacity to both high and low HER2 expressing tumor cells.

Age modifies the pituitary TSH response to thyroid failure

DEFF Research Database (Denmark)

Carlé, Allan; Laurberg, Peter; Pedersen, Inge B.

2007-01-01

Objective: To investigate the association between serum TSH, total T4 and various patient characteristics when hypothyroidism is diagnosed in a population, and to study how age, sex and serum T4 levels influenced pituitary TSH response. Design: A computer-based register linked to laboratory datab......, and longer time may be needed after thyroid hormone withdrawal before elderly patients with thyroid cancer reach sufficiently high TSH values to allow for an effective radio-iodine treatment....... patients. Conclusions: For the same degree of thyroid failure, the serum TSH is lower among the elderly. This is most likely caused by a decrease in the hypothalamic/pituitary response to low serum T4. A certain increase in serum TSH may indicate more severe hypothyroidism in an old than in a young patient...

Radioiodine therapy in non-toxic multinodular goitre. The possibility of effect-amplification with recombinant human TSH (rhTSH)

Energy Technology Data Exchange (ETDEWEB)

Bonnema, Steen J.; Nielsen, Viveque E.; Hegedues, Laszlo [Odense Univ. Hospital (Denmark). Dept. of Endocrinology and Metabolism

2006-12-15

There is no consensus regarding the optimum treatment of benign non-toxic goitre. L-thyroxine suppressive therapy is widely used, but there is poor evidence of its efficacy, and it may have serious adverse effects on health. Surgery is first choice in large goitres or if malignancy is suspected. {sup 131}I therapy results in a one-year goitre reduction of around 40% in multinodular goitres, usually with a high degree of patient satisfaction and improvement of the inspiratory capacity. The effect is attenuated with increasing goitre size. The risk of hypothyroidism is 22-58% within 5-8 years. A sufficient thyroid {sup 131}I uptake is mandatory for {sup 131}I therapy to be feasible and pre-stimulation with recombinant human TSH (rhTSH) increases this considerably. This leads to an increased absorbed thyroid dose by approx.75%, mainly in those patients with the lowest thyroid {sup 131}I uptake, and a more homogeneous intrathyroidal isotope distribution. Pre-stimulation with even a small dose of rhTSH seems to allow a reduction of the {sup 131}I activity while still achieving a mean goitre reduction of approximately 40% within a year. A significantly lower extrathyroidal radiation is achieved by this approach. With an unchanged {sup 131}I activity, rhTSH pre-stimulation improves the goitre reduction by 30-50%. However, this is at the expense of a higher rate of hypothyroidism, cervical pain and transient thyrotoxicosis. Of particular concern is the observation made in healthy persons, that rhTSH results in a transient average thyroid volume increase of 35%. A similar goitre swelling may cause problems in susceptible patients during rhTSH-augmented {sup 131}I therapy. Thus, this concept still needs a closer evaluation before routine use.

Direct evidence that ganglioside is an integral component of the thyrotropin receptor

International Nuclear Information System (INIS)

Kielczynski, W.; Harrison, L.C.; Leedman, P.J.

1991-01-01

Gangliosides were extracted from purified human and porcine thyrotropin (TSH) receptors (TSH-R) and were detected by probing with an 125 I-labeled sialic acid-specific lectin, Limax flavus agglutinin. Gangliosides copurified with human and porcine TSH-R migrated between monosialoganglioside GM1 and disialoganglioside GD1a. Ceramide glycanase digestion of the purified human TSH-R-associated glycolipid confirmed its ganglioside nature. It was resistant to Vibrio cholerae sialidase, which digest all gangliosides except GM1, but was sensitive to Arthrobacter ureafaciens sialidase, which digests all gangliosides including GM1. These findings indicate that the human TSH-R contains ganglioside that belongs to the galactosyl(β1→ 3)-N-acetylgalactosaminyl(β1→ 4)-[N-acetylneuraminyl(α2→ 3)]galactosyl(β1 → 4)glucosyl(β1 → 1)ceramide (GM1) family. Its intimate association with receptor protein implies a key role for ganglioside in the structure and function of the TSH-R

New-Onset Headache in Patients With Autoimmune Encephalitis Is Associated With anti-NMDA-Receptor Antibodies.

Science.gov (United States)

Schankin, Christoph J; Kästele, Fabian; Gerdes, Lisa Ann; Winkler, Tobias; Csanadi, Endy; Högen, Tobias; Pellkofer, Hannah; Paulus, Walter; Kümpfel, Tania; Straube, Andreas

2016-06-01

We tested the hypotheses (i) that autoimmune encephalitis is associated with new-onset headache, and (ii) that the occurrence of headache is associated with the presence of anti-N-methyl-D-aspartate (NMDA)-receptor antibodies. Autoimmune encephalitis presents with cognitive dysfunction as well as neuro-psychiatric symptoms. Its pathophysiology might involve antibody-mediated dysfunction of the glutamatergic system as indicated by the presence of anti-NMDA-receptor antibodies in some patients. In this cross-sectional study, patients with autoimmune encephalitis were assessed with a standardized interview for previous headache and headache associated with autoimmune encephalitis. Headache was classified according to the International Classification of Headache Disorders, second edition. Clinical and paraclinical findings were correlated with the occurrence of headache. Of 40 patients with autoimmune encephalitis, 19 did not have a history of headache. Of those, nine suffered from encephalitis-associated headache. Seven of these nine had anti-NMDA-receptor antibodies in contrast to only two among the remaining 10 patients without new-onset headache (P = .023, odds ratio: 14, 95% confidence interval: 1.5; 127). In most patients headache occurred in attacks on more than 15 days/month, was severe, and of short duration (less than 4 hours). International Headache Society criteria for migraine were met in three patients. New-onset headache is a relevant symptom in patients with autoimmune encephalitis who have no history of previous headache, especially in the subgroup with anti-NMDA-receptor antibodies. This indicates a thorough investigation for secondary headaches including anti-NMDA-R antibodies for patients with new-onset headache and neuropsychiatric findings. Glutamatergic dysfunction might be important for the generation of head pain but may only occasionally be sufficient to trigger migraine-like attacks in nonmigraineurs. © 2016 American Headache Society.

Measurement of Thyroid-Stimulating Hormone (TSH) In Vitro

Energy Technology Data Exchange (ETDEWEB)

Kirkham, K. E.; Hunter, W. M.; Jeffery, F. H.; Bennie, J. G. [Medical Research Council Clinical Endocrinology Unit, Edinburgh, Scotland (United Kingdom)

1970-02-15

Many of the methods of assay proposed for the quantitative measurement of human thyroid-stimulating hormone (H-TSH) have encountered major difficulties in relation to sensitivity and specificity. The development of radioimmunoassay techniques for the measurement of H-TSH not only resulted in increased sensitivity over the majority of existing techniques, but led to improvements in specificity and practicability. The purpose of this communication is to compare serum TSH values measured by a method of bioassay in vitro with those obtained by a radioimmunoassay developed in this laboratory using reagents provided by the National Pituitary Agency, United States of America. In the bioassay technique goitrous guinea-pig thyroid tissue is incubated in vitro with {sup 131}I and H-TSH during which time the tissue takes up {sup 131}I and binds it in organic combination. Measurements of the radioactive content of the culture medium are made before and after the addition of KSCN in order to discharge any {sup 131}I present in the tissue as iodide, the difference in count-rate being indirectly proportional to the amount of H-TSH present in the incubation fluid. The method can detect as little as 1.0 mU/100 ml serum. The radioimmunoassay technique used was that described by Odell and Garigan in instructions accompanying the reagents. However, modifications to their technique included the use of antiserum at a final dilution of 1/120 000 and the addition of H-TSH at a final concentration of 0.4 ng/ml to mixtures of antiserum and the standard preparation after an incubation period of five days. After a further five days incubation period, the separation of bound and free {sup 131}I-H-TSH was carried out by precipitating the bound hormone with NaCl and ethanol. The lower limit of detection in terms of the H-TSH standard A (MRC) is 5 {mu}U/ml serum (0.5 mU/100 ml). Serum was obtained from children aged one month to 16 years, adults aged 18-40 years and 66-85 years, patients

Association between the clinical classification of hypothyroidism and reduced TSH in LT4 supplemental replacement treatment for pregnancy in China.

Science.gov (United States)

Zhang, Lyu; Zhang, Zhaoyun; Ye, Hongying; Zhu, Xiaoming; Li, Yiming

2016-01-01

The study was aimed to evaluate the effects of levothyroxine (LT4) supplemental replacement treatment for pregnancy and analyze the associations between the clinical classification of hypothyroidism and reduced thyroid-stimulating hormone (TSH) in LT4 therapy. Totally, 195 pregnant women with hypothyroidism receiving routine prenatal care were enrolled. They were categorized into three groups: overt hypothyroidism (OH), subclinical hypothyroidism (SCH) with negative thyroperoxidase antibody (TPOAb), and SCH with positive TPOAb. The association between the clinical classification and reduced TSH in LT4 supplemental replacement treatment was assessed. The results indicated that reduced TSH was significantly different among the groups according to the clinical classifications (p = 0.043). The result was also significantly different between patients with OH and patients with SCH and negative TPOAb (p = 0.036). Similar result was reported for the comparison between patients with OH and patients with SCH and positive TPOAb (p = 0.016). Multiple variable analyses showed that LT4 supplementation, gestational age and the variable of clinical classifications were associated with reduced TSH independently. Our data suggested that the therapeutic effect of substitutive treatment with LT4 was significantly associated with different clinical classifications of hypothyroidism in pregnancy and the treatment should begin as soon as possible after diagnosis.

Subcellular localization of estradiol receptor in MCF7 cells studied with nanogold-labelled antibody fragments.

Science.gov (United States)

Kessels, M M; Qualmann, B; Thole, H H; Sierralta, W D

1998-01-01

Ultrastructural localization studies of estradiol receptor in hormone-deprived and hormone-stimulated MCF7 cells were done using F(ab') fragments of three different antibodies (#402, 13H2, HT277) covalently linked to nanogold. These ultra-small, non-charged immunoreagents, combined with a size-enlargement by silver enhancement, localized estradiol receptor in both nuclear and cytoplasmic areas of non-stimulated target cells; stimulation with the steroid induced a predominantly nuclear labelling. In the cytoplasm of resting cells, tagging was often observed at or in the proximity of stress fibers. In the nucleus a large proportion of receptor was found inside the nucleolus, specially with the reagent derived from antibody 13H2. We postulate that different accessibilities of receptor epitopes account for the different labelling densities observed at cytoskeletal elements and the nucleoli.

Basic Evaluation of Analytical Performance and Clinical Utility of Immunoradiometric TSH Assay

International Nuclear Information System (INIS)

Suhy, Il Kyo; Cho, Bo Youn; Lee, Hong Kyu; Koh, Chang Soon; Min, Hun Ki; Lee, Mun Ho

1987-01-01

To assess the analytic performance of immunoradiometric TSH assay (IRMA TSH), assay precision determined by intra and interassay variance, assay accuracy determined by dilution and recovery study, were evaluated by using two commercial kit (Abott and Daichi). Normal range of basal serum TSH and TRH stimulated TSH increment were also determined in 234 healthy subjects (male 110, female 124; age 20-70) and 30 volunteers (male 10, female 20; age 21-26). In addition, basal TSH levels of 70 patients with untreated hyperthyroidism, 50 untreated hypothyroidism, and 60 euthyroidism were measured to assess the clinical utility of IRMA TSH. The detection limit of IRMA TSH was 0.04 mU/l and 0.08 mU/l by Abott Kit and Daichi kit respectively. Using Abott kit, intraassay variance were 2.0, 3.1 and 1.4% in mean TSH concentration 2.4, 31.6 and 98.2 mU/l repectively and interassay variance were 2.0 and 3.2% in mean TSH concentration 2.3 and 31.3 mU/l. Mean recovery rate was 92.5% and dilution study showed nearly straight line. When Daichi kit was used, intrasssay variance were 5.6, 5.2 and 6.2% in mean TSH concentration of 2.4, 31.6 and 98.2 mU/1 respectively and interassay variance were 7.1 and 7.4% in mean TSH of 2.3 and 31.3 mU,/l. Mean recovery rate was 89.9%. Normal range of basal TSH and TRH stimulated peak TSH were 0.38-4.02 mU/1 and 2.85-30.8 mU/1 repectively (95% confidence interval, Abott kit used). Sensitivity and specificity of basal TSH levels for diagnosing hypothyroidism as well as specificity for diagnosing hyperthyroidism were 100% by using both kit. Sensitivity of basal TSH level for diagnosing hyperthyroidism was 100% when TSH levels were measured by Abott kit while that was 80.9% when measured by Daichi kit. These results suggest that IRMA TSH was very precise and accurate method and might be used as a first line test in the evaluation of thyroid function

Characterization of Notch1 antibodies that inhibit signaling of both normal and mutated Notch1 receptors.

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Miguel Aste-Amézaga

2010-02-01

Full Text Available Notch receptors normally play a key role in guiding a variety of cell fate decisions during development and differentiation of metazoan organisms. On the other hand, dysregulation of Notch1 signaling is associated with many different types of cancer as well as tumor angiogenesis, making Notch1 a potential therapeutic target.Here we report the in vitro activities of inhibitory Notch1 monoclonal antibodies derived from cell-based and solid-phase screening of a phage display library. Two classes of antibodies were found, one directed against the EGF-repeat region that encompasses the ligand-binding domain (LBD, and the second directed against the activation switch of the receptor, the Notch negative regulatory region (NRR. The antibodies are selective for Notch1, inhibiting Jag2-dependent signaling by Notch1 but not by Notch 2 and 3 in reporter gene assays, with EC(50 values as low as 5+/-3 nM and 0.13+/-0.09 nM for the LBD and NRR antibodies, respectively, and fail to recognize Notch4. While more potent, NRR antibodies are incomplete antagonists of Notch1 signaling. The antagonistic activity of LBD, but not NRR, antibodies is strongly dependent on the activating ligand. Both LBD and NRR antibodies bind to Notch1 on human tumor cell lines and inhibit the expression of sentinel Notch target genes, including HES1, HES5, and DTX1. NRR antibodies also strongly inhibit ligand-independent signaling in heterologous cells transiently expressing Notch1 receptors with diverse NRR "class I" point mutations, the most common type of mutation found in human T-cell acute lymphoblastic leukemia (T-ALL. In contrast, NRR antibodies failed to antagonize Notch1 receptors bearing rare "class II" or "class III" mutations, in which amino acid insertions generate a duplicated or constitutively sensitive metalloprotease cleavage site. Signaling in T-ALL cell lines bearing class I mutations is partially refractory to inhibitory antibodies as compared to cell

Clinical classification of supressed and low normal basal serum TSH concentrations in euthyroidism

International Nuclear Information System (INIS)

Seidel, C.; Ziegelitz, D.; Correns, H.J.

1981-01-01

By use of highly sensitive and accurate TSH radioimmunoassay it can be shown up that beginnung with suppressed TSH-levels in serum during increasing TSH-levels TSH response after TRH injection increases concomitantly, i.e. there is positive correlation between basal TSH and TSH response after TRH. TRH mediated TSH-increase shows positive correlation to thyroidal suppressibility with thyroid hormones. The results demonstrate the importance of a highly sensitive and accurate TSH radioimmunoassay for clinical work especially for exclusion of hyperthyroidism or thyroidal autonomy for therapeutics of goiter, prevention of reoccurring goiter and control of thyroidal suppression. (orig.) [de

Clinical classification of suppressed and low normal basal serum TSH concentrations in euthyroidism

Energy Technology Data Exchange (ETDEWEB)

Seidel, C.; Ziegelitz, D.; Correns, H.J.

1981-02-01

By use of highly sensitive and accurate TSH radioimmunoassay it can be shown that beginning with suppressed TSH-levels in serum during increasing TSH-levels TSH response after TRH injection increases concomitantly, i.e. there is positive correlation between basal TSH and TSH response after TRH. TRH mediated TSH-increase shows positive correlation to thyroidal suppressibility with thyroid hormones. The results demonstrate the importance of a highly sensitive and accurate TSH radioimmunoassay for clinical work especially for exclusion of hyperthyroidism or thyroidal autonomy for therapeutics of goiter, prevention of reoccurring goiter and control of thyroidal suppression.

Yeni bir TSH reseptör aktive edici mutasyon ile ilişkili ailevi hipertiroidi: Beş vaka takdimi

NARCIS (Netherlands)

K. Demir (Korcan); Tunç, S. (Selma); A.A.A. van Mullem (Alies); T.J. Visser (Theo)

2015-01-01

textabstractFamilial non-autoimmune hyperthyroidism, a rare disorder that results from activating germline mutations in the TSH receptor gene, is inherited in an autosomal dominant fashion and has a variable age at onset. Here, we present a family, five members of which were determined to have

Use of recombinant, human TSH radioiodine therapy in patients with differentiated thyroid carcinoma; Radioiodtherapie des differenzierten Schilddruesenkarzinoms nach Vorbehandlung mit rekombinantem, humanem TSH

Energy Technology Data Exchange (ETDEWEB)

Luster, M. [Wuerzburg Univ. (Germany). Klinik und Poliklinik fuer Nuklearmedizin

2001-12-01

We describe the use of recombinant human TSH (rhTSH) in conjunction with ablative radioiodine therapy (RIT) in 11 patients (16 total treatments) with advanced and/or recurrent DTC (5 papillary, 6 follicular) for whom withdrawal of thyroid hormone suppressive therapy (THST) to increase serum TSH was not an option. Indications for rhTSH use in these patients included inability to tolerate withdrawal of thyroid hormones due to poor physical condition or inability to achieve sufficient serum TSH levels after THST withdrawal. All patients had undergone thyroidectomy and most (9/11) had received prior radioablative therapy after THST withdrawal. In 7 cases (5 patients), post-therapy Tg levels assessed at a mean of 4.3 months (range 2-10 months) after I-131 therapy were decreased by at least 30% compared to pre-therapy levels. In an additional 3 patients, whole body scans performed at follow-up indicated decreased or stabilized tumor burden compared to pre-therapy scans or marked clinical improvement was found. Three patients died of progressive disease within 2 months of therapy before follow-up assessments occurred. No adverse events were reported among the 8 surviving patients. The results suggest that rhTSH offers a promising alternative to THST withdrawal to allow radioablative therapy under maximal TSH stimulation in patients with advanced recurrent DTC who would not otherwise be able to receive this treatment. This therapeutic indication extends the clinical potential of the new agent, already demonstrated to be effective for use with I-131 for diagnostic purposes. However in some patients suffering from highly aggressive tumors the poor prognosis will not be improved. (orig.) [German] An unserer Klinik liegen bislang Erfahrungen mit 16 Radioiodtherapien (RIT) (z.T. mehrfache Anwendung) unter rhTSH vor. Die ueberwiegende Mehrzahl der Patienten wurde wegen einer fortgeschrittenen Tumorerkrankung mit dem Risiko einer lebensbedrohlichen Verschlechterung in

Recombinant human TSH in differentiated thyroid cancer: a nuclear medicine perspective

Energy Technology Data Exchange (ETDEWEB)

Zanotti-Fregonara, P. [CEA, DSV, I2BM, SHFJ, LMNRB, Orsay (France); Rubello, D. [Osped S Maria Misericordia, IRCCS, IOV, Dept Nucl Med, PET Ctr, I-45100 Rovigo (Italy); Hindie, E. [Hop St Louis, Dept Nucl Med, Paris (France)

2008-07-01

The use of recombinant human thyroid-stimulating hormone (rhTSH) in differentiated thyroid cancer (DTC) is widely discussed in the literature with regard to the diagnostic and therapeutic aspects of the management of DTC patients. However, some controversy about the appropriate indications, advantages and potential disadvantages of the use of rhTSH may still exist within the community of nuclear medicine physicians. In our opinion, the clinical benefits of rhTSH in avoiding hypothyroidism outweigh its somewhat lesser diagnostic accuracy. However, we disagree on designating rhTSH as the 'golden standard' to obtain TSH stimulation, as suggested by some authors. Thus, the first follow-up examination after ablation, which is determinant for patients' prognostic classification, can be either done under rhTSH stimulation or after hormone withdrawal. In our practice, and for higher risk patients, we still favour performing the initial follow-up after thyroid hormone withdrawal. rhTSH also shows the ability to enhance radioiodine concentration into thyroid cells. This characteristic is obviously of great interest among the nuclear medicine community. In clinical practice, it seems preferable to perform {sup 131}I treatment for metastatic disease during hypothyroidism. rhTSH may find its utility for the treatment of specific populations of patients, i.e. those in whom hormone withdrawal is medically contraindicated or in whom adequate endogenous TSH levels cannot be obtained due to reduced pituitary reserve or continued thyroxine production by metastatic tissue. In conclusion, rhTSH has demonstrated to be a reliable alternative to hypothyroidism for the stimulation of Tg in the follow-up of thyroid cancer patients. However, its use must be more carefully chosen in the therapeutic setting. Our feeling is that rhTSH should no tbe used for remnant ablation in high-risk patients and for the treatment of metastatic disease, except for specific populations of

Recombinant human TSH in differentiated thyroid cancer: a nuclear medicine perspective

International Nuclear Information System (INIS)

Zanotti-Fregonara, P.; Rubello, D.; Hindie, E.

2008-01-01

The use of recombinant human thyroid-stimulating hormone (rhTSH) in differentiated thyroid cancer (DTC) is widely discussed in the literature with regard to the diagnostic and therapeutic aspects of the management of DTC patients. However, some controversy about the appropriate indications, advantages and potential disadvantages of the use of rhTSH may still exist within the community of nuclear medicine physicians. In our opinion, the clinical benefits of rhTSH in avoiding hypothyroidism outweigh its somewhat lesser diagnostic accuracy. However, we disagree on designating rhTSH as the 'golden standard' to obtain TSH stimulation, as suggested by some authors. Thus, the first follow-up examination after ablation, which is determinant for patients' prognostic classification, can be either done under rhTSH stimulation or after hormone withdrawal. In our practice, and for higher risk patients, we still favour performing the initial follow-up after thyroid hormone withdrawal. rhTSH also shows the ability to enhance radioiodine concentration into thyroid cells. This characteristic is obviously of great interest among the nuclear medicine community. In clinical practice, it seems preferable to perform 131 I treatment for metastatic disease during hypothyroidism. rhTSH may find its utility for the treatment of specific populations of patients, i.e. those in whom hormone withdrawal is medically contraindicated or in whom adequate endogenous TSH levels cannot be obtained due to reduced pituitary reserve or continued thyroxine production by metastatic tissue. In conclusion, rhTSH has demonstrated to be a reliable alternative to hypothyroidism for the stimulation of Tg in the follow-up of thyroid cancer patients. However, its use must be more carefully chosen in the therapeutic setting. Our feeling is that rhTSH should no tbe used for remnant ablation in high-risk patients and for the treatment of metastatic disease, except for specific populations of patients. (O.M.)

Experimental and climical investigations of a TSH radioimmunoassay

International Nuclear Information System (INIS)

Offenberger, P.

1979-01-01

The system hypothalamus-pitnitary-thyroid was studied in 427 patients by radioimmunological TSH determination prior to i.v. injection of 600 μg of synthetic TSH and 30 min p.i. Different commercial TSH test kits were used. The RIA was found to be a sensitive indicator of the functional state of the system. Higher accuracy can be achieved by observing certain criteria. The TSH-RIA is a valuable tool for diagnosis and therapy control of thyroid diseases. With some slight methodological modifications, it has become part of the routine programme of the Giessen thyroid laboratory. The RIA is best suited for early detection of disturbances in the pitnitary-thyroid system; it is less efficient in course control of thyroid diseases. It can be carried out within 30 minutes and, except for two withdrawals of blood, imposes no strain on the patient. (orig./MG) [de

Termitarium-inhabiting Bacillus endophyticus TSH42 and Bacillus cereus TSH77 colonizing Curcuma longa L.: isolation, characterization, and evaluation of their biocontrol and plant-growth-promoting activities.

Science.gov (United States)

Chauhan, Ankit Kumar; Maheshwari, Dinesh Kumar; Kim, Kangmin; Bajpai, Vivek K

2016-10-01

Bacillus strains were isolated from termitarium soil and screened for their antifungal activity through the production of diffusible and volatile metabolites. Further, the bacterial strains that showed antifungal activity were evaluated for their biocontrol potential on the basis of their plant-growth-promoting attributes. Termitarium-inhabiting Bacillus strains TSH42 and TSH77 significantly reduced the growth of pathogenic fungus Fusarium solani, controlled the symptoms of rhizome rot in turmeric (Curcuma longa L.), and demonstrated various plant-growth-promoting traits in different in vitro assays. On the basis of morphological, physiological, biochemical, and 16S rDNA characteristics, isolates TSH42 and TSH77 were identified as Bacillus endophyticus (KT379993) and Bacillus cereus (KT379994), respectively. Through liquid chromatography - mass spectrometry analysis, acidified cell-free culture filtrate (CFCF) of B. cereus TSH77 was shown to contain surfactin and fengycin, while CFCF of B. endophyticus TSH42 contained iturin in addition to surfactin and fengycin. Treatment of the turmeric (C. longa L.) plants with TSH42 and TSH77 significantly reduced the percentage incidence of rhizome rot disease caused by F. solani. The same treatment also increased the fresh rhizome biomass and plant growth in greenhouse conditions.

Ultrasensitive TSH: a new approach to hyperthyroidism diagnosis

International Nuclear Information System (INIS)

Gibold, G.; Liehn, J.C.; Deltour, G.; Delisle, M.J.

1986-01-01

The value of new ultrasensible and rapid immunoradiometric assay of thyroid stimulating hormone (TSH) for the diagnosis of hyperthyroidism was assessed in 130 patients with suspected hyperthyroidism and in 330 controls. The diagnosis was established by the clinical evaluation, thyroid scintigraphy and serum concentrations of thyroid hormones. Using the ROC (Receiver Operating Characteristic) curve methodology which allows the optimization of sensitivity and specificity, the physician can choose the Cut-off value between hyperthyroidism and euthyroidism. Two points of the curve seem to be interesting: using the cut-off value of 0.1 mUI/1, sensitivity is 0.98 and specificity is 0.98; using the cut-off value of 0.3 mUI/1, sensitivity is 1.00 and specificity is 0.92. Using the association TSH and FT4 (Free Thyroxin), sensitivity is 0.94 and specificity is 0.99. Sixty four per cent of euthyroid patients with TSH under 0.3 mUI/1 have one or several hot nodules and only two have no thyroid disease. A TRH (Thyrotrophin Releasing Hormone) test was carried out in 63 patients with suspected thyrotoxicosis: basal and TRH stimulated TSH levels were under 0.1 mUI/1. This immunoradiometric assay for TSH may simplify the approach to thyroid function testing in patients with suspected thyrotoxicosis: a basal TSH under 0.3 mUI/1 is sufficient to confirm a clinical suspicion of thyrotoxicosis without TRH test within four hours. In a department devoted to testing thyroid function, this new method provides a great benefit in cost and work [fr

Mouse Hepatitis Virus Strain A59 and Blocking Antireceptor Monoclonal Antibody Bind to the N-Terminal Domain of Cellular Receptor

Science.gov (United States)

Dveksler, Gabriela S.; Pensiero, Michael N.; Dieffenbach, Carl W.; Cardellichio, Christine B.; Basile, Alexis A.; Elia, Patrick E.; Holmes, Kathryn V.

1993-03-01

Mouse hepatitis virus (MHV) strain A59 uses as cellular receptors members of the carcinoembryonic antigen family in the immunoglobulin superfamily. Recombinant receptor proteins with deletions of whole or partial immunoglobulin domains were used to identify the regions of receptor glycoprotein recognized by virus and by antireceptor monoclonal antibody CC1, which blocks infection of murine cells. Monoclonal antibody CC1 and MHV-A59 virions bound only to recombinant proteins containing the entire first domain of MHV receptor. To determine which of the proteins could serve as functional virus receptors, receptor-negative hamster cells were transfected with recombinant deletion clones and then challenged with MHV-A59 virions. Receptor activity required the entire N-terminal domain with either the second or the fourth domain and the transmembrane and cytoplasmic domains. Recombinant proteins lacking the first domain or its C-terminal portion did not serve as viral receptors. Thus, like other virus receptors in the immunoglobulin superfamily, including CD4, poliovirus receptor, and intercellular adhesion molecule 1, the N-terminal domain of MHV receptor is recognized by the virus and the blocking monoclonal antibody.

Serum thyrotropin (TSH) levels in patients with suppressed pituitary function

International Nuclear Information System (INIS)

Vasavada, P.; Chen, I.; Maxon, H.; Barnes, E.; Sperling, M.

1984-01-01

The diagnosis of borderline hyperthyroidism is difficult. A sensitive radioimmunoassay capable of detecting subnormal levels of serum TSH may be of value in confirming this diagnosis because of the suppressed pituitary function in this disease state. This sensitive assay may also be useful in monitoring the suppression of pituitary function in thyroid cancer patients receiving thyroid hormone therapy. A sensitive radioimmunoassay capable of detecting serum TSH levels as low as 0.25 μU/m1 with coefficients of variation less than 17.2% was used to measure serum TSH levels in 80 healthy subjects, 44 hyperthyroid patients, and 25 athyrotic thyroid cancer patients on daily suppressive doses of thyroxine. All healthy subjects had detectable TSH levels with a mean value of 1.17 and two standard deviation ranges of 0.41 - 2.70 μU/m1 (lognormal distribution). Although the mean +-1 SEM value of 0.63 +- 0.003 μUm1 for hyperthyroid patients and 0.76 +- 0.08 μU/ml for thyroid cancer patients were significantly lower than that of healthy subjects (t-test, p<0.05), subnormal levels of serum TSH were found in only 28.6% (12/42) and 24% (6/25) of hyperthyroid and thyroid cancer patients, respectively. TSH stimulation tests performed in 6 of the cancer patients all gave suppressed responses. Because of considerable overlap, serum TSH levels alone cannot distinguish hyperthyroidsm from euthyroidism. However, a sensitive TSH radioimmunoassay such as the one described here may be of value in evaluating the extent of pituitary suppression in thyroid cancer therapy

Discovery of functional monoclonal antibodies targeting G-protein-coupled receptors and ion channels.

Science.gov (United States)

Wilkinson, Trevor C I

2016-06-15

The development of recombinant antibody therapeutics is a significant area of growth in the pharmaceutical industry with almost 50 approved monoclonal antibodies on the market in the US and Europe. Despite this growth, however, certain classes of important molecular targets have remained intractable to therapeutic antibodies due to complexity of the target molecules. These complex target molecules include G-protein-coupled receptors and ion channels which represent a large potential target class for therapeutic intervention with monoclonal antibodies. Although these targets have typically been addressed by small molecule approaches, the exquisite specificity of antibodies provides a significant opportunity to provide selective modulation of these target proteins. Given this opportunity, substantial effort has been applied to address the technical challenges of targeting these complex membrane proteins with monoclonal antibodies. In this review recent progress made in the strategies for discovery of functional monoclonal antibodies for these challenging membrane protein targets is addressed. © 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

Characteristics of specific immunological indicators in patients with postoperative relapse of Graves’ disease

Directory of Open Access Journals (Sweden)

Yu.V. Buldigina

2018-02-01

Full Text Available Background. Activity of autoimmune processes had a leading role in the development of relapse of hyperthyroidism. Level of thyroid-stimulating hormone (TSH receptor antibodies is a basic factor that predetermines the relapse and can be used as a criterion to evaluate its development. A research aim was to study the structural and functional state of the thyroid gland, levels of thyroid peroxidase antibodies and TSH receptor antibodies in patients with postoperative relapse of Graves’ disease during antithyroid therapy. Mate­rials and methods. The group of patients consisted of 25 wo­men aged 23 to 73 years (an average of 53.56 ± 2.31 years. The period from the first surgical treatment to the development of relapse of thyrotoxicosis ranged from 1 to 29 years and avera­ged 13.33 ± 1.66 years. Results. It was found that the le­vels of TSH receptor antibodies, which are the main factors in the pathogenesis of Graves’ disease, are not decreased on the background of drug treatment that indicates a lack of perspective of conservative therapy for the post-operative relapse of this disease. Conclusions. When the state of medication compensation for thyrotoxicosis is achieved, it is recommended to conduct the therapy with I131 or surgical treatment of the relapse of Graves’ disease.

Multiple thyrotropin β-subunit and thyrotropin receptor-related genes arose during vertebrate evolution.

Directory of Open Access Journals (Sweden)

Gersende Maugars

Full Text Available Thyroid-stimulating hormone (TSH is composed of a specific β subunit and an α subunit that is shared with the two pituitary gonadotropins. The three β subunits derive from a common ancestral gene through two genome duplications (1R and 2R that took place before the radiation of vertebrates. Analysis of genomic data from phylogenetically relevant species allowed us to identify an additional Tshβ subunit-related gene that was generated through 2R. This gene, named Tshβ2, present in cartilaginous fish, little skate and elephant shark, and in early lobe-finned fish, coelacanth and lungfish, was lost in ray-finned fish and tetrapods. The absence of a second type of TSH receptor (Tshr gene in these species suggests that both TSHs act through the same receptor. A novel Tshβ sister gene, named Tshβ3, was generated through the third genomic duplication (3R that occurred early in the teleost lineage. Tshβ3 is present in most teleost groups but was lostin tedraodontiforms. The 3R also generated a second Tshr, named Tshrb. Interestingly, the new Tshrb was translocated from its original chromosomic position after the emergence of eels and was then maintained in its new position. Tshrb was lost in tetraodontiforms and in ostariophysians including zebrafish although the latter species have two TSHs, suggesting that TSHRb may be dispensable. The tissue distribution of duplicated Tshβs and Tshrs was studied in the European eel. The endocrine thyrotropic function in the eel would be essentially mediated by the classical Tshβ and Tshra, which are mainly expressed in the pituitary and thyroid, respectively. Tshβ3 and Tshrb showed a similar distribution pattern in the brain, pituitary, ovary and adipose tissue, suggesting a possible paracrine/autocrine mode of action in these non-thyroidal tissues. Further studies will be needed to determine the binding specificity of the two receptors and how these two TSH systems are interrelated.

Time to reconsider nonsurgical therapy of benign nontoxic multinodular goitre. Focus on recombinant human TSH (rhTSH) augmented radioiodine therapy

DEFF Research Database (Denmark)

Fast, Søren; Nielsen, Viveque; Bonnema, Steen

2009-01-01

alternatives are needed. Until recently, levothyroxine therapy was the preferred non-surgical alternative, but due to low efficacy and potential side-effects, it is not recommended for routine use in recent international guidelines. Conventional radioiodine (131I)-therapy has been used for two decades......, which makes 131I-therapy less feasible. Another challenge is the negative correlation between initial goitre size and goitre volume reduction (GVR). With its ability to more than double the thyroid 131I-uptake, recombinant human TSH (rhTSH) increases the absorbed radiation dose and thus enhances the GVR...... efficacy. Thus, although in its infancy, and still experimental, rhTSH-augmented 131I-therapy may profoundly alter the nonsurgical treatment of benign non-toxic MNG....

Fetal/Neonatal Thyrotoxicosis in a Newborn From a Hypothyroid Woman With Hashimoto Thyroiditis.

Science.gov (United States)

Kiefer, Florian W; Klebermass-Schrehof, Katrin; Steiner, Manuel; Worda, Christof; Kasprian, Gregor; Diana, Tanja; Kahaly, George J; Gessl, Alois

2017-01-01

Fetal/neonatal thyrotoxicosis is a rare but potentially life-threatening condition. It is most commonly observed in poorly controlled Graves disease during pregnancy. Here we describe a fetus/newborn patient with thyrotoxicosis who was born of a woman with Hashimoto thyroiditis and levothyroxine-treated hypothyroidism. Transplacental passage of stimulating thyrotropin (TSH) receptor antibodies, which were measured by a cell-based bioassay, was the underlying mechanism of fetal/neonatal thyrotoxicosis, although the mother had no history of hyperthyroidism. Diagnosis and management of fetal hyperthyroidism can be challenging. TSH receptor antibody testing should be considered in pregnant women with any history of autoimmune thyroid disease and symptoms of fetal hyperthyroidism. Copyright © 2017 by the Endocrine Society

Drug of the year: programmed death-1 receptor/programmed death-1 ligand-1 receptor monoclonal antibodies.

Science.gov (United States)

Robert, Caroline; Soria, Jean-Charles; Eggermont, Alexander M M

2013-09-01

Programmed death-1 receptor (PD-1)/its ligand (PD-L1) antibodies have changed the landscape in oncology in 2013. The most mature results have been obtained in advanced melanoma patients. They indicate important response rates and high quality responses or prolonged duration. Also in renal cancer and in lung cancer remarkable activity has been demonstrated. Thus it is clear that these antibodies have a very broad potential and trials in many tumour types are being initiated. Breaking tolerance at the tumour site is a potent phenomenon and the potential for synergy with other checkpoint inhibitors such as ipilimumab have also been demonstrated in 2013. Long term tumour control now seems achievable and thus the concept of a clinical cure is emerging by modulation of the immune system. These antibodies bring immunotherapy to the forefront and indicate that immune-modulation will be a key component of therapeutic strategies from now on. Because of all these reasons PD-1/PD-L1 antibodies are considered 'drug of the year'. Copyright © 2013 Elsevier Ltd. All rights reserved.

Radionuclide treatment of thyrotoxicosis in children

International Nuclear Information System (INIS)

Roca, I.; Negre, M.

2007-01-01

In adult population thyrotoxicosis occurs in 2% of women and about 10% as often in men. Symptoms and signs can vary widely between patients. Diagnosis of thyrotoxicosis is based on the blood level of free thyroxine (T 4 ), thyrotropin (TSH, thyroid-simulating hormone) and the iodine uptake measured with I 131 . These diseases, including Graves' disease and functioning nodules, require long-term management. Thyrotoxicosis is relatively infrequent in the pediatric population, with a clear differentiation between sex (more frequent in girls) and age (puberty). Most pediatric patients with thyrotoxicosis have Graves' disease. In this case, the TSH receptor is stimulated by antibodies. In Graves' disease the thyroid develops a lymphocytic infiltrate as well as follicular hyperplasia. Activated T cells initiate B cell proliferation and TSH receptor antibody production. Hashimototo's disease may also result in hyperthyroidism, although in this case the excess thyroid hormone is discharged from an inflamed gland and is not the result of TSH receptor stimulation. The goal of treatment of Graves' disease are to efficiently control symptoms and restore euthyroidism. The available treatments are antithyroid drugs, radioiodine and surgery. Opinions vary as to the optimal form of therapy and not always a single treatment results in permanent euthyroidism

Thyrotropin modulates receptor-mediated processing of the atrial natriuretic peptide receptor in cultured thyroid cells

International Nuclear Information System (INIS)

Tseng, Y.L.; Burman, K.D.; Lahiri, S.; Abdelrahim, M.M.; D'Avis, J.C.; Wartofsky, L.

1991-01-01

In a prior study of atrial natriuretic peptide (ANP) binding to cultured thyroid cells, we reported that at 4 C, more than 95% of bound ANP is recovered on cell membranes, with negligible ANP internalization observed. Since ANP binding was inhibited by TSH, we have further studied TSH effects on postbinding ANP processing to determine whether this phenomenon reflects enhanced endocytosis of the ANP-receptor complex. An ANP chase study was initiated by binding [125I] ANP to thyroid cells at 4 C for 2 h, followed by incubation at 37 C. ANP processing was then traced by following 125I activity at various time intervals in three fractions: cell surface membranes, incubation medium, and inside the cells. Radioactivity released into medium represented processed ANP rather than ANP dissociated from surface membranes, since prebound [125I]ANP could not be competitively dissociated by a high concentration of ANP (1 mumol/L) at 37 C. Chase study results showed that prebound ANP quickly disappeared from cell membranes down to 34% by 30 min. Internalized ANP peaked at 10 min, with 21% of initial prebound ANP found inside the cells. At the same time, radioactivity recovered in incubation medium sharply increased between 10-30 min from 8% to 52%. Preincubation of cells with chloroquine (which blocks degradation of the ANP-receptor complex by inhibiting lysosomal hydrolase) caused a 146% increase in internalized [125I]ANP by 30 min (39% compared to 15% control), while medium radioactivity decreased from 52% to 16%, suggesting that processing of the receptor complex is mediated via lysosomal enzymes. In chase studies employing cells pretreated with chloroquine, TSH stimulated the internalization rate of ANP-receptor complex. By 30 min, TSH significantly reduced the membrane-bound ANP, and the decrease was inversely correlated to the increase in internalized radioactivity

Asp330 and Tyr331 in the C-terminal cysteine-rich region of the luteinizing hormone receptor are key residues in hormone-induced receptor activation

NARCIS (Netherlands)

M.W.P. Bruysters (Martijn); M. Verhoef-Post (Miriam); A.P.N. Themmen (Axel)

2008-01-01

textabstractThe luteinizing hormone (LH) receptor plays an essential role in male and female gonadal function. Together with the follicle-stimulating hormone (FSH) and thyroid stimulating hormone (TSH) receptors, the LH receptor forms the family of glycoprotein hormone receptors. All glycoprotein

A camelid single-domain antibody neutralizes botulinum neurotoxin A by blocking host receptor binding

Energy Technology Data Exchange (ETDEWEB)

Yao, Guorui; Lam, Kwok-ho; Weisemann, Jasmin; Peng, Lisheng; Krez, Nadja; Perry, Kay; Shoemaker, Charles B.; Dong, Min; Rummel, Andreas; Jin, Rongsheng (BCH); (Cornell); (Tufts CTSI); (UCI); (MHH)

2017-08-07

Antibody treatment is currently the only available countermeasure for botulism, a fatal illness caused by flaccid paralysis of muscles due to botulinum neurotoxin (BoNT) intoxication. Among the seven major serotypes of BoNT/A-G, BoNT/A poses the most serious threat to humans because of its high potency and long duration of action. Prior to entering neurons and blocking neurotransmitter release, BoNT/A recognizes motoneurons via a dual-receptor binding process in which it engages both the neuron surface polysialoganglioside (PSG) and synaptic vesicle glycoprotein 2 (SV2). Previously, we identified a potent neutralizing antitoxin against BoNT/A1 termed ciA-C2, derived from a camelid heavy-chain-only antibody (VHH). In this study, we demonstrate that ciA-C2 prevents BoNT/A1 intoxication by inhibiting its binding to neuronal receptor SV2. Furthermore, we determined the crystal structure of ciA-C2 in complex with the receptor-binding domain of BoNT/A1 (HCA1) at 1.68 Å resolution. The structure revealed that ciA-C2 partially occupies the SV2-binding site on H_CA1, causing direct interference of HCA1 interaction with both the N-glycan and peptide-moiety of SV2. Interestingly, this neutralization mechanism is similar to that of a monoclonal antibody in clinical trials, despite that ciA-C2 is more than 10-times smaller. Taken together, these results enlighten our understanding of BoNT/A1 interactions with its neuronal receptor, and further demonstrate that inhibiting toxin binding to the host receptor is an efficient countermeasure strategy.

Antibodies to a soluble form of a tumor necrosis factor (TNF) receptor have TNF-like activity

DEFF Research Database (Denmark)

Engelmann, H; Holtmann, H; Brakebusch, C

1990-01-01

Immunological cross-reactivity between tumor necrosis factor (TNF) binding proteins which are present in human urine (designated TBPI and TBPII) and two molecular species of the cell surface receptors for TNF is demonstrated. The two TNF receptors are shown to be immunologically distinct, to differ....... These antibodies are cytotoxic to cells which are sensitive to TNF toxicity, induce resistance to TNF toxicity, enhance the incorporation of thymidine into normal fibroblasts, inhibit the growth of chlamydiae, and induce the synthesis of prostaglandin E2. Monovalent F(ab) fragments of the polyclonal antibodies...

Hypothalamic-pituitary thyroid axis alterations in female mice with deletion of the neuromedin B receptor gene.

Science.gov (United States)

Oliveira, Karen J; Paula, Gabriela S M; Império, Guinever E; Bressane, Nina O; Magalhães, Carolina M A; Miranda-Alves, Leandro; Ortiga-Carvalho, Tania M; Pazos-Moura, Carmen C

2014-11-01

Neuromedin B, a peptide highly expressed at the pituitary, has been shown to act as autocrine/paracrine inhibitor of thyrotropin (TSH) release. Here we studied the thyroid axis of adult female mice lacking neuromedin B receptor (NBR-KO), compared to wild type (WT) littermates. They exhibited slight increase in serum TSH (18%), with normal pituitary expression of mRNA coding for α-glycoprotein subunit (Cga), but reduced TSH β-subunit mRNA (Tshb, 41%), lower intra-pituitary TSH content (24%) and increased thyroid hormone transporter MCT-8 (Slc16a2, 44%) and thyroid hormone receptor β mRNA expression (Thrb, 39%). NBR-KO mice exhibited normal thyroxine (T4) and reduced triiodothyronine (T3) (30%), with no alterations in the intra-thyroidal content of T4 and T3 or thyroid morphological changes. Hypothalamic thyrotropin-releasing hormone (TRH) mRNA (Trh) was increased (68%), concomitant with a reduction in type 2 deiodinase mRNA (Dio2, 30%) and no changes in MCT-8 and thyroid hormone receptor mRNA expression. NBR-KO mice exhibited a 56% higher increase in serum TSH in response to an acute single intraperitoneal injection of TRH concomitant with a non-significant increase in pituitary TRH receptor (Trhr) mRNA at basal state. The phenotype of female NBR-KO mice at the hypothalamus-pituitary axis revealed alterations in pituitary and hypothalamic gene expression, associated with reduced serum T3, and higher TSH response to TRH, with apparently normal thyroid morphology and hormonal production. Thus, results confirm that neuromedin B pathways are importantly involved in secretory pathways of TSH and revealed its participation in the in vivo regulation of gene expression of TSH β-subunit and pituitary MCT8 and Thrb and hypothalamic TRH and type 2 deiodinase. Copyright © 2014 Elsevier B.V. All rights reserved.

Synthetic α subunit peptide 125-147 of human nicotinic acetylcholine receptor induces antibodies to native receptor

International Nuclear Information System (INIS)

McCormick, D.J.; Griesmann, G.E.; Huang, Z.; Lennon, V.A.

1986-01-01

A synthetic peptide corresponding to residues 125-147 of the Torpedo acetylcholine receptor (AChR) α subunit proved to be a major antigenic region of the AChR. Rats inoculated with 50 μg of peptide (T α 125-147) developed T cell immunity and antibodies to native AChR and signs of experimental autoimmune myasthenia gravis. They report the synthesis and preliminary testing of a disulfide-looped peptide comprising residues 125-147 of the human AChR α subunit. Peptide H α 125-147 differs from T α 125-147 at residues 139 (Glu for Gln) and 143 (Ser for Thr). In immunoprecipitation assays, antibodies to Torpedo AChR bound 125 I-labelled Hα 125-147 antibody bound Hα 125-147, but monoclonal antibodies to an immunodominant region of native AChR bound neither Hα 125-147 nor T α 125-147. Rats immunized with H α 125-147 produced anti-mammalian muscle AChR antibodies that induced modulation of AChRs from cultured human myotubes. Thus, region 125-147 of the human AChR α subunit is extracellular in muscle, and is both antigenic and immunogenic. It remains to be determined whether or not autoantibodies to this region may in part cause the weakness or myasthenia gravis in man

Thyroid antibody-negative euthyroid Graves’ ophthalmopathy

Directory of Open Access Journals (Sweden)

Arshiya Tabasum

2016-06-01

Full Text Available TSH receptor antibodies (TRAbs are the pathological hallmark of Graves’ disease, present in nearly all patients with the disease. Euthyroid Graves’ ophthalmopathy (EGO is a well-recognized clinical entity, but its occurrence in patients with negative TRAbs is a potential source of diagnostic confusion. A 66-year-old female presented to our endocrinology clinic with right eye pain and diplopia in the absence of thyroid dysfunction. TRAbs were negative, as measured with a highly sensitive third-generation thyrotropin-binding inhibitory immunoglobulin (TBII ELISA assay. CT and MRI scans of the orbit showed asymmetrical thickening of the inferior rectus muscles but no other inflammatory or malignant orbital pathology. Graves’ ophthalmopathy (GO was diagnosed on the basis of the clinical and radiological features, and she underwent surgical recession of the inferior rectus muscle with complete resolution of the diplopia and orbital pain. She remained euthyroid over the course of follow-up but ultimately developed overt clinical and biochemical hyperthyroidism, 24 months after the initial presentation. By this time, she had developed positive TRAb as well as thyroid peroxidase antibodies. She responded to treatment with thionamides and remains euthyroid. This case highlights the potential for negative thyroid-specific autoantibodies in the presentation of EGO and underscores the variable temporal relationship between the clinical expression of thyroid dysfunction and orbital disease in the natural evolution of Graves’ disease.

Agonistic Human Monoclonal Antibodies against Death Receptor 4 (DR4) | NCI Technology Transfer Center | TTC

Science.gov (United States)

The National Cancer Institute is seeking parties interested in licensing human monoclonal antibodies (mAbs) that bind to death receptor 4 ("DR4"). The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and its functional receptors, DR4 and DR5, have been recognized as promising targets for cancer treatment.

Study on the technical parameters of two different systems of RIA performed with solid-phase antibody test tubes prepared with magnetic microparticle covalence conjagation or conventional physical absorption

International Nuclear Information System (INIS)

Chen Zhiqiang; Wang Chengmin; Tang Baojun

2007-01-01

Objective: To investigate a new method of preparation of solid-phase antibody with flurorescein isothioeynate (FITC)-anti FITC magnetic nanoparticles system (for FT 3 and TSH). Methods: FT 3 and TSH monoclonal antibody IgC was la- belied with FITC. Anti-FITC magnetic mieroparticles was prepared and conjugated with the FITC labelled antibody to form the solid - phase coated test tube for RIA. Solid-phase test tube prepared with the conventional physical absorption method was also used for RIA and the technical parameters of the two systems were compared. Results: For FT 3 , the sensitivity was 0.18pmol/L with the new method and 0.43pmol/L with the conventional method. Other parameters were; intra-CV, 8.96% vs 16.26%; inter-CV, 15.25% vs 18.83%, correlation with PR method r=0.9825 vs r=0.9102. For TSH, sensitivity was 0.061 μIU/ml vs 0.04 μ IU/ml, intra- CV, 7.6% vs 6.92%, inter-CV, 8.55% vs 14.23%, correlation between the new and conventional method, r=0. 9987. TSH RIA was especially rapid with the new technic: 79 min vs 190 min. Conclusion: For FT 3 and TSH RIA, the new method takes much less time with increased homogeniety. (authors)

Increased expression of pro-angiogenic factors and vascularization in thyroid hyperfunctioning adenomas with and without TSH receptor activating mutations.

Science.gov (United States)

Celano, Marilena; Sponziello, Marialuisa; Tallini, Giovanni; Maggisano, Valentina; Bruno, Rocco; Dima, Mariavittoria; Di Oto, Enrico; Redler, Adriano; Durante, Cosimo; Sacco, Rosario; Filetti, Sebastiano; Russo, Diego

2013-02-01

Autonomously functioning thyroid nodules (AFTN) are known to receive an increased blood influx necessary to sustain their high rate of growth and hormone production. Here, we investigated the expression of hematic and lymphatic vases in a series of 20 AFTN compared with the contralateral non-tumor tissues of the same patients, and the transcript levels of proteins involved in the control of vascular proliferation, including the vascular endothelial growth factor (VEGF) and platelet-derived growth factors (PDGF) and their receptors and the endothelial nitric oxide synthase (eNOS). In parallel, the expression of the differentiation markers sodium/iodide symporter (NIS), thyroperoxidase (TPO), thyroglobulin (Tg), and TSH receptor (TSHR) was also investigated. The data were further analyzed comparing subgroups of tumors with or without mutations in the TSHR gene. Analysis by means of CD31 and D2-40 immunostaining showed in AFTN an increased number of hematic, but not lymphatic, vessels in parallel with an enhanced proliferation rate shown by increased Ki67 staining. Quantitative RT-PCR analysis revealed an increase of VEGF, VEGFR1 and 2, PDGF-A, PDGF-B, and eNOS expression in tumor versus normal tissues. Also, higher transcript levels of NIS, TPO, and Tg were detected. Comparison of the two subgroups of samples revealed only few differences in the expression of the genes examined. In conclusion, these data demonstrate an increased expression of angiogenesis-related factors associated with an enhanced proliferation of hematic, but not lymphatic, vessels in AFTNs. In this context, the presence of TSHR mutations may only slightly influence the expression of pro-angiogenic growth factors.

Characterization of a purified nicotinic receptor from rat brain by using idiotypic and anti-idiotypic antibodies

International Nuclear Information System (INIS)

Abood, L.G.; Langone, J.J.; Bjercke, R.; Lu, X.; Banerjee, S.

1987-01-01

The availability of an anti-nicotine monoclonal antibody has made it possible to further establish the nature of the nicotine recognition proteins purified from rat brain by affinity chromatography and to provide a highly sensitive assay for determining [ 3 H]nicotine binding to the purified material. An enantiomeric analogue of nicotine. (-)-6-hydroxymethylnicotine, was used to prepare the affinity column. In addition, with the use of an anti-idiotypic monoclonal antibody, it was confirmed that the recognition site for nicotine resides on a protein complex composed of two components with molecular masses of 62 and 57 kDa. It was also demonstrated that the same two proteins could be purified by immunoaffinity chromatography with the use of an anti-idiotypic monoclonal antibody. With the use of the anti-nicotine antibody to measure [ 3 H]nicotine binding, the purified material was shown to bind 250 pmol/mg of protein. By utilizing a procedure in which the purified receptor protein was conjugated to membranes by disulfide bonds, a binding activity of 80 pmol/mg was obtained. With the availability of sterospecific monoclonal antibodies to (-)-nicotine as well as monoclonal anti-idiotypic antibodies derived when the anti-nicotine antibodies were used as immunogens, additional procedures became available for the further characterization of the purified nicotine receptor and examining its (-)-[ 3 H]nicotine-binding characteristics

MRI of the TSH (thyroid stimulating hormone) -secreting pituitary adenoma

International Nuclear Information System (INIS)

Kang, Byung Chul; Kim, Dong Ik; Chung, Tae Sup; Cho, Yong Kook; Lee, Eun Gig; Jung, Joon Keun

1995-01-01

To demonstrate and evaluate the value of MRI findings of the TSH(Thyroid-Stimulating Hormone, TSH, Thyrotropin)-secreting pituitary adenoma. The authors reviewed retrospectively the MR images of 4 patients with TSH-secreting pituitary adenoma. Evaluation of the anatomical location, signal characteristics, enhancement patterns, size, shape and circunferential changes were made. No characteristic common MR findings in size, shape, signal intensity, and circumferential changes of TSH-secreting pituitary adenoma waere observed among 4 cases (size; 5 x 7 mm to 10 x 11 mm, shape; ovoid to round signal intensity; high in 1 case on T1 and T2WI, isosignal intensity in the other 3 cases, circumferential change; stalk deviation in 1 case, no stalk deviation in 3 cases). But, the tumors were centrally located at the anterior pituitary gland and showed relatively homogeneous signal intensity on MR images of all 4 patients. We conclude that centrally-located mass at the anterior pituitary gland with homogeneous signal intensity on MR image may be suggestive of the TSH-secreting pituitary adenoma, although the MR findings are not specific for the disease

Recombinant TSH in follow-up and therapy of differentiated thyroid carcinoma

International Nuclear Information System (INIS)

Luster, M.; Reiners, C.

2000-01-01

I-131-scintigraphy and serum thyroglobulin testing - if possible under stimulation of thyrotropin - are besides physical examination and ultrasonography crucial for the optimal follow-up of patients with well-differentiated thyroid carcinoma. This required physicians to withdraw patients from thyroid hormone suppression therapy (THST) for several weeks in order to raise endogenous TSH-levels. Clinical hypothyroidism often results in substantial patient discomfort, with sometimes major psychic alterations; the subsequent disability to work is occasionally an unpleasant consequence from an economical point of view. The temporary use of bovine, and for a short period of time human TSH is obsolete today because of a high risk of allergic reactions or the potential transmission of the Creutzfeldt-Jakob disease, respectively. Lately recombinant human TSH (rhTSH, Thyrogen trademark ), a hormone that was developed with the help of genetic engineering techniques, is available; its pharmacological safety has been demonstrated in previous phase-I/II-studies. The results of a phase-III-study showed in the majority of patients a marked rise in thyroglobulin levels after rhTSH. In all cases an adequate TSH level (>100 mU/l) was achieved after i.m. injection of recombinant TSH. Wholebody-scans showed a high level of accordance (>90%) in addition to a substantially lower background-activity. A tumour-background-ratio corresponding to conventional imaging could be demonstrated. (orig.) [de

Influence of D-thyroxine on plasma thyroid hormone levels and TSH secretion

International Nuclear Information System (INIS)

Gless, K.H.; Oster, P.; Huefner, M.; Heidelberg Univ.

1977-01-01

Triiodothyronine (T 3 ), thyroxine (T 4 ), basal TSH and TSH after stimulation with TRH were determined by labelling with Iodine 127 in healthy subjects and patients treated with D-thyroxine (DT 4 ). After a dosage of 6 mg DT 4 , the D/L T 4 plasma concentration rose about 4-fold 4 hours after application and was only moderately elevated 14 hours later. To achieve constantly elevated T 4 levels, 3 mg DT 4 were applied in the further experiment every 12 hours. The D/L T 4 plasma concentration rose 2.5-4-fold, and there was a small but significant increase of the D/L T 3 plasma concentration. 74 hours after onset of treatment basal TSH was below detecable limits and the increase of TSH 30 min after injection of 200 μg TRH (TRH test) was only about 15% compared to zero time. The time course of TSH suppression was investigated after treatment with DT 4 and LT 4 (single dosage of 3 mg). TRH-tests were performed before, 10, 26, 50 and 74 hours after the first dosage of D or LT 4 . There was no difference in the time course of basal TSH and TSH stimulated by TRH. In 10 patients on DT 4 longterm therapy, basal and stimulated TSH were found to be below the detectable limits of 0.4 μg/ml. Our results show that (1) plasma half-life of DT 4 is less than 1 day, (2) TSH suppression after D and LT 4 treatment is very similar, and (3) in patients on lang-term DT 4 treatment, TSH plasma concentration is below detectable limits even after stimulation with TRH. (orig.) [de

Higher TSH Levels Within the Normal Range Are Associated With Unexplained Infertility.

Science.gov (United States)

Orouji Jokar, Tahereh; Fourman, Lindsay T; Lee, Hang; Mentzinger, Katherine; Fazeli, Pouneh K

2018-02-01

Unexplained infertility (UI), defined as the inability to conceive after 12 months of unprotected intercourse with no diagnosed cause, affects 10% to 30% of infertile couples. An improved understanding of the mechanisms underlying UI could lead to less invasive and less costly treatment strategies. Abnormalities in thyroid function and hyperprolactinemia are well-known causes of infertility, but whether thyrotropin (TSH) and prolactin levels within the normal range are associated with UI is unknown. To compare TSH and prolactin levels in women with UI and women with a normal fertility evaluation except for an azoospermic or severely oligospermic male partner. Cross-sectional study including women evaluated at a large academic health system between 1 January 2000 and 31 December 2012 with normal TSH (levels within the normal range of the assay and ≤5 mIU/L) and normal prolactin levels (≤20 ng/mL) and either UI (n = 187) or no other cause of infertility other than an azoospermic or severely oligospermic partner (n = 52). TSH and prolactin. Women with UI had significantly higher TSH levels than controls [UI: TSH 1.95 mIU/L, interquartile range: (1.54, 2.61); severe male factor: TSH 1.66 mIU/L, interquartile range: (1.25, 2.17); P = 0.003]. This finding remained significant after we controlled for age, body mass index, and smoking status. Nearly twice as many women with UI (26.9%) had a TSH ≥2.5 mIU/L compared with controls (13.5%; P < 0.05). Prolactin levels did not differ between the groups. Women with UI have higher TSH levels compared with a control population. More studies are necessary to determine whether treatment of high-normal TSH levels decreases time to conception in couples with UI. Copyright © 2017 Endocrine Society

Minimization of nonspecific binding to improve the sensitivity of a magnetic immunoradiometric assay (IRMA) for human thyrotropin (hTSH)

International Nuclear Information System (INIS)

Peroni, C.N.; Ribela, M.T.C.P.; Bartolini, P.

1996-01-01

An IRMA of hTSH, based on magnetic solid phase separation, was studied especially in terms of its nonspecific bindings (B 0 ). These were identified as a product of the interaction between radioiodinated anti-hTSH monoclonal antibody ( 125 I-mAB) and the uncoupled magnetizable cellulose particle (matrix). The negative effects of B 0 on the assay performance were minimized and practically eliminated, in the optimized system, with tracer storage at 4 deg. C, repurification and pre-incubation with the same matrix, serum addition during incubation and solid phase saturation with milk proteins. These findings were used in order to reproducibly decrease non specific binding to values 60 /B 0 ) into values of 300-500. This way, hTSH IRMAs were obtained with functional sensitivities of about 0.05 mlU/L and analytical sensitivities of the order of 0.02 mlU/L, which represent an approximate 10-fold increase in sensitivity when compared with non-optimized system. A more optimistic sensitivity calculation, based on Rodbard's definition, provided values down to 0.008 mlU/L. Such sensitivities, moreover, were obtained in a very reproducible way and all over the useful tracer life. (author). 10 refs, 1 fig., 8 tabs

Successful combination immunotherapy of anti-gamma aminobutyric acid (GABA)A receptor antibody-positive encephalitis with extensive multifocal brain lesions.

Science.gov (United States)

Fukami, Yuki; Okada, Hiroaki; Yoshida, Mari; Yamaguchi, Keiji

2017-08-31

A 78-year old woman who presented with akinetic mutism was admitted to our hospital. Brain MRI showed multifocal increased T 2 /FLAIR signal with extensive cortical-subcortical involvement. We suspected autoimmune encephalitis and the patient received methylprednisolone pulse. Her conscious level gradually recovered, but later relapsed again and presented with refractory status epilepticus. We treated her with intravenous immunoglobulin, plasma exchange and pulsed cyclophosphamide, with satisfactory response. A brain biopsy showed perivascular lymphocytic infiltrates and reactive gliosis. Anti-gamma aminobutyric acid (GABA) A receptor antibodies test came back to be positive after her recovery, and the diagnosis of anti-GABA A receptor antibody-positive encephalitis was made. This is a very rare case where brain biopsies were performed in a patient with anti-GABA A receptor antibody-positive encephalitis.

Prevalence of elevated serum anti-N-methyl-D-aspartate receptor antibody titers in patients presenting exclusively with psychiatric symptoms: a comparative follow-up study.

Science.gov (United States)

Ando, Yoshihito; Shimazaki, Haruo; Shiota, Katsutoshi; Tetsuka, Syuichi; Nakao, Koichi; Shimada, Tatsuhiro; Kurata, Kazumi; Kuroda, Jinichi; Yamashita, Akihiro; Sato, Hayato; Sato, Mamoru; Eto, Shinkichi; Onishi, Yasunori; Tanaka, Keiko; Kato, Satoshi

2016-07-08

Increasing numbers of patients with elevated anti-N-methyl-D-aspartate (NMDA) receptor antibody titers presenting exclusively with psychiatric symptoms have been reported. The aim of the present study was to clarify the prevalence of elevated serum anti-NMDA receptor antibody titers in patients with new-onset or acute exacerbations of psychiatric symptoms. In addition, the present study aimed to investigate the association between elevated anti-NMDA receptor titers and psychiatric symptoms. The present collaborative study included 59 inpatients (23 male, 36 female) presenting with new-onset or exacerbations of schizophrenia-like symptoms at involved institutions from June 2012 to March 2014. Patient information was collected using questionnaires. Anti-NMDA receptor antibody titers were measured using NMDAR NR1 and NR2B co-transfected human embryonic kidney (HEK) 293 cells as an antigen (cell-based assay). Statistical analyses were performed for each questionnaire item. The mean age of participants was 42.0 ± 13.7 years. Six cases had elevated serum anti-NMDA antibody titers (10.2 %), four cases were first onset, and two cases with disease duration >10 years presented with third and fifth recurrences. No statistically significant difference in vital signs or major symptoms was observed between antibody-positive and antibody-negative groups. However, a trend toward an increased frequency of schizophrenia-like symptoms was observed in the antibody-positive group. Serum anti-NMDA receptor antibody titers may be associated with psychiatric conditions. However, an association with specific psychiatric symptoms was not observed in the present study. Further studies are required to validate the utility of serum anti-NMDA receptor antibody titer measurements at the time of symptom onset.

Maintenance immunosuppression with intermittent intravenous IL-2 receptor antibody therapy in renal transplant recipients.

LENUS (Irish Health Repository)

Gabardi, Steven

2011-09-01

To report what we believe to be the first 2 cases of long-term (>24 months) intermittent intravenous interleukin-2 receptor antibody (IL-2RA) therapy for maintenance immunosuppression following renal transplantation.

Antibody-induced activation of the epidermal growth factor receptor tyrosine kinase requires the presence of detergent

NARCIS (Netherlands)

Spaargaren, M.; Defize, L. H.; de Laat, S. W.; Boonstra, J.

1990-01-01

Activation of the epidermal growth factor receptor (EGF-R) tyrosine kinase was investigated in membrane preparations as well as intact A431 cells, using anti-EGF-R antibodies directed against extra- and intracellular receptor domains. In vitro assay conditions were mimicked on whole cells by a mild

Clinical evaluation of the 2nd generation radio-receptor assay for anti-thyrotropin receptor antibodies (TRAb) in Graves' disease

International Nuclear Information System (INIS)

Giovanella, L.; Ceriani, L.; Garancini, S.

2002-01-01

Full text: Detection of autoantibodies to the TSH receptor by radioreceptorial assays (RRA) is largely requested in clinical practice for the diagnosis of Graves' disease and its differentiation from diffuse thyroid autonomy. Additionally, TRAb measurement during antithyroid drug treatment can be useful to evaluate the risk of disease's relapse alter therapy discontinuation. Nevertheless, some patients affected by Graves' disease are TRAb negative when 1st generation assay is used. Recently a new RRA method for TRAb assay was developed by using human recombinant TSH-receptor and solid-phase technique. Aim of our work was the comparison between 1st and 2nd generation TRAb assays in Graves' disease patients and, particularly, the evaluation of 2nd generation test in a sub-group of patients affected by Graves' disease but with negative 1st generation TRAb assay. We evaluated the diagnostic performance of a newly developed 2nd generation TRAb assay (DYNOtest(r) TRAK human, BRAHMS Diagnostica GmbH, Germany) in 46 patients affected by Graves' disease with negative 1st generation TRAb assay (TRAK Assay(r), BRAHMS Diagnostica GmbH, Germany) . A control groups of 50 Graves' disease patients with positive 1st generation TRAb assay, 50 patients affected by Hashimoto's thyroiditis and 50 patients affected by nodular goiter were also examined. 41 out of 46 patients affected by Graves' disease with negative 1st generation TRAb assay showed a positive 2nd generation test. The overall sensitivity of the 2nd generation test was significantly improved respect the 1st generation assay in Graves' disease patients (χ 2 = 22.5, p<0.0001). 1 and 3 out of 50 patients affected by Hashimoto's thyroiditis were positive by 1st and 2nd generation TRAB assay, respectively. All these patients showed primary hypothyroidism. No differences resulted in euthyroid Hashimoto's thyroiditis sub-group and in nodular goiter control group. The 2nd generation TRAB assay is clearly more sensitive than the 1

Serum TSH and the response to radioiodine treatment of toxic multinodular goitre

DEFF Research Database (Denmark)

Pedersen-Bjergaard, U; Kirkegaard, B C

1997-01-01

A retrospective analysis of data from 73 consecutive patients with toxic multinodular goitre treated with iodine-131 (131I) during a 2-year period was performed to investigate if serum TSH at the time of 131I treatment influences the outcome. The dose of 131I was calculated according to a model...... compensating for thyroid size estimated by palpation and 24-h 131I uptake. Serum TSH was determined by a third-generation assay with a functional sensitivity of 0.03 mU/l. A significantly more pronounced response to 131I treatment was observed in patients with TSH > 0.0 mU/l than in patients with TSH = 0.0 m......U/l (P = 0.0006. This difference resulted in a threefold lower frequency of non-responders and a fivefold higher rate of early hypothyroidism in the group with detectable serum TSH. While the high frequency of hypothyroidism among patients with measurable serum TSH can be explained by destruction...

Quality of life changes and clinical outcomes in thyroid cancer patients undergoing radioiodine remnant ablation (RRA) with recombinant human TSH (rhTSH): a randomized controlled study.

Science.gov (United States)

Taïeb, D; Sebag, F; Cherenko, M; Baumstarck-Barrau, K; Fortanier, C; Farman-Ara, B; De Micco, C; Vaillant, J; Thomas, S; Conte-Devolx, B; Loundou, A; Auquier, P; Henry, J F; Mundler, O

2009-07-01

Recombinant human TSH (rhTSH) has become the modality of choice for radioiodine remnant ablation (RRA) in low-risk thyroid cancer patients. The aims of the present prospective randomized study were to evaluate the impact of TSH stimulation procedure (hypothyroidism vs. rhTSH) on quality of life (QoL) of thyroid cancer patients undergoing RRA and to evaluate efficacy of both procedures. L-T4 was initiated in both groups after thyroidectomy. After randomization, L-T4 was discontinued in hypothyroid (hypo) group and continued in rhTSH group. A measure of 3.7 GBq of radioiodine was given to both groups. The functional assessment of chronic illness therapy-fatigue (FACIT-F) was administered from the early postoperative period to 9 months. Socio-demographic parameters, anxiety and depression scales were also evaluated (CES-D, BDI and Spielberger state-trait questionnaires). At 9 months, patients underwent an rhTSH stimulation test, diagnostic (131)I whole body scan (dxWBS) and neck ultrasonography. A total of 74 patients were enrolled for the study. There was a significant decrease in QoL from baseline (t0) to t1 (RRA period) in the hypothyroid group with significant differences in FACIT-F TOI (P hypothyrodism. However, there is a wide heterogeneity in the clinical impact of hypothyroidism.

Antibody guided diagnosis and therapy of brain gliomas using radiolabeled monoclonal antibodies against epidermal growth factor receptor and placental alkaline phosphatase

International Nuclear Information System (INIS)

Kalofonos, H.P.; Pawlikowska, T.R.; Hemingway, A.

1989-01-01

Twenty-seven patients with brain glioma were scanned using 123 I-labeled monoclonal antibodies against epidermal growth factor receptor (EGFR1) or placental alkaline phosphatase (H17E2). Successful localization was achieved in 18 out of 27 patients. Eleven out of 27 patients were also studied using a nonspecific control antibody (11.4.1) of the same immunoglobulin subclass and observable tumor localization was also achieved in five patients. The specificity of targeting was assessed by comparing images obtained with specific and nonspecific antibodies and by examining tumor and normal tissue biopsies after dual antibody administration. Ten patients with recurrent grade III or IV glioma who showed good localization of radiolabeled antibody were treated with 40-140 mCi of 131 I-labeled antibody delivered to the tumor area intravenously (n = 5) or by infusion into the internal carotid artery (n = 5). Six patients showed clinical improvement lasting from 6 mo to 3 yr. One patient continues in remission (3 yr after therapy), but the other five who responded initially relapsed 6-9 mo after therapy and died. No major toxicity was attributable to antibody-guided irradiation. Targeted irradiation by monoclonal antibody may be clinically useful and should be explored further in the treatment of brain gliomas resistant to conventional forms of treatment

[Clinical studies on regulatory system of thyroid hormone secretion and serum triiodothyronine. Part. I. Solid-state radioimmunoassy for human serum TSH and its clinical application (author's transl)].

Science.gov (United States)

Takeda, Y

1975-01-20

A solid-state RIA method using a plastic microtiter plate for human TSH was developed: 1) The choice of carrier protein for standard TSH was critical in this method and pooled sera from untreated Graves patients was found to be suitable for this purpose. The mean lowest detectable TSH level was 0.2 muU/assay, which was almost equal to those reported by other methods. This method is superior in simple assay procedure, especially in the separation of bound and free TSH and in the shorter incubation time required in the double antibody method. 2) Serum TSH concentration in 22 normal subjects, 17 patients with Graves' disease, 35 Hashimoto's thyroiditis, 18 primary hypothyrodism, 16 simple goiter, 4 nodular goiter and 7 secondary hypothyroidism was estimated as 4.7 +/- 2.0 muU/ml (mean +/- s.d.), 2.1 +/- 0.2 mu/U/ml, 14.1 +/- 26.5 muU/ml, 211 +/- 177 muU/ml, 3.6 +/- 2.4 muU/ml, 3.2 +/- 2.4 muU/ml and 2.6 +/- 1.0 muU/ml, respectively. 3) A statistically significant and hyperbolic inverse correlation (r= --0.37, N=90) was found between TSH and T4 levels. Some cases with normal T4 level were found to be high in TSH levels. It was also noted that 36 of 65 euthyroid cases (55.4%) who had been treated with 131I for Graves' disease showed elevated TSH levels. 4) After intravenous injection of 500 mug TRH, TSH level reached its peak value of 8 to 32 muU/ml at 15 to 45 minutes in normal subjects. Low to no response was found in patients with Graves' disease. An exaggerated response in patients with primary hypothyroidism to TRH was observed and an inhibitory process in TSH production at the pituitary level was suggested in patients with Cushing syndrome. Hypothyroid patients with pituitary lesion showed low or no response, on the other hand some hypothyroid patients with lesions around the pituitary and hypothalamus showed high basal TSH and exaggerated response to TRH.

Recombinant TSH (Thyrogen) administration to a patient with metastatic well differentiated thyroid carcinoma in whom six weeks of T-4 withdrawal led to a sub-optimal TSH response

International Nuclear Information System (INIS)

Tenorio, L.E.; Achong, D.; Bidot, P.

2002-01-01

Objectives: A 72 y.o. white man was diagnosed with follicular thyroid carcinoma in 1991. He was partially treated with partial thyroidectomy. Pulmonary nodules evident on Radiograph were explained to the patient as 'benign in nature'. No I-131 therapy or follow up was scheduled. Seven years later, the pulmonary nodules proved to be metastatic thyroid carcinoma. Endogenous TSH levels failed to raise following T-4 withdrawal, most likely secondary to endogenous production of T-4 by metastatic cancer. Recombinant TSH (Thyrogen) stimulation before I-131 therapy was considered to improve I-131 tumor uptake. Materials and method: In an emergency room visit in June 1997 for an unrelated condition, a chest X-rays detected pulmonary nodules. He had no dyspnea, no hemoptysis, and no chest pain. CT guided biopsy demonstrated metastatic thyroid carcinoma. Pleural fluid was positive for presence of Thyroglobulin. Left hemi-thyroidectomy was performed on September 1997. His TSH was 14 mIU/mL six weeks after T-4 withdrawal. Serum thyroglobulin (sTG) level was 10100 ng/mL on 10/20/97 (Nl. less than 0.5 mIU/mL), Antithyroglobulin antibody test was negative. A Thallium-201 whole body scan demonstrated mild pulmonary uptake similar to the chest X-Rays findings (the lesser the Tl-210 uptake by the tumor, the better the response to I-131). The patient was enrolled in a compassionate use protocol for Thyrogen. Thyrogen 0.9 mg q/24h was administered. Results: The TSH after each dose of Thyrogen was > 100 mIU/mL. 199.7 mCi of I-131 were administered orally. A post therapy whole body scan (WBS) demonstrated multiple functional metastases in both lungs, some of them not shown in the previous Tl-201 scan. His sTG dropped to 2515 ng/mL on 1/29/1998, and a CT demonstrated reduction in size of the pulmonary nodules. A Tl-201 WBS dated 6/1/98 showed uptake in the left hilar region, with poor uptake in previously positive Tl-201 nodules. However, follow up Tl-201 demonstrated progressive

Functional characteristics of three new germline mutations of the thyrotropin receptor gene causing autosomal dominant toxic thyroid hyperplasia

Energy Technology Data Exchange (ETDEWEB)

Tonacchera, M.; Van Sande, J.; Cetani, F. [Universite Libre de Bruxelles, Brussels (Belgium)] [and others

1996-02-01

We report three unrelated families in which hyperthyroidism associated with thyroid hyperplasia was transmitted in an autosomal dominant fashion, in the absence of signs of autoimmunity. Exon 10 of the TSH receptor gene was directly sequenced after PCR amplification from DNA of peripheral leukocytes. In one family, a C to A transversion resulted in an S505R substitution in the third transmembrane segment; in the second, an A to T transversion caused an N650Y substitution in the sixth transmembrane segment; and in the third family, an A to G transition resulted in an N670S substitution in the seventh transmembrane segment. When expressed by transfection in COS-7 cells, each mutated receptor displayed an increase in constitutive stimulation of cAMP production; no effect on basal accumulation of inositol phosphates (IP) could be detected. In binding studies, cells transfected with wild-type of mutated receptors showed similar levels of expression, with the mutated receptors displaying similar or slightly increased affinity for bovine TSH (bTSH) binding. Cells transfected with S505R and N650Y mutants showed a similar cAMP maximal TSH-stimulated accumulation over the cells transfected with the wild type, whereas N670S transfectants showed a blunted response with an increase in EC{sub 50}. A higher IP response to 100 mU/mL bTSH over that obtained with the wild-type receptor was obtained in cells transfected with N650Y; in contrast, cells transfected with S505R showed a blunted IP production (50% less), and the N670S mutant completely lost the ability to stimulate IP accumulation in response to bTSH. The differential effects of individual mutations on stimulation by bTSH of cAMP or IP accumulation suggest that individual mutant receptors may achieve different active conformations with selective abilities to couple to G{sub s}{alpha} and to G{sub q}{alpha}. 17 refs., 8 figs.

Re-engineering therapeutic antibodies for Alzheimer's disease as blood-brain barrier penetrating bi-specific antibodies.

Science.gov (United States)

Pardridge, William M

2016-12-01

Therapeutic antibodies are large molecule drugs that do not cross the blood-brain barrier (BBB). Therefore, drug development of therapeutic antibodies for Alzheimer's disease (AD) requires that these molecules be re-engineered to enable BBB delivery. This is possible by joining the therapeutic antibody with a transporter antibody, resulting in the engineering of a BBB-penetrating bispecific antibody (BSA). Areas covered: The manuscript covers transporter antibodies that cross the BBB via receptor-mediated transport systems on the BBB, such as the insulin receptor or transferrin receptor. Furthermore, it highlights therapeutic antibodies for AD that target the Abeta amyloid peptide, beta secretase-1, or the metabotropic glutamate receptor-1. BSAs are comprised of both the transporter antibody and the therapeutic antibody, as well as IgG constant region, which can induce immune tolerance or trigger transport via Fc receptors. Expert opinion: Multiple types of BSA molecular designs have been used to engineer BBB-penetrating BSAs, which differ in valency and spatial orientation of the transporter and therapeutic domains of the BSA. The plasma pharmacokinetics and dosing regimens of BSAs differ from that of conventional therapeutic antibodies. BBB-penetrating BSAs may be engineered in the future as new treatments of AD, as well as other neural disorders.

[Monosymptomatic hyperthyroidism and TSH-producing adenoma: successful therapy with octreotide].

Science.gov (United States)

Mayinger, B; Axelos, D; Pavel, M; Hahn, E G; Hensen, J

1999-01-29

Magnetic resonance imaging (MRI) of the central nervous system was performed on a 72-year-old woman who was hyperthyroid without suppression of the thyroid-stimulating hormone (TSH) and had complained of a recent onset of headaches. MRI demonstrated a space-occupying lesion, 1 cm in diameter, in the anterior pituitary. The clinical symptoms were marked by a long-standing monosymptomatic illness of rapidly changing mood swings with depressive and manic phases. Endocrinological-biochemical tests showed hyperthyroidism (fT3 10.55 pmol/l and fT4 39 pmol/l) but no TSH suppression (TSH: 2.9 microU/ml). Octreotide scintigraphy documented an activity-rich area in the anterior pituitary and the upper anterior mediastinum. Mediastinal MRI revealed a 5 cm space-occupying mass lying on the right atrium. 131I scintigraphy identified the mass as a retrosternal goitre. As an operation on the anterior pituitary would have carried a high risk for the patient who was in a poor general condition and she had refused to be operated, treatment with octreotide, a long-acting somatostatin analogue, was initiated. This achieved a euthyroid state with partly suppressed TSH, and the patient's emotional swings ceased. If hyperthyroidism coexists with non-suppressed TSH levels, a TSH-producing hypophyseal adenoma should be considered in the differential diagnosis despite its rarity. Octreotide administration is an effective and safe treatment and is the method of choice, especially when there are contraindications to surgical resection of the anterior pituitary.

Assessment of basal and stimulated TSH in the diagnosis of overt and subclinical hyperthyroidism

International Nuclear Information System (INIS)

Reinhardt, M.; Schuemichen, C.; Schaechtele, S.; Zimmerlin, M.; Moser, E.

1995-01-01

A TRH test was performed in 171 consecutive patients with a TSH basal below the reference range. TSH basal , TSH stimulated and ΔTSH were determined and compared, using assays of the second and third generation. Free thyroid hormones were elevated in 48 and normal in 123 patients. The sensitivity of all evaluated parameters to assess overt hyperthyroidism was between 94 and 98% with both assays, using a defined TSH threshold (mean of patients with overt hyperthyroidism + 2 standard deviations). However, specificity was much lower, only 34 and 23%, respectively, for the TSH basal . Significant improvement followed TRH-testing: specificity rose to 63 and 57%. The superior reproducibility of TSH values in the lower range, using the third generation assays, was of little value in the differentiation between subclinical and overt hyperthyroidism. (orig.) [de

Congenital hypothyroidism screening in term neonates using umbilical cord blood TSH values

Directory of Open Access Journals (Sweden)

Ravi Bhatia

2018-01-01

Full Text Available Congenital hypothyroidism remains one of the most common preventable causes of mental retardation among children. Screening for congenital hypothyroidism remains one of the most cost-effective tools to prevent mental retardation in the population. Umbilical cord blood thyroid-stimulating hormone (TSH levels remain an attractive and a practical step for screening for congenital hypothyroidism. The aims of this study were as follows: (1 to find normative values of cord blood TSH for the study group and (2 to use cord blood TSH levels as a marker for screening of congenital hypothyroidism. Cord blood of 1824 neonates who were of term gestation, weighed >2.5 kg at birth, whose mothers were off thyroid medication were a part of the study group. Umbilical cord blood was collected at the time of delivery and TSH was estimated. All babies who had a cord blood TSH value of >20 mIU/L were called bay on day 7 of life for a full thyroid profile. Cord blood samples of 1824 neonates were tested for TSH. Male–female ratio was 979:845 = 1.15:1. The birth weights ranged between 2.5 and 4.5 kg with an average birth weight of 2.811 kg. Mean (standard deviation TSH value was 7.725 (8.99. TSH values ranged between 1.2 and 100 mIU/ml. TSH values corresponding to the 3rd, 10th, 25th, 50th, 90th, 95th, and 97th percentile were 2.32, 4.05, 5.67, 7.5, 12, 20.63, and 30.88, respectively. Out of the 88 babies recalled for repeat testing, 80 babies only turned up; eventually one turned out to be hypothyroid on repeat testing. The incidence of congenital hypothyroidism in our study was 1 in 1824. To conclude, we can safely use a cutoff of cord blood TSH value of >20 mIU/L for the purpose of screening for congenital hypothyroidism. For logistic angles, a higher cutoff of >30 mIU/L can be used. Large population-based studies are required to establish normative values for cord blood TSH in our country.

The Changes of Serum TSH in Various States of Thyroid Function

International Nuclear Information System (INIS)

Ro, Heung Kyu

1975-01-01

The serum concentrations of thyrotropin (TSH) were measured by means of radioimmunoassay, in 98 cases of normal controls, 51 cases of hyperthyroidism, 80 cases of primary hypothyroidism and 4 cases of secondary hypothyroidism to evaluate the diagnostic significance in various functional states of the thyroid. The obtained data were analyzed in correlation with other thyroid function test values in various phases of the functional thyroid diseases. The results were as follows: 1) The serum TSH concentration in normal control group was (1.3-8.0 μU/ml). 2) The measurement of serum TSH was more significant in diagnostic accuracy compared with that of serum T 4 (75.0±12.2%). Free T-4 Index (64.2±15.2%), serum T 3 (41.0±21.0%) or T 3 resin uptake (41.1±15.8%) in evaluation of primary hypothyroidism. 3) In case of overt hypothyroidism, the serum TSH and T 4 were both abnormal, compatible with the clinical diagnosis, while in case of preclinical or mild hypothyroidism, the serum T 4 (41.2±23.8% or 50.0±25.0%) was much less reliable than serum TSH. 4) In the treatment of primary hypothyroidism with desiccated thyroid, the administration of 1 grain of the hormone per day was sufficient to suppress the serum concentration of TSH to normal range. It showed that the measurement of serum TSH concentration was a significant criteria in evaluating the efficiency of the treatment of hypothyroidism. 5) The measurement of serum TSH concentration is a very significant method in the early detection of hypothyroidism induced during or after the treatment of the hyperthyroidism with antithyroid drugs or radioactive Iodine ( 131 I).

The Anti-Acetylcholine Receptor Antibody Test in Suspected Ocular Myasthenia Gravis

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Jung Jin Lee

2014-01-01

Full Text Available Aim. To estimate the clinical significance of anti-acetylcholine receptor antibody (anti-AChR-Ab levels in suspected ocular myasthenia gravis. Methods. In total, 144 patients complaining of fluctuating diplopia and ptosis were evaluated for serum levels of anti-acetylcholine receptor antibody and their medical charts were retrospectively reviewed. Subjects were classified into three groups: variable diplopia only, ptosis only, and both variable diplopia and ptosis. We investigated serum anti-AChR-Ab titer levels and performed thyroid autoantibody tests. Results. Patients’ chief complaints were diplopia (N=103, ptosis (N=12, and their concurrence (N=29. Abnormal anti-AChR-Ab was observed in 21 of 144 patients (14.1%. Between the three groups, mean age, number of seropositive patients, and mean anti-AChR-Ab level were not significantly different (P=0.224, 0.073, and 0.062, resp.. Overall, 27.5% of patients had abnormal thyroid autoantibodies. Conclusion. The sensitivity of anti-AChR-Ab was 14.1% in suspected ocular myasthenia gravis and seropositivity in myasthenia gravis patients showed a high correlation with the presence of thyroid autoantibodies.

Immunodetection of Luteinizing Hormone (LH, Follicle-Stimulating Hormone (FSH, Thyroid Stimulating Hormone (TSH and Prolactin (PRL in Brachionus calyciflorus (Rotifera: Monogononta

Directory of Open Access Journals (Sweden)

Jesús Alvarado-Flores

2009-12-01

Full Text Available The endocrine system controls and coordinates behavioral, biochemical, and physiological processes through signal mechanisms using neuropeptides or products of neurosecretory cells. Among invertebrates, this system is poorly studied in rotifers, in which estrogens and androgens significantly affect sexual reproduction. This is the first report of the presence of the Luteinizing Hormone (LH, Follicle-Stimulating Hormone (FSH, Thyroid Stimulating Hormone (TSH and Prolactin (PRL in rotifers. Analyses included the avidin-biotin-peroxidase complex method with primary antibodies LH (Anti-Rat LH serum for RIA, PRL (Anti-Rat PRL serum for RIA, FSH (Anti-Rat FSH serum for RIA and TSH (Anti-Rat TSH serum for RIA. These hormones were found in females, males and parthenogenetic and sexual eggs of the freshwater Brachionus calyciflorus. The immunoreactivity of FSH, LH, TSH and PRL in females was observed in: ovaries, cerebrum, mastax, stomach, lorica, and the stomach gland. However, in males LH was observed only at the trochal disk and cerebrum. The hormones FSH, TSH and PRL, were observed in testicles, contractil vesicles, and cementary gland of males. Regarding amictic or parthenogenetic eggs, the hormones LH, FSH, TSH, and PRL were located mainly in the micromeres, and the staining in the macromeres was weak. On the other hand, in the mictic or sexual eggs the inner shell is stained for the hormones PRL and LH, opposite to the staining of FSH and TSH, located mainly in the embryo. In general, immuno-reactivity was observed in areas important for the reproductive, excretory, digestive and developmental processes. Rev. Biol. Trop. 57 (4: 1049-1058. Epub 2009 December 01.Se logró detectar la presencia de las hormonas: Hormona Luteinizante (LH, Hormona Folículo Estimulante (FSH, Hormona Estimulante de la Tiroides (TSH y Prolactina (PRL en Brachionus calyciflorus siendo el primer reporte de la presencia de dichas hormonas en rotíferos. Estas hormonas fueron

Hashimoto's thyroiditis following Graves' disease.

Science.gov (United States)

Umar, Husaini; Muallima, Nur; Adam, John M F; Sanusi, Harsinen

2010-01-01

Both Graves' disease and chronic thyroiditis (Hashimoto's thyroiditis) are autoimmune diseases of thyroid gland. Graves' disease is caused by stimulation of TSH receptor located on the thyroid gland by an antibody, which is known as TSH receptor antibody (TRAb). Furthermore, this may lead to hyperplasia and hyperfunction of the thyroid gland. On the contrary, the cause of Hashimoto's thyroiditis is thought due to a TSH stimulation-blocking antibody (TSBAb) which blocks the action of TSH hormone and subsequently brings damage and atrophy to thyroid gland. Approximately 15-20% of patients with Graves' disease had been reported to have spontaneous hypothyroidism resulting from the chronic thyroiditis (Hashimoto's disease). Pathogenesis for chronic thyroiditis following anti-thyroid drug treatment in patients with Graves' disease remains unclear. It has been estimated that chronic thyroiditis or Hashimoto's disease, which occurs following the Graves' disease episode is due to extended immune response in Graves' disease. It includes the immune response to endogenous thyroid antigens, i.e. thyroid peroxidase and thyroglobulin, which may enhance lymphocyte infiltration and finally causes Hashimoto's thyroiditis. We report four cases of chronic thyroiditis (Hashimoto's disease) in patients who have been previously diagnosed with Graves' hyperthyroidism. In three cases, Hashimoto's thyroiditis occurs in 7 to 25 years after the treatment of Grave's disease; while the other case has it only after few months of Grave's disease treatment. The diagnosis of Hashimoto's disease (chronic thyroiditis) was based on clinical manifestation, high TSHs level, positive thyroid peroxidase antibody and thyroglobulin antibody, and supported by positive results of fine needle aspiration biopsy. Moreover, the result of histopathological test has also confirmed the diagnosis in two cases. All cases have been successfully treated by levothyroxine treatment.

Relationship Among Pulmonary Hypertension, Autoimmunity, Thyroid Hormones and Dyspnea in Patients With Hyperthyroidism.

Science.gov (United States)

Zuhur, Sayid Shafi; Baykiz, Derya; Kara, Sonat Pinar; Sahin, Ertan; Kuzu, Idris; Elbuken, Gulsah

2017-04-01

Previous studies have reported conflicting results regarding the mechanisms underlying the pathophysiology of pulmonary hypertension (PHT) in patients with hyperthyroidism. Therefore, in this study, we investigated the association between PHT and thyroid-stimulating hormone (TSH) receptor antibody, thyroid peroxidase antibody, thyroglobulin antibody, TSH, fT3, fT4 and dyspnea during daily activities in a large population of patients with hyperthyroidism. A total of 129 consecutive patients with hyperthyroidism, 37 with hypothyroidism and 38 euthyroid controls were enrolled in this study. The modified medical research council scale was used for the assessment of dyspnea in daily activities. All the patients and euthyroid controls underwent transthoracic echocardiography for the assessment of PHT. Mild PHT was present in 35%, 36%, 13.5% and 5% of the patients with Graves׳ disease, toxic multinodular goiter, hypothyroidism and euthyroid controls, respectively. Pulmonary vascular resistance (PVR) was higher in hyperthyroid patients with PHT than in those without PHT. Moreover, a significant positive correlation was found between modified medical research council scale and pulmonary artery systolic pressure as well as PVR in patients with hyperthyroidism. No association was found between PHT and serum TSH receptor antibody, thyroid peroxidase antibody, thyroglobulin antibody, TSH, fT3 and fT4 levels. Mild PHT is present in a significant proportion of patients with hyperthyroidism, regardless of etiology. PVR appears to be the main cause of PHT in patients with hyperthyroidism, and neither autoimmunity nor thyroid hormones are associated with PHT in these patients. Mild dyspnea during daily activities in patients with hyperthyroidism may be related to PHT; however, severe dyspnea requires further evaluation. Copyright © 2017 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.

Radioreceptor assay for TBII in the spectrum of thyroid stimulating immunoglobulins

Energy Technology Data Exchange (ETDEWEB)

Bliddal, H.

1986-01-01

Thyroid stimulating immunoglobulins have been measured by several different methods among which the radioreceptor assay for TBII has been mostly employed. This technique is review in detail and it is concluded that the present method has the advantage of a larger stability aquired by the use of a purified plasma membrane fraction produced from autopsy material. TBII has been found in 60 to 80 percent in untreated Graves' disease while the percentage of positive patients decreases after any kind of treatment. Thus, TBII descreases during long term antithyroid treatment and by the end of such treatment TBII has a certain prognostic value. In the present study TBII was correlated to several other methods of measurement, primarily with the thyroid adenylate cyclase stimulating antibodies. In Graves's disease a general correlation was found with significant differences in TBII and TSAb activity in some cases. In contrast, a dissociation between two tests was often found in Hashimoto's thyroiditis and several other diseases with a low occurence of these antibodies, e.g. IDDM. Based on the present results it is concluded that thyroid stimulating immunoglobulins are heterogenous and probably polyclonal antibodies directed against several different epitopes on the TSH receptor with different affinity for the binding side of TSH. An activation in vitro by adenylate cyclase is apparently possible by-passing this binding side, and in some sera antibodies have been described which block the adenylate cyclase in vitro without affecting the binding of TSH. It is concluded that these antibodies are a major factor in the pathogenesis of thyrotoxicosis in Graves' disease, while differences in expression and affinity of antibodies against the TSH receptor may explain the lack of clinical correlation in other diseases. 193 refs.

Ultrasensitive human thyrotropin (h TSH) immunoradiometric assay (IRMA) set up, through identification and minimization of non specific bindings; Ensaio imunoradiometrico ultra-sensivel de tireotrofina humana (hTSH) obtido mediante a identificacao e minimizacao de ligacoes inespecificas

Energy Technology Data Exchange (ETDEWEB)

Peroni, C N

1994-12-31

An IRMA of h TSH, based on magnetic solid phase separation, was studied especially for what concerns its non specific bindings. These were identified as a product of the interaction between an altered form of radioiodinated anti-h TSH monoclonal antibody ({sup 125} I-m AB) and the uncoupled magnetizable cellulose particle (matrix). Apparently this form of {sup 125} I-m AB is a type of aggregate that can be partly resolved from the main peak on Sephadex G-200 and further minimized via a single pre-incubation with the same matrix. Solid phase saturation with milk proteins, tracer storage at 4{sup 0} C and serum addition during incubation were also found particularly effective is preventing its formation. These findings were used in order to reproducibly decrease non specific bindings to values <0.1% (or <70 cpm), increasing thus the signal-to-noise ratio (B{sub 60}/B{sub O}) up to values of 300-500. This way we obtained h TSH radio assays with functional sensitivities of about 0.05 m IU/L and analytical sensitivities of the order of 0.02 m IU/L, which classify them at least as among the best second generation assays and that are excellent indeed for magnetic IRMA s. A more optimistic sensitivity calculation, based on Rodbard`s definition, provided values down to 0.008 m IU/L. Such sensitivities, moreover, were obtained in a very reproducible way and all over the useful tracer life. (author). 83 refs, 13 figs, 25 tabs.

Clinical value of determination of TSH-binding inhibiting immunoglobulins (TBII) by a radioreceptor assay

International Nuclear Information System (INIS)

Heberling, H.J.; Bierwolf, B.; Lohmann, D.

1986-01-01

The clinical value of a commercial kit for determination of TBII was evaluated. 50 patients with untreated Graves' disease, 21 patients with Graves' disease before and during medical therapy, 18 patients after finishing medical therapy and 10 patients after surgical treatment were examined. Besides these, 41 patients with other thyroid diseases and 36 patients without any thyroid disorder were included. In 47 (94%) of 50 patients with untreated Graves' disease TBII were detectable in serum using a TSH standard curve. Binding activities exceeding 10 U/l TSH equivalents were regarded as positive. In other thyroid diseases TBII were negative with the exception of 3 of 22 patient with autonomously functioning thyroid nodules. After 12 months of antithyroid drug treatment of 19 patients the incidence of positive antibody findings was 26%. During follow-up after medical therapy (1-9 years) 7 of 18 patients had increased TBII in correlation with clinical and functional findings. The determination of TBII by TRAK assay proved to be a sensitive and specific method. The assay can be used to differentiate between hyperthyroidism of autoimmune or non-immunogenic origin. Thus the method seems to be helpful for the follow-up under medical treatment of patients with Graves' disease. (author)

Antibodies Against Hypocretin Receptor 2 Are Rare in Narcolepsy.

Science.gov (United States)

Giannoccaro, Maria Pia; Waters, Patrick; Pizza, Fabio; Liguori, Rocco; Plazzi, Giuseppe; Vincent, Angela

2017-02-01

Recently, antibodies to the hypocretin receptor 2 (HCRTR2-Abs) were reported in a high proportion of narcolepsy patients who developed the disease following Pandemrix® vaccination. We tested a group of narcolepsy patients for the HCRTR2-Abs using a newly established cell-based assay. Sera from 50 narcolepsy type 1 (NT1) and 11 narcolepsy type 2 (NT2) patients, 22 patients with other sleep disorders, 15 healthy controls, and 93 disease controls were studied. Cerebrospinal fluid (CSFs) from three narcoleptic patients were subsequently included. Human embryonic kidney cells were transiently transfected with human HCRTR2, incubated with patients' sera for 1 hr at 1:20 dilution and then fixed. Binding of antibodies was detected by fluorescently labeled secondary antibodies to human immunoglobulin G (IgG) and the different IgG subclasses. A nonlinear visual scoring system was used from 0 to 4; samples scoring ≥1 were considered positive. Only 3 (5%) of 61 patients showed a score ≥1, one with IgG1- and two with IgG3-antibodies, but titers were low (1:40-1:100). CSFs from these patients were negative. The three positive patients included one NT1 case with associated psychotic features, one NT2 patient, and an NT1 patient with normal hypocretin CSF levels. Low levels of IgG1 or IgG3 antibodies against HCRTR2 were found in 3 of 61 patients with narcolepsy, although only 1 presented with full-blown NT1. HCRTR2-Abs are not common in narcolepsy unrelated to vaccination. © Sleep Research Society 2016. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.

Evaluation of Commercial TSH Immunoassay in Indonesia

International Nuclear Information System (INIS)

Darlina

1998-01-01

An evaluation and comparison of the performance of a number of commercially available TSH kits in Indonesia have been made to guide the potential users in selecting the methods and kits most suitable for their intended purpose. The kits selected for this study comprise a wide variety of immunology methodology; magnetic RIA (Amerlex-M, Amersham), IRMA coated well (Amerwell, Amersham), IRMA coated tube (DPC), microcellulose particle IRMA (Netria), and ELIA (Amerlite, Amersham). The parameters of performance evaluated are: detection limit, working range, recovery, within and between assay precision, and the capability to distinguish hypothyroid, normal and hyperthyroid subjects. Reasonable detection limits are found with all IRMA kits ( 500 mIU/L) while magnetic RIA the narrowest (3-110 mIU/L). In term of the precision, magnetic RIA and ELIA have the best value, <10% for between assay and <8% for within assay, however all other methods also have sufficiently good precision (<15% and 10% respectively for between assay and within assay). All methods have the capability to identify hypothyroid, normal, and hyperthyroid subjects except for magnetic RIA which does not clearly distinguish between normal and hyperthyroid subject. Reasonably good recovery (90% - 120%) was obtained with all methods, except for magnetic RIA with only 81% recovery. It can be concluded that except magnetic RIA, all methods evaluated give useful and reliable results for measuring very low to very high concentration without dilution of sample. Magnetic RIA TSH gives meaningful results only for normal and high TSH concentration with necessary dilution for very high TSH concentration

Prevalence of normal TSH value among patients with autonomously functioning thyroid nodule.

Science.gov (United States)

Treglia, Giorgio; Trimboli, Pierpaolo; Verburg, Frederik A; Luster, Markus; Giovanella, Luca

2015-07-01

International guidelines significantly diverge on the effectiveness of thyroid scintigraphy (TS) in the initial work-up of thyroid nodules. In particular, the role of TS to detect or exclude the presence of autonomously functioning thyroid nodules (AFTN) in patients with normal serum thyrotropin (TSH) is still a matter to debate. Here, we aimed to review the literature on the prevalence of normal TSH value among patients with AFTN and meta-analyse data of the retrieved eligible papers. A comprehensive literature search of studies published from January 2000 to December 2014 on AFTN detected by TS was performed. Records reporting serum TSH values in AFTN were selected. Pooled prevalence of AFTN with normal TSH values was calculated on a per-patient analysis including 95% confidence intervals (95% CI). Eight records including 2761 AFTN were selected for the meta-analysis. Pooled prevalence of AFTN with normal TSH detected by TS was 50% (95% CI: 32-68%). Selection bias in the included studies and heterogeneity among studies were potential limitations of the meta-analysis. Present meta-analysis shows that about one in two patients with AFTN demonstrated by TS has a TSH value within normal references. As a consequence, TSH measurement may not be considered as effective as a single tool to detect or exclude AFTN, and TS remains mandatory. © 2015 Stichting European Society for Clinical Investigation Journal Foundation.

Differences in human skin between the epidermal growth factor receptor distribution detected by EGF binding and monoclonal antibody recognition

DEFF Research Database (Denmark)

Green, M R; Couchman, J R

1985-01-01

, the eccrine sweat glands, capillary system, and the hair follicle outer root sheath, generally similar in pattern to that previously reported for full-thickness rat skin and human epidermis. The same areas also bound EGF-R1 but in addition the monoclonal antibody recognized a cone of melanin containing......Two methods have been used to examine epidermal growth factor (EGF) receptor distribution in human scalp and foreskin. The first employed [125I]EGF viable explants and autoradiography to determine the EGF binding pattern while the second used a monoclonal antibody to the human EGF receptor to map...... whether EGF-R1 could recognize molecules unrelated to the EGF receptor, the EGF binding and EGF-R1 recognition profiles were compared on cultures of SVK14 cells, a SV40 transformed human keratinocyte cell line. EGF binding and EGF-R1 monoclonal antibody distribution on these cells was found to be similar...

A case of late-onset, thymoma-associated myasthenia gravis with ryanodine receptor and titin antibodies and concomitant granulomatous myositis.

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Stefanou, M I; Komorowski, L; Kade, S; Bornemann, A; Ziemann, U; Synofzik, M

2016-09-13

Myasthenia gravis is an autoimmune neuromuscular disorder, which has only rarely been reported to co-manifest with myositis. The diagnosis of concomitant myositis in patients with myasthenia gravis is clinically challenging, and requires targeted investigations for the differential diagnosis, including EMG, autoantibody assays, muscle biopsy and, importantly, imaging of the mediastinum for thymoma screening. This report presents a case-vignette of a 72-year-old woman with progressive proximal muscle weakness and myalgias, diagnosed with thymoma-associated myasthenia and bioptically verified granulomatous myositis, with positive autoantibody status for ryanodine receptor and titin antibodies. The diagnosis of concurrent myositis and myasthenia gravis, especially in the presence of ryanodine receptor and titin antibodies, should lead neurologists to adopt different treatment strategies compared to those applied in myasthenia or myositis alone. Moreover, further evidence is warranted that titin and, particularly, ryanodine receptor antibodies may co-occur or be pathophysiologically involved in myasthenia-myositis cases.

Antibody guided irradiation of brain glioma by arterial infusion of radioactive monoclonal antibody against epidermal growth factor receptor and blood group A antigen

Energy Technology Data Exchange (ETDEWEB)

Epenetos, A.A.; Courtenay-Luck, N.; Pickering, D.; Hooker, G.; Lavender, J.P.; McKenzie, C.G. (Hammersmith Hospital, London (UK)); Durbin, H. (Imperial Cancer Research Fund, London (UK). Labs.)

1985-05-18

In a patient with recurrent grade IV glioma of the brain resistant to conventional treatment an antibody guided isotopic scan showed uptake by the tumour of a monoclonal antibody (9A) that was developed against epidermal growth factor receptor but cross reacted with blood group A antigen. As a therapeutic attempt antibody labelled with 1665 MBq (45.0 mCi) iodine-131 was delivered to the tumour area by infusion into the internal carotid artery. Computed tomography showed regression of the tumour after treatment, and an appreciable and sustained clinical improvement was noted without any toxicity. Delivery of irradiation guided by monoclonal antibody delivered by arterial infusion of the tumour area may be of clinical value in the treatment of brain gliomas resistant to conventional forms of treatment.

Synthetic. cap alpha. subunit peptide 125-147 of human nicotinic acetylcholine receptor induces antibodies to native receptor

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McCormick, D.J.; Griesmann, G.E.; Huang, Z.; Lennon, V.A.

1986-03-05

A synthetic peptide corresponding to residues 125-147 of the Torpedo acetylcholine receptor (AChR) ..cap alpha.. subunit proved to be a major antigenic region of the AChR. Rats inoculated with 50 ..mu..g of peptide (T ..cap alpha.. 125-147) developed T cell immunity and antibodies to native AChR and signs of experimental autoimmune myasthenia gravis. They report the synthesis and preliminary testing of a disulfide-looped peptide comprising residues 125-147 of the human AChR ..cap alpha.. subunit. Peptide H ..cap alpha.. 125-147 differs from T ..cap alpha.. 125-147 at residues 139 (Glu for Gln) and 143 (Ser for Thr). In immunoprecipitation assays, antibodies to Torpedo AChR bound /sup 125/I-labelled H..cap alpha.. 125-147 antibody bound H..cap alpha.. 125-147, but monoclonal antibodies to an immunodominant region of native AChR bound neither H..cap alpha.. 125-147 nor T ..cap alpha.. 125-147. Rats immunized with H ..cap alpha.. 125-147 produced anti-mammalian muscle AChR antibodies that induced modulation of AChRs from cultured human myotubes. Thus, region 125-147 of the human AChR ..cap alpha.. subunit is extracellular in muscle, and is both antigenic and immunogenic. It remains to be determined whether or not autoantibodies to this region may in part cause the weakness or myasthenia gravis in man.

High frequency of positive anti-thyroid peroxidase antibodies (ATPO) in adult subjects without known thyroid disease, Santiago de Chile

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Lanas, Alejandra; Letelier, Carolina; Caamano, Edgardo; Massardo, Teresa; Gonzalez, Patricio; Araya, Veronica

2010-01-01

Background: Anti-thyroid peroxidase antibodies have a pathogenic role in Hashimoto thyroiditis. Between 10 and 19% of individuals without thyroid disease, have positive titers of these antibodies. Aim: To study the frequency of positive titers of anti-thyroid peroxidase antibodies in healthy individuals. Material and Methods: A blood sample, to measure anti-thyroid peroxidase antibodies and thyroid stimulating hormone (TSH) by chemiluminescence assay, was obtained from 67 women and 62 men aged 45 ± 14 years, without a personal or familiar history of thyroid diseases and normal thyroid palpation. The cutoff point of the manufacturer to consider positive a titer of anti-thyroid peroxidase antibodies was set at 35 IU/ml. Results: Twenty-eight women and 28 men had positive antibody titers (43% of the sample). Subjects in the upper tercile of anti-thyroid peroxidase antibody titers had a higher TSH than those in the second tercile, although within normal limits (1.73 ± 0.74 and 1.37 ± 0.59 mlU/L, respectively p = 0.02) Conclusions: Forty three percent of the studied subjects without personal or familial history of thyroid diseases had positive titers of anti-thyroid peroxidase antibodies. Further prospective studies should evaluate whether this observation discloses an increase in thyroid autoimmune disease in a population with increased iodine intake

Shark Variable New Antigen Receptor (VNAR Single Domain Antibody Fragments: Stability and Diagnostic Applications

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Stewart Nuttall

2013-01-01

Full Text Available The single variable new antigen receptor domain antibody fragments (VNARs derived from shark immunoglobulin new antigen receptor antibodies (IgNARs represent some of the smallest known immunoglobulin-based protein scaffolds. As single domains, they demonstrate favorable size and cryptic epitope recognition properties, making them attractive in diagnosis and therapy of numerous disease states. Here, we examine the stability of VNAR domains with a focus on a family of VNARs specific for apical membrane antigen 1 (AMA-1 from Plasmodium falciparum. The VNARs are compared to traditional monoclonal antibodies (mAbs in liquid, lyophilized and immobilized nitrocellulose formats. When maintained in various formats at 45 °C, VNARs have improved stability compared to mAbs for periods of up to four weeks. Using circular dichroism spectroscopy we demonstrate that VNAR domains are able to refold following heating to 80 °C. We also demonstrate that VNAR domains are stable during incubation under potential in vivo conditions such as stomach acid, but not to the protease rich environment of murine stomach scrapings. Taken together, our results demonstrate the suitability of shark VNAR domains for various diagnostic platforms and related applications.

Initial diagnosis and follow-up in thyroid dysfunctions by use of immunoradiometric TSH measurement

International Nuclear Information System (INIS)

Joseph, K.

1985-01-01

4.245 patient studies with a highly sensitive immunoradiometric TSH assay revealed a normal range from 0.1 to 3.5 mU/l. Hyperthyroid patients had TSH values 6.0 mU/l. The results of TRH stimulation after nasal application of 2 mg TRH are strongly related to basal TSH measurement, thus, a demand on TRH tests exists only in basal TSH concentrations 0.1 to 0.3 mU/l and 3.5 to 6.0 mU/l for latent function anomalies. During T 4 therapy basal TSH values below 0.3 mU/l are indicative for sufficient suppression, for proof of overdosage T 3 parameters have to be used. In antithyroid drug therapy basal TSH measurement is important after the initial phase of therapy for precise antithyroid drug dosage. Therefore, the highly sensitive TSH measurement is the most important initial parameter for exclusion or evidence of thyroid function anomaly. (orig.) [de

HUBUNGAN ANTARA STATUS TSH IBU HAMIL DENGAN RIWAYAT KEHAMILAN DAN KELAHIRAN DI DAERAH ENDEMIK GAKI

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Yusi Dwi Nurcahyani

2013-02-01

Full Text Available Background: Excess of iodine during pregnancy can give a special problem. Diagnosis of hyperthyroidism during pregnancy can cause first-trimester spontaneous abortions, high rates ofstill births and neonatal deaths, two- to threefold increases in the frequency of low birth weight infants, preterm delivery, fetal or neonatal hyperthyroidism, and intrauterine growth retardation. Odjective: These studies examine the relationship between TSH levels in pregnant women with a history of pregnancy and birth mothers in1DD endemic areas. Method: This study is a non-intervention with cross sectional comparative design. ln previous research carried out screening for pregnant women who live in areas of endemic iodine deficiency disorder. From the results of screening found 67 pregnant women, where 32 pregnant women have a lower TSH «0.3 ulll/ml and 35 pregnant women had normal TSH levels (0.3-3.611'1U/ml. After giving birth mothers checked TSH level again and recorded the history o[his birth. Result: ln this study there was no difference for complaints during pregnancy that leads to the signs ofhyperthvroidism between group of pregnant women with low TSH and group of pregnant women with normal TSH. There was no significant difference between postpartum maternal TSH and TSH babies group ofpregnant women with low TSH and group ofpregnant women with normal TSH. There was a significant differencefor TSH mother before and after deli velJl. Conclusions: Low serum TSH value has no effect on the clinical state ofpregnant women and infants born allegedly under the influence of the increase olhCG in the .first trimester of pregnancy, is not because of the circumstances leading to hyperthyroid mothers. But in this study hCG levels pregnant women are not were measured. Key words: low TSH, pregnant women, birth mothet.

Hyperthyroidism in Patients with Graves' Ophthalmopathy, and Thyroidal, Skeletal and Eye Muscle Specific Type 2 Deiodinase Enzyme Activities.

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Molnár, Ildikó; Szentmiklósi, József A; Somogyiné-Vári, Éva

2017-09-01

Graves' ophthalmopathy is characterized by hyperthyroidism, which is associated with higher serum T 3 levels than T 4 due to deiodinase enzymes.The effect of Graves' patient's sera (n=52) with elevated thyroid hormone and TSH receptor or thyroid peroxidase antibody (anti-TPO) levels was investigated on thyroidal, skeletal and eye muscle type 2 deiodinase enzyme (DII) activities. DII activities were measured with 125 I-T 4 substrate, while thyroid hormone and antibody levels with immunoassays.In Graves' ophthalmopathy, sera with elevated FT 4 or FT 3 levels reduced DII activites remarkably in all tissue fractions. Thyroidal DII activities were lower than those using eye muscle fraction (0.6±0.22 vs 1.14±0.43 pmol/mg/min, PEffect of sera with increased FT 3 levels demonstrated also reduced DII activities in patients with Graves' ophthalmopathy after methimazole therapy compared to those who had no ophthalmopathy (2.88±2 vs 20.42±11.82 pmol/mg/min, PHyperthyroid sera with TSH receptor antibodies resulted in increased DII activities, while sera with anti-TPO antibodies were connected to lower DII activities in Graves' ophthalmopathy.In summary, the actions of hyperthyroid sera derived from patients with Graves' disease were tested on tissue-specific DII activities. Elevated FT 4 level-induced DII inactivation is present in Graves' ophthalmopathy, which seems to be also present at the beginning of methimazole therapy. Stimulating TSH receptor antibiodies increased DII activities via their nongenomic effects using sera of hyperthyroid Graves' ophthalmopathy, but anti-TPO antibodies could influence DII activities via altering FT 4 levels. © Georg Thieme Verlag KG Stuttgart · New York.

Excess TSH causes abnormal skeletal development in young mice with hypothyroidism via suppressive effects on the growth plate.

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Endo, Toyoshi; Kobayashi, Tetsuro

2013-09-01

Hypothyroidism in the young leads to irreversible growth failure. hyt/hyt Mice have a nonfunctional TSH receptor (TSHR) and are severely hypothyroid, but growth retardation was not observed in adult mice. We found that epiphysial cartilage as well as cultured chondrocytes expressed functional TSHR at levels comparable to that seen in the thyroid, and that addition of TSH to cultured chondrocytes suppressed expression of chondrocyte differentiation marker genes such as Sox-9 and type IIa collagen. Next, we compared the long bone phenotypes of two distinct mouse models of hypothyroidism: thyroidectomized (THYx) mice and hyt/hyt mice. Although both THYx and hyt/hyt mice were severely hypothyroid and had similar serum Ca(2+) and growth hormone levels, the tibia was shorter and the proliferating and hypertrophic zones in the growth plate was significantly narrower in THYx mice than in hyt/hyt mice. Supplementation of hyt/hyt mice thyroid hormone resulted in a wider growth plate compared with that of wild-type mice. Expressions of chondrocyte differentiation marker genes Sox-9 and type IIa collagen in growth plate from THYx mice were 52 and 60% lower than those of hyt/hyt mice, respectively. High serum TSH causes abnormal skeletal development in young mice with hypothyroidism via suppressive effects on the growth plate.

Association of TSH With Cardiovascular Disease Risk in Overweight and Obese Children During Lifestyle Intervention.

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Rijks, Jesse M; Plat, Jogchum; Dorenbos, Elke; Penders, Bas; Gerver, Willem-Jan M; Vreugdenhil, Anita C E

2017-06-01

Overweight and obese children have an increased risk to develop cardiovascular diseases (CVDs) in which thyroid-stimulating hormone (TSH) has been suggested as an intermediary factor. However, results of cross-sectional studies are inconclusive, and intervention studies investigating changes in TSH concentrations in association with changes in cardiovascular risk parameters in overweight and obese children are scarce. To gain insight in associations of circulating TSH concentrations and cardiovascular risk parameters in overweight and obese children. Nonrandomized lifestyle intervention. Centre for Overweight Adolescent and Children's Healthcare. Three hundred thirty euthyroid overweight and obese children. Long-term lifestyle intervention. TSH concentrations, pituitary TSH release in response to thyrotropin-releasing hormone (TRH), and cardiovascular risk parameters. At baseline, serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triacylglycerol (TAG), and monocyte chemotactic protein 1 concentrations were significantly associated with serum TSH concentrations. TSH release by the pituitary in response to exogenous TRH was not associated with cardiovascular risk parameters. During lifestyle intervention, several cardiovascular risk parameters significantly improved. In children whose body mass index z score improved, changes in TSH concentrations were significantly associated with changes in TC, LDL-C, and TAG concentrations. In euthyroid overweight and obese children, circulating TSH concentrations are positively associated with markers representing increased CVD risk. Changes in TSH concentrations are also associated with changes in lipid concentrations in children with successful weight loss, which is consistent with TSH being an intermediary factor in modulating lipid and lipoprotein metabolism. Copyright © 2017 Endocrine Society

Obtaining of stimulating hormone of the thyroid (hTSH) of Human Hypophysis

International Nuclear Information System (INIS)

Ayala, Jorge H; Carvajal G, Claudia; Anzola V, Cecilia; Gomez de, Myrian

1993-01-01

Thyroid-stimulating hormone (TSH) was extracted from human frozen pituitary glands using a method for the integral extraction of most hormones present in the gland. A specific immunoradiometric method (IRMA) was standardized and used for the analysis of TSH content. The immunology potency of the final TSH preparation was 1365 mUI/mg by IRMA. Characterization by SDS-PAGE demonstrated the multicomponent nature of the hormone

Elevated TSH in adults treated for hypothyroidism is associated with increased mortality.

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Akirov, Amit; Gimbel, Hannah; Grossman, Alon; Shochat, Tzipora; Shimon, Ilan

2017-01-01

Numerous studies investigated the link between hypothyroidism and mortality, but a definite conclusion is hard to reach as these were limited by a number of factors, including age of participants, comorbidities and single measurement of thyroid function. To evaluate the association between TSH and fT4 levels and mortality in patients with levothyroxine-treated hypothyroidism. Observational data of hospitalized patients (2011-2014). TSH and fT4 levels obtained between at least 30 days after discharge and until death or end of follow-up were collected. Median TSH and fT4 levels were stratified into categories. In total, 611 patients with treated hypothyroidism, aged 60-80 years (72% females, mean age 71 ± 6 years) were included in the study. All-cause mortality up to 66 months after discharge, by TSH and fT4 categories. During follow-up, the average numbers of TSH and fT4 measurements were 5.5 ± 3.8 and 2.5 ± 4.2 per patient respectively. Mortality rates were 28%, 29% and 54% with median TSH of 0.5-2.5, 2.5-5.0 and 5.0-10.0 IU/L respectively. Adjusted hazard ratios for mortality with median TSH between 5.0 and 10.0 IU/L were 2.3 (95% CI: 1.6-3.4) and 2.2 (95% CI: 1.6-3.2) compared with patients with TSH between 0.5-2.5 IU/L and 2.5-5 IU/L respectively. There was no difference in mortality between patients with median fT4 10-15 or 15-20 pmol/L. In treated hypothyroid adult patients and serial measurements of thyroid function tests, median TSH levels of 5-10 IU/L are associated with increased mortality with no effect of fT4 levels. Treatment should aim at achieving euthyroidism to improve survival. © 2017 European Society of Endocrinology.

Stereotypic Movements in Case of Sporadic Creutzfeldt-Jakob Disease: Possible Role of Anti-NMDA Receptor Antibodies

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Michelle Molina

2012-12-01

Full Text Available Sporadic Creutzfeldt-Jakob disease (sCJD and anti-NMDA receptor antibody encephalitis (NMDAE can both produce a rapidly progressive dementia with resulting state of catatonia or akinetic mutism. Both are associated with movement disorders. In published case series, myoclonus appears to be the most frequent movement disorder in sCJD, while stereotypic, synchronized, one-cycle-per-second movements such as arm or leg elevation, jaw opening, grimacing, head turning, and eye deviation are seen in NMDAE. We report a case of a 59-year-old woman with rapidly worsening cognitive disturbance leading to a nearly catatonic state interrupted by stereotypic movements. sCJD was diagnosed via periodic sharp wave complexes on EEG as well as cerebrospinal fluid (CSF 14-3-3 and tau protein elevation. Characteristic movement disorder of NMDAE was present in absence of ovarian mass or CSF pleiocytosis. Given prior case reports of presence of anti-NMDA receptor antibodies in sCJD, we propose that the movement disorder in this case was caused by anti-NMDA receptor antibodies whose formation was secondary to neuronal damage from prion disease. It is important to consider sCJD even in cases that have some clinical features suggestive of NMDAE.

Clinical evaluation of thyrotropin-releasing hormone (TRH) test with a sensitive immunoradiometric thyrotropin (TSH) assay kit

International Nuclear Information System (INIS)

Nakamura, Saeko; Demura, Reiko; Yamanaka, Yukako; Ishiwatari, Naoko; Jibiki, Kazuko; Odagiri, Emi; Demura, Hiroshi

1987-01-01

Thyrotropin-releasing hormone (TRH) test was performed using a commercially available immunoradiometric thyrotropin (TSH) assay kit (RIA-gnost hTSH) in patients with endocrine diseases. The basal serum concentration of TSH ranged from 0.2 to 2.9 μU/ml in healthy subjects. The values for endocrine diseases, except for Graves' disease, were almost within the normal range. A significant increase in TSH values caused by TRH test was observed in females compared with males (4.4 - 24.7 μU/ml vs 4.1 - 12.3 μU/ml). In cases of Graves' disease, there was a good correlation between the basal TSH value and the response of TSH to TRH. However, in the other endocrine diseases, including acromegaly, prolactinoma, anorexia nervosa, Cushing syndrome, and hypopituitarism, the response of TSH to TRH did not necessarily correlated with the basal TSH value. TRH test would be of value in elucidating pathophysiologic features, as well as in accurately diagnosing secretion reserve of TSH. (Namekawa, K.)

Clinical evaluation of thyrotropin-releasing hormone (TRH) test with a sensitive immunoradiometric thyrotropin (TSH) assay kit

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Nakamura, Saeko; Demura, Reiko; Yamanaka, Yukako; Ishiwatari, Naoko; Jibiki, Kazuko; Odagiri, Emi; Demura, Hiroshi

1987-10-01

Thyrotropin-releasing hormone (TRH) test was performed using a commercially available immunoradiometric thyrotropin (TSH) assay kit (RIA-gnost hTSH) in patients with endocrine diseases. The basal serum concentration of TSH ranged from 0.2 to 2.9 ..mu..U/ml in healthy subjects. The values for endocrine diseases, except for Graves' disease, were almost within the normal range. A significant increase in TSH values caused by TRH test was observed in females compared with males (4.4 - 24.7 ..mu..U/ml vs 4.1 - 12.3 ..mu..U/ml). In cases of Graves' disease, there was a good correlation between the basal TSH value and the response of TSH to TRH. However, in the other endocrine diseases, including acromegaly, prolactinoma, anorexia nervosa, Cushing syndrome, and hypopituitarism, the response of TSH to TRH did not necessarily correlated with the basal TSH value. TRH test would be of value in elucidating pathophysiologic features, as well as in accurately diagnosing secretion reserve of TSH. (Namekawa, K.).

Study on serum thyroid peroxidase antibody levels in autoimmune thyroid disease

International Nuclear Information System (INIS)

Zhang Zhixiang; Zheng Lan; Xu Shujin; Guan Jinghua

2008-01-01

Objective: To investigate the clinical significance of changes of serum thyroid peroxidase antibody (TPO-Ab) in patients with hyperthyroidism, hypothyroidism and simple goiter. Methods: Serum TPO-Ab, TMA,TGA and FT 3 , FT 4 , TSH levels were measured with radioimmunoassay(RIA) in 69 patients with hyperthyroidism, 53 patients with hypothyroidism, 45 patients with simple goiter and 20 controls. Results: The positive rate of thyroid peroxidase antibody (TPO-Ab) (82%-92.5%) was higher than that of thyroidglobulim antibody(TGA) (44.2%) and thyroid microsome antibody(TMA) (60.4-69.8%) in all patients with AICD. Conclusion: TPO-Ab could be taken as an important indicator in assessment of treatment and prognosis in patients with auto- immune thyroid diseases. (authors)

An assessment of radioimmunoassay procedures for determination of anti-acetylcholine receptor antibodies in the sera of patients with myasthenia gravis

International Nuclear Information System (INIS)

Carter, B.; Harrison, R.; Lunt, G.G.; Morris, H.; Savage-Marengo, T.; Stephenson, F.A.

1981-01-01

A reproducible radioimmunoassay procedure for the determination of anti-acetylcholine receptor antibodies in the sera of patients with myasthenia gravis is described and examined in detail. The assay combines features of a number of methods previously outlined and allows repeat determinations of antibody titre in a given myasthenic serum sample with coefficient of variation 6%. The mean +- standard deviation for normal human serum anti-acetylcholine receptor antibodies was found by this procedure to be 0.024 +- 0.033 nmol/l α-bungarotoxin binding sites whereas the range for myasthenic patients was 0-139.14 nmol/l with a mean value of 7.55 nmol/l α-bungarotoxin binding sites. (author)

Clinical Utility of Acetylcholine Receptor Antibody Testing in Ocular Myasthenia Gravis.

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Peeler, Crandall E; De Lott, Lindsey B; Nagia, Lina; Lemos, Joao; Eggenberger, Eric R; Cornblath, Wayne T

2015-10-01

The sensitivity of acetylcholine receptor (AChR) antibody testing is thought to be lower in ocular myasthenia gravis (OMG) compared with generalized disease, although estimates in small-scale studies vary. There is little information in the literature about the implications of AChR antibody levels and progression from OMG to generalized myasthenia gravis. To test the hypothesis that serum AChR antibody testing is more sensitive in OMG than previously reported and to examine the association between AChR antibody levels and progression from OMG to generalized myasthenia gravis. A retrospective, observational cohort study was conducted of 223 patients (mean [SD] age, 59.2 [16.4] years; 139 [62.3%] male) diagnosed with OMG between July 1, 1986, and May 31, 2013, at 2 large, academic medical centers. Baseline characteristics, OMG symptoms, results of AChR antibody testing, and progression time to generalized myasthenia gravis (if this occurred) were recorded for each patient. Multiple logistic regression was used to measure the association between all clinical variables and antibody result. Kaplan-Meier survival analysis was performed to examine time to generalization. Among the 223 participants, AChR antibody testing results were positive in 158 participants (70.9%). In an adjusted model, increased age at diagnosis (odds ratio [OR], 1.03; 95% CI, 1.01-1.04; P = .007) and progression to generalized myasthenia gravis (OR, 2.92; 95% CI, 1.18-7.26; P = .02) were significantly associated with positive antibody test results. Women were less likely to have a positive antibody test result (OR, 0.36; 95% CI, 0.19-0.68; P = .002). Patients who developed symptoms of generalized myasthenia gravis had a significantly higher mean (SD) antibody level than those who did not develop symptoms of generalized myasthenia gravis (12.7 [16.5] nmol/L vs 4.2 [7.9] nmol/L; P = .002). We demonstrate a higher sensitivity of AChR antibody testing than previously reported in the

Ultrasensitive human thyrotropin (h TSH) immunoradiometric assay (IRMA) set up, through identification and minimization of non specific bindings

International Nuclear Information System (INIS)

Peroni, C.N.

1994-01-01

An IRMA of h TSH, based on magnetic solid phase separation, was studied especially for what concerns its non specific bindings. These were identified as a product of the interaction between an altered form of radioiodinated anti-h TSH monoclonal antibody ( 125 I-m AB) and the uncoupled magnetizable cellulose particle (matrix). Apparently this form of 125 I-m AB is a type of aggregate that can be partly resolved from the main peak on Sephadex G-200 and further minimized via a single pre-incubation with the same matrix. Solid phase saturation with milk proteins, tracer storage at 4 0 C and serum addition during incubation were also found particularly effective is preventing its formation. These findings were used in order to reproducibly decrease non specific bindings to values 60 /B O ) up to values of 300-500. This way we obtained h TSH radio assays with functional sensitivities of about 0.05 m IU/L and analytical sensitivities of the order of 0.02 m IU/L, which classify them at least as among the best second generation assays and that are excellent indeed for magnetic IRMA s. A more optimistic sensitivity calculation, based on Rodbard's definition, provided values down to 0.008 m IU/L. Such sensitivities, moreover, were obtained in a very reproducible way and all over the useful tracer life. (author). 83 refs, 13 figs, 25 tabs

Immunoglobulin Heavy Chain Variable Region and Major Histocompatibility Region Genes Are Linked to Induced Graves' Disease in Females From Two Very Large Families of Recombinant Inbred Mice

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Aliesky, Holly; Banuelos, Bianca; Magana, Jessica; Williams, Robert W.; Rapoport, Basil

2014-01-01

Graves' hyperthyroidism is caused by antibodies to the TSH receptor (TSHR) that mimic thyroid stimulation by TSH. Stimulating TSHR antibodies and hyperthyroidism can be induced by immunizing mice with adenovirus expressing the human TSHR A-subunit. Prior analysis of induced Graves' disease in small families of recombinant inbred (RI) female mice demonstrated strong genetic control but did not resolve trait loci for TSHR antibodies or elevated serum T4. We investigated the genetic basis for induced Graves' disease in female mice of two large RI families and combined data with earlier findings to provide phenotypes for 178 genotypes. TSHR antibodies measured by inhibition of TSH binding to its receptor were highly significantly linked in the BXD set to the major histocompatibility region (chromosome 17), consistent with observations in 3 other RI families. In the LXS family, we detected linkage between T4 levels after TSHR-adenovirus immunization and the Ig heavy chain variable region (Igvh, chromosome 12). This observation is a key finding because components of the antigen binding region of Igs determine antibody specificity and have been previously linked to induced thyroid-stimulating antibodies. Data from the LXS family provide the first evidence in mice of a direct link between induced hyperthyroidism and Igvh genes. A role for major histocompatibility genes has now been established for genetic susceptibility to Graves' disease in both humans and mice. Future studies using arrays incorporating variation in the complex human Ig gene locus will be necessary to determine whether Igvh genes are also linked to Graves' disease in humans. PMID:25051451

Use of monoclonal immunoradiometric assays for sensitive TSH measurements: evaluation of four commercially obtainable kits

International Nuclear Information System (INIS)

Smitz, J.; Schiettecatte, J.; Stierteghem, A.C. van; Jonckheer, M.H.

1987-01-01

Four commerically available monoclonal immunoradiometric methods for the assay of TSH are tested. These four kits are: RIA-GNOST TSH code 0CPL of Behring, SUCROSEP TSH IRMA of Boots, TSH-IRMA-CT-100 of Medgenix, TSH-RIA bead II Ultrasensitive of Abbott. The accuracy, sensitivity and reproducibility of the four kits are compared. The methods are also clinically evaluated. The authors concluded that the kits of Abbott, Behring and Boots are suitable for use in the routine laboratory. 4 refs.; 4 figs.; 7 tabs

Misdiagnosis of Graves' Disease with Apparent Severe Hyperthyroidism in a Patient Taking Biotin Megadoses.

Science.gov (United States)

Barbesino, Giuseppe

2016-06-01

Accurate immunoassays measuring minute quantities of hormones are the cornerstone of the practice of endocrinology. Despite tremendous advances in this field, novel pitfalls in these tests emerge from time to time. Oral biotin can interfere with immunoassays of several hormones. The purpose of this report is to relate an extreme case of such interference. A patient with progressive multiple sclerosis was found to have extremely elevated free thyroxine, triiodothyronine, and suppressed thyrotropin (TSH) levels. His TSH receptor binding inhibiting antibody level was also elevated. This constellation of laboratory findings suggested a diagnosis of severe Graves' disease. All of the assays yielding abnormal results employed the biotin-streptavidin affinity in their design. The patient had no symptoms of hyperthyroidism, and detailed review of his medications revealed intake of megadoses of biotin. Temporary discontinuation of biotin treatment resulted in complete resolution of the biochemical abnormalities. Non-physiologic biotin supplementation may interfere with several immunoassays, including thyroid hormones, TSH, thyroglobulin, and TSH receptor binding inhibiting antibody, leading to erroneous diagnoses. Questioning for biotin intake should be part of the evaluation for patients undergoing endocrine tests. Interruption of biotin supplementation for at least two days prior to biotin-sensitive tests should be sufficient to avoid major misdiagnoses.

An Evaluation by TSH Radioimmunoassay on Familial Thyroid Disorders

International Nuclear Information System (INIS)

Kim, Ji Yeul

1989-01-01

The occurrence of thyroid disorders is connected with iodine deficiency, defective synthesis or releasing of thyroid hormone and endemicity. Genetic factors are known as a single gene defects, interaction of multiple genes with environmental factors, as well as chromosomal aberrations. Diofnosis thyroid disorders is enforced by 13I uptake test, thyroid scanning with 131 I or 99m Tc and serum radioimmunoassays of T3, T4, free T4 and TSH. They were largely classified as hypothyroidism, hyperthyroidism, simple goiter and normal. The pedigree of 58 families was drawn by propositus, and then the correlation between thyroid disorders and TSH levels was analyzed. The results are as follows: 1) The offsprings and their mothers of 15 families were hypothyroidism, THS level was 5 folds for offsprings and 4 folds for mothers in comparison with control group. 2) 13 families were hyperthyroidism in siblings but their mothers were normal in thyroid function, TSH level of the siblings was lower than control group. 3) Though the offsprings and their mothers of 10 families were similar to TSH level of control group, they are all simple goiter, familial thyroid disorders, in other thyroid function test. The familial thyroid disorders suggested that these transmitted from mothers to offsprings with X-linked dominant or autosomal dominant inheritance.

Reversible adrenal insufficiency and heterophile antibodies in a case of autoimmune polyendocrinopathy syndrome.

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Kharb, Sandeep; Gundgurthi, Abhay; Dutta, Manoj K; Garg, M K

2013-12-01

A 27-year-old male was admitted with diabetic ketoacidosis and altered sensorium with slurring of speech and ataxia. He was managed with intravenous insulin and fluids and later shifted to basal bolus insulin regimen and during further evaluation was diagnosed to be suffering from primary hypothyroidism and adrenal insufficiency. He was started on thyroxin replacement and steroids only during stress. After three months of follow up he was clinically euthyroid. His glycemic control was adequate on oral anti-hyperglycemic drugs and adrenal insufficiency recovered. However, his thyrotropin levels were persistently elevated on adequate replacement doses of thyroxin. His repeat TSH was estimated after precipitating serum with polyethylene glycol which revealed normal TSH. Here we report reversible adrenal insufficiency with hypothyroidism with falsely raised TSH because of presence of heterophile antibodies in a case of poly glandular endocrinopathy syndrome.

Measurement of thyrotropin receptor antibodies (TRAK) with a second generation assay in patients with Graves' disease; Die Bestimmung von Thyreotropin-Rezeptor-Antikoerpern (TRAK) mit einem Assay der zweiten Generation bei Patienten mit Morbus Basedow

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Zoephel, K.; Wunderlich, G.; Franke, W.G. [Klinik und Poliklinik fuer Nuklearmedizin, Technische Univ. Dresden (Germany); Koch, R. [Inst. fuer Medizinische Informatik und Biometrie, Technische Univ. Dresden (Germany)

2000-06-01

Aim: The detection of TSH-receptor-antibodies (TRAb) in patients (pts) with Graves' disease (GD) is routinely used in nuclear medicine laboratories. It is performed by commercial, porcine radioreceptorassays (RRA) measuring TSH binding inhibitory activity. A second generation assay using the human, recombinant TSH-receptor was developed during the last years. The manufacturer composed this new assay as a coated tube RRA (CT RRA) and claimed a higher sensitivity for GD. Methods: TRAb was measured in 207 pts with various thyroid disorders and 205 healthy controls using the new coated tube RRA (Fa. B.R.A.H.M.S. Diagnostica GmbH, Berlin, Germany) as well as a conventional RRA (Fa. Medipan Diagnostica GmbH, Selchow, Germany): 60 pts suffering from GD showing a relapse after anti-thyroid drug treatment and before radioiodine therapy, 109 pts with disseminated autonomia (DA) and 38 pts suffering from Hashimoto's thyroiditis. A ROC-analysis was performed to find the optimal decision threshold level for positivity. Results: We found 42/60 TRAb-positive pts with GD in the established RRA (threshold 6 U/L) and 52/60 in the CT RRA, respectively. The sensitivity increased from 70% (RRA) to 86,7% (CT RRA). The CT RRA found 2 false positives (one Hashimoto's and one healthy control) and the RRA detected 3 Hashimoto's and 2 healthy controls as false positive. Conclusion: The increased sensitivity of CT RRA for GD provides an advantage compared to conventional RRA, especially in GD-patients relapsing afte antithyroid drug treatment. Functional sensitivity and Interassayvariation of CT RRA are very precisely compared to conventional RRA. Handling of the new assay is also improved. (orig.) [German] Ziel: Die Bestimmung der TSH-Rezeptorantikoerper (TRAK) bei Patienten mit Morbus Basedow ist fester Bestandteil der nuklearmedizinischen In-vitro-Diagnostik. Seit kurzem ist die Bestimmung mit einem TRAK-Assay moeglich, bei dem im Gegensatz zu den herkoemmlichen

TR{alpha}- and TSH-mRNA levels after temporal exposition with methimazole in zebrafish, Danio rerio

Energy Technology Data Exchange (ETDEWEB)

Schulz, A.E.I.; Stocker, A.; Hollosi, L.; Schramm, K.W. [Inst. of Ecological Chemistry, GSF - National Research Center for Environment and Health (Germany)

2004-09-15

The group of dioxin and dioxin-like substances are highly persistent in the environment. There are evidences from present investigations that a variety of substances are capable of disrupting the endocrine system in the aquatic environment. These substances are called endocrine disruptors. Dioxin and related compounds can act as endocrine disruptors. Aquatic animals like amphibian and fish are especially affected of the impact of these compounds. Investigations concerned so far in particular the domain of reproduction biology and the thyroid axis especially. Recent investigations showed that the TR{alpha}-mRNA level change after a short temporal expression with T3, methimazole and amiodarone. The objective of the project is to identify effects of thyroid endocrine disruptors on the regulation of gene expression of the thyroid receptors TR{alpha}a, TR{beta} and thyroid stimulating hormone TSH and associated effects on other system. In preliminary studies the effects of the drug methimazole as model substance on gene expression of TR{alpha} and TSH were investigated. Methimazole is an inhibitor of the thyroid peroxidase so that the formation of thyroid hormones is disrupted.

Effects of thyroxine (T4) and triiodothyronine (T3) on the thyrotropin (TSH) response to TSH-releasing hormone (TRH) in the rat

International Nuclear Information System (INIS)

Boado, R.J.; Ulloa, E.R.; Zaninovich, A.A.

1982-01-01

Wistar rats were treated with 7.8 or 260 nmols T4/100 g BW, 1.5 or 260 nmols T3/100 g BW, or saline as control. Twenty minutes later 1 μg TRH/100 g BW was injected iv. Heparinized blood samples were drawn at times 0 and 30 minutes (10 min post-TRH) for determination of plasma TSH, T4 and T3 by RIA. Other group of rats were administered with 150 μCi of 3',5'- 125 I-T4 prepared by iodination of 3,5-diiodothyronine. Thirty minutes later the hypophyses were removed, and chromatographed. Other group of animals were treated with 5 mg of iopanoic acid (IOP)/100 g BW. Thereafter, rats were injected iv with 260 nmols T4 or T3/100 g BW and the TRH-test performed as described above. In the control group there was a 11-fold increase in plasma TSH at 10 minutes post-TRH. In rats treated with 260 nmols T4 the post-TRH increment in plasma TSH was 5+-1-fold (p 125 I-T3 in the hypophyses 30 minutes after 125 I-T4 administration. The present data indicate that T4 is capable of depressing the release of TSH in response to TRH stimulation in normal rats. (M.E.L.) [es

An Antibody Blocking Activin Type II Receptors Induces Strong Skeletal Muscle Hypertrophy and Protects from Atrophy

Science.gov (United States)

Minetti, Giulia C.; Sheppard, KellyAnn; Ibebunjo, Chikwendu; Feige, Jerome N.; Hartmann, Steffen; Brachat, Sophie; Rivet, Helene; Koelbing, Claudia; Morvan, Frederic; Hatakeyama, Shinji

2014-01-01

The myostatin/activin type II receptor (ActRII) pathway has been identified to be critical in regulating skeletal muscle size. Several other ligands, including GDF11 and the activins, signal through this pathway, suggesting that the ActRII receptors are major regulatory nodes in the regulation of muscle mass. We have developed a novel, human anti-ActRII antibody (bimagrumab, or BYM338) to prevent binding of ligands to the receptors and thus inhibit downstream signaling. BYM338 enhances differentiation of primary human skeletal myoblasts and counteracts the inhibition of differentiation induced by myostatin or activin A. BYM338 prevents myostatin- or activin A-induced atrophy through inhibition of Smad2/3 phosphorylation, thus sparing the myosin heavy chain from degradation. BYM338 dramatically increases skeletal muscle mass in mice, beyond sole inhibition of myostatin, detected by comparing the antibody with a myostatin inhibitor. A mouse version of the antibody induces enhanced muscle hypertrophy in myostatin mutant mice, further confirming a beneficial effect on muscle growth beyond myostatin inhibition alone through blockade of ActRII ligands. BYM338 protects muscles from glucocorticoid-induced atrophy and weakness via prevention of muscle and tetanic force losses. These data highlight the compelling therapeutic potential of BYM338 for the treatment of skeletal muscle atrophy and weakness in multiple settings. PMID:24298022

Fetal neonatal hyperthyroidism: diagnostic and therapeutic approachment

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Kurtoğlu, Selim; Özdemir, Ahmet

2017-01-01

Fetal and neonatal hyperthyroidism may occur in mothers with Graves’ disease. Fetal thyrotoxicosis manifestation is observed with the transition of TSH receptor stimulating antibodies to the fetus from the 17th–20th weeks of pregnancy and with the fetal TSH receptors becoming responsive after 20 weeks. The diagnosis is confirmed by fetal tachycardia, goiter and bone age advancement in pregnancy and maternal treatment is conducted in accordance. The probability of neonatal hyperthyroidism is high in the babies of mothers that have ongoing antithyroid requirement and higher antibody levels in the last months of pregnancy. Clinical manifestation may be delayed by 7–17 days because of the antithyroid drugs taken by the mother. Neonatal hyperthyroidism symptoms can be confused with sepsis and congenital viral infections. Herein, the diagnosis and therapeutic approach are reviewed in cases of fetal neonatal hyperthyroidism. PMID:28439194

Characterization of ductal and lobular breast carcinomas using novel prolactin receptor isoform specific antibodies

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Heger Christopher D

2010-12-01

Full Text Available Abstract Background Prolactin is a polypeptide hormone responsible for proliferation and differentiation of the mammary gland. More recently, prolactin's role in mammary carcinogenesis has been studied with greater interest. Studies from our laboratory and from others have demonstrated that three specific isoforms of the prolactin receptor (PRLR are expressed in both normal and cancerous breast cells and tissues. Until now, reliable isoform specific antibodies have been lacking. We have prepared and characterized polyclonal antibodies against each of the human PRLR isoforms that can effectively be used to characterize human breast cancers. Methods Rabbits were immunized with synthetic peptides of isoform unique regions and immune sera affinity purified prior to validation by Western blot and immunohistochemical analyses. Sections of ductal and lobular carcinomas were stained with each affinity purified isoform specific antibody to determine expression patterns in breast cancer subclasses. Results We show that the rabbit antibodies have high titer and could specifically recognize each isoform of PRLR. Differences in PRLR isoform expression levels were observed and quantified using histosections from xenografts of established human breast cancer cells lines, and ductal and lobular carcinoma human biopsy specimens. In addition, these results were verified by real-time PCR with isoform specific primers. While nearly all tumors contained LF and SF1b, the majority (76% of ductal carcinoma biopsies expressed SF1a while the majority of lobular carcinomas lacked SF1a staining (72% and 27% had only low levels of expression. Conclusions Differences in the receptor isoform expression profiles may be critical to understanding the role of PRL in mammary tumorigenesis. Since these antibodies are specifically directed against each PRLR isoform, they are valuable tools for the evaluation of breast cancer PRLR content and have potential clinical importance in

Stable expression of human thyrotropin (hTSH) in mammalian cells (CHO) expressing α2,6 sialyltransferase

International Nuclear Information System (INIS)

Damiani, Renata

2009-01-01

A CHO cell line, previously genetically modified by the introduction of rat α2,6-sialyltransferase cDNA, generated for the first time a human-like sialylated recombinant hTSH (hlsr-hTSH) more similar to the native hormone, with 61% of α2,3- and 39% of α2,6-linked sialic acid residues. The best clone, when submitted to gene amplification with up to 8 μM methotrexate, presented a secretion level of ∼2 μg hTSH/10 6 cells/day, useful for product purification and characterization. The relative molecular masses (M r ) of the heterodimer and of the α- and β-subunits of purified hlsr-hTSH, determined by MALDI-TOF mass spectrometry, and the relative hydrophobicities, determined by RP-HPLC, were not remarkably different from those presented by two r-hTSH preparations secreted by normal CHO cells. Some differences were observed, though, in N-glycan composition, with more tri- and much more tetra-sialylated structures in hlsr-hTSH. When analyzed via an in vivo bioassay based on hTSH-induced T 4 release in mice, hlsr-hTSH was shown to be equipotent (p > 0.05) with the commercial preparation of r-hTSH (Thyrogen), and 1.5-fold more potent than native hTSH (p < 0.001). (author)

TSH elevations as the first laboratory evidence for pseudohypoparathyroidism type Ib (PHP-Ib)†

Science.gov (United States)

Molinaro, Angelo; Tiosano, Dov; Takatani, Rieko; Chrysis, Dionisios; Russell, William; Koscielniak, Nikolas; Kottler, Marie-Laure; Agretti, Patrizia; De Marco, Giuseppina; Ahtiainen, Petteri; Christov, Marta; Mäkitie, Outi; Tonacchera, Massimo; Jüppner, Harald

2014-01-01

Hypocalcemia and hyperphosphatemia because of resistance towards parathyroid hormone (PTH) in the proximal renal tubules are the most prominent abnormalities in patients affected by pseudohypoparathyroidism type Ib (PHP-Ib). In this rare disorder that is caused by GNAS methylation changes, resistance can occur towards other hormones, such as thyroid-stimulating hormone (TSH), that mediate their actions through G protein-coupled receptors. However, these additional laboratory abnormalities are usually not recognized until PTH-resistant hypocalcemia becomes clinically apparent. We now describe four pediatric patients, first diagnosed with subclinical or overt hypothyroidism between the ages of 0.2 and 15 years, who developed overt PTH-resistance 3-20 years later. Although anti-TPO antibodies provided a plausible explanation for hypothyroidism in one of these patients, this and two other patients revealed broad epigenetic GNAS abnormalities, which included loss of methylation (LOM) at exons AS, XL and A/B, and gain of methylation at exon NESP55, i.e. findings consistent with PHP-Ib. LOM at GNAS exon A/B alone led in the fourth patient to the identification of a maternally inherited 3-kb STX16 deletion, a well-established cause of autosomal dominant PHP-Ib. Although GNAS methylation changes were not detected in additional pediatric and adult patients with subclinical hypothyroidism (23 pediatric and 39 adult cases), hypothyroidism can obviously be the initial finding in PHP-Ib patients. One should therefore consider measuring PTH, along with calcium and phosphate, in patients with unexplained hypothyroidism for extended periods of time to avoid hypocalcemia and associated clinical complications. PMID:25403028

[Construction of a phage antibody library and screening of anti-epidermal growth factor receptor variant III single chain antibody].

Science.gov (United States)

Han, Dong-gang; Duan, Xiao-yi; Guo, You-min; Zhou, Qi; Wang, Quan-ying; Yang, Guang-xiao

2010-01-01

To obtain specific anti-epidermal growth factor receptor variant III (EGFRvIII) single chain antibody (ScFv) by phage antibody library display system. The total RNA was extracted from the spleen B cells of BALB/c mice immunized with pep-3-OVA protein, and the first-strand cDNA was synthesized by reverse transcription. Antibody VH and VL gene fragments were amplified and joined to a ScFv gene with the linker. The ScFv gene was ligated into the phagemid vector pCANTAB5E, which was transformed into competent E. coli TG1. The transformed cells were then infected with M13KO7 helper phage to yield the recombinant phage to construct the phage ScFv library. Pep-3-BSA protein was used to screen the phage antibody library and ELISA carried out to characterize the activity of the antibody. The VH and VL gene fragments of the antibody were about 350 bp and 320 bp in length as analyzed by agarose gel electrophoresis. The ScFv gene was 780 bp, consistent with the expected length. The recombinant phagemid with ScFv gene insert was rescued, and an immune phage ScFv library with the content of 5.0x10(6) was constructed. The recombinant ScFv phage had a titer of 3.0x10(4) cfu/ml, and the fourth phage harvest yielded 56 times as much as that of the first one. SDS-PAGE demonstrated a molecular mass of the soluble ScFv of about 28 kD. ELISA results indicated good specificity of the ScFv to bind EGFRvIII. An immune phage ScFv library is successfully constructed, and the ScFv antibody fragment is capable of specific binding to EGFRvIII.

Radioiodine remnant ablation in differentiated thyroid cancer after combined endogenous and exogenous TSH stimulation.

Science.gov (United States)

Vrachimis, A; Schober, O; Riemann, B

2012-01-01

Radioiodine remnant ablation (RRA) after (near-)total thyroidectomy (TE) is a key element in patients with differentiated thyroid cancer (DTC). The use of exogenous TSH stimulation (rhTSH) prior to RRA has shown promising results as compared to conventional thyroid hormone withdrawal (THW). As yet, the efficacy of RRA after brief THW and single rhTSH administration has not been assessed. The study sample comprised 147 patients with DTC referred to our center between May 2008 and September 2010. All patients received TE with subsequent RRA. None of these 147 patients had evidence of distant metastasis. 93 patients had endogenous TSH stimulation 4-5 weeks after surgery (group I) and twenty-six received two rhTSH injections (group II). 28 patients were treated with a single rhTSH injection after a brief THW (group III). RRA-Efficacy was assessed three months after therapy by diagnostic whole-body scan and measurement of the tumour marker thyroglobulin (Tg) under TSH stimulation. Three categories of success were defined for remnant ablation. Based on the definition of successful remnant ablation no visible uptake and a Tg ≤ 2.0 ng/ml (category 1) was seen in 62/93 patients in group I, in 17/26 patients in group II (p = n.s.) and in 12/28 patients in group III (p 2.0 ng/ml (category 3) was found in 3/93 patients in group I and 1/26 patients in group II but in no patient in group III. The third strategy of remnant ablation using a single injection of rhTSH after a brief THW period resulted in a significant higher rate of patients with residual uptake in the thyroid bed and a Tg level below 2 ng/ml three months after remnant ablation in comparison to THW. However, the overall efficacy of the third protocol was not significantly different as compared to two rhTSH injections. Under the aspect of the supply shortage of rhTSH the combined endogenous and exogenous TSH stimulation may be an attractive alternative for remnant ablation in differentiated thyroid cancer.

Human agonistic TRAIL receptor antibodies Mapatumumab and Lexatumumab induce apoptosis in malignant mesothelioma and act synergistically with cisplatin

Directory of Open Access Journals (Sweden)

Felley-Bosco Emanuela

2007-10-01

Full Text Available Abstract Background The incidence of malignant pleural mesothelioma (MPM is associated with exposure to asbestos, and projections suggest that the yearly number of deaths in Western Europe due to MPM will increase until 2020. Despite progress in chemo- and in multimodality therapy, MPM remains a disease with a poor prognosis. Inducing apoptosis by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL or agonistic monoclonal antibodies which target TRAIL-receptor 1 (TRAIL-R1 or TRAIL-R2 has been thought to be a promising cancer therapy. Results We have compared the sensitivity of 13 MPM cell lines or primary cultures to TRAIL and two fully human agonistic monoclonal antibodies directed to TRAIL-R1 (Mapatumumab and TRAIL-R2 (Lexatumumab and examined sensitization of the MPM cell lines to cisplatin-induced by the TRAIL-receptor antibodies. We found that sensitivity of MPM cells to TRAIL, Mapatumumab and Lexatumumab varies largely and is independent of TRAIL-receptor expression. TRAIL-R2 contributes more than TRAIL-R1 to death-receptor mediated apoptosis in MPM cells that express both receptors. The combination of cisplatin with Mapatumumab or Lexatumumab synergistically inhibited the cell growth and enhanced apoptotic death. Furthermore, pre-treatment with cisplatin followed by Mapatumumab or Lexatumumab resulted in significant higher cytotoxic effects as compared to the reverse sequence. Combination-induced cell growth inhibition was significantly abrogated by pre-treatment of the cells with the antioxidant N-acetylcysteine. Conclusion Our results suggest that the sequential administration of cisplatin followed by Mapatumumab or Lexatumumab deserves investigation in the treatment of patients with MPM.

The diagnostic effects of s-TSH and TRH stimulating test on subclinical thyroid function

International Nuclear Information System (INIS)

Lu Shujun; Wang Wenliang; Lu Shuyan; Zheng Linong; Hu Changjun; Fang Xiaozheng; Zheng Huian; Ma Meizhen

2002-01-01

The study was carried out to investigate the diagnostic effects of supersensitive TSH on diagnosing subclinical thyroid function with only once s-TSH detection and with TRH stimulating tests. TRH stimulating tests have been undertaken for 90 patients with different thyroid disease and 58 normal subjects. Diagnostic basal levels of s-TSH test in control group, subclinical hyperthyroidism group and subclinical hypothyroidism group were 2.20 +- 1.85 mIU/L, 0.54 +- 0.3 mIU/L and 9.08 +- 6.3 mIU/L, respectively, the levels of subclinical hyperthyroidism and subclinical hypothyroidism group were significantly higher than that of normal subjects group (P s -TSH>30 mIU/L. Dynamic observing of TRH stimulating tests have more effect than that of only once s-TSH detection in diagnosing subclinical thyroid function

Blood-brain barrier drug delivery of IgG fusion proteins with a transferrin receptor monoclonal antibody.

Science.gov (United States)

Pardridge, William M

2015-02-01

Biologic drugs are large molecules that do not cross the blood- brain barrier (BBB). Brain penetration is possible following the re-engineering of the biologic drug as an IgG fusion protein. The IgG domain is a MAb against an endogenous BBB receptor such as the transferrin receptor (TfR). The TfRMAb acts as a molecular Trojan horse to ferry the fused biologic drug into the brain via receptor-mediated transport on the endogenous BBB TfR. This review discusses TfR isoforms, models of BBB transport of transferrin and TfRMAbs, and the genetic engineering of TfRMAb fusion proteins, including BBB penetrating IgG-neurotrophins, IgG-decoy receptors, IgG-lysosomal enzyme therapeutics and IgG-avidin fusion proteins, as well as BBB transport of bispecific antibodies formed by fusion of a therapeutic antibody to a TfRMAb targeting antibody. Also discussed are quantitative aspects of the plasma pharmacokinetics and brain uptake of TfRMAb fusion proteins, as compared to the brain uptake of small molecules, and therapeutic applications of TfRMAb fusion proteins in mouse models of neural disease, including Parkinson's disease, stroke, Alzheimer's disease and lysosomal storage disorders. The review covers the engineering of TfRMAb-avidin fusion proteins for BBB targeted delivery of biotinylated peptide radiopharmaceuticals, low-affinity TfRMAb Trojan horses and the safety pharmacology of chronic administration of TfRMAb fusion proteins. The BBB delivery of biologic drugs is possible following re-engineering as a fusion protein with a molecular Trojan horse such as a TfRMAb. The efficacy of this technology will be determined by the outcome of future clinical trials.

Radioimmunological determination of triiodo-thyronine (T3) and thyroidastimulating hormone (TSH) in routine diagnosis

International Nuclear Information System (INIS)

Vollmer, U.J.; Schmidt, H.A.E.

1974-01-01

The radioimmunological determination of triiodothyronine and thyroid-stimulating hormone (TSH) provides two new methods for functional diagnoses of the thyroid. Changes and disturbances of the control mechanism had been difficult to detect with conventional methods. The measurement of the basal TSH rate has further therapeutic and diagnostic consequences such as, e.g., the determination of growth stages of strumae or preclinical hypothyreosis on the basis of increased basal TSH values. The results of the TRH test enable a more exact clarification. Substitution therapy should take into account the rate of the remaining basal TSH secretion as well as the clinical picture. The determination of the serum T 3 concentration enables the diagnosis of isolated triiodothyronine hyperthyreosis. Continuous control of the thyrostatic therapy by T 3 and TSH determination helps to prevent a condition in which hyperthyreosis persists even though all the normal parameters indicate a euthyroid function. The development of a preclinical hypothyreosis can also be detected early. The increased basal TSH secretion after strumectomy is a further proof of the urgent need for consequent prophylaxis of relapses (orig./AK) [de

Influence of TSH on uptake of [18F]fluorodeoxyglucose in human thyroid cells in vitro

International Nuclear Information System (INIS)

Deichen, J.T.; Schmidt, C.; Prante, O.; Maschauer, S.; Kuwert, T.; Papadopoulos, T.

2004-01-01

Recent clinical evidence suggests that positron emission tomography with fluorine-18 fluorodeoxyglucose (FDG-PET) is more accurate in detecting thyroid carcinomatous tissue at high than at low TSH levels. The aim of this study was to determine the influence of TSH on FDG uptake in human thyroid cells in vitro. Monolayers of human thyroid tissue were cultured after mechanical disintegration and enzymatic digestion of samples from patients undergoing surgery for nodular goitre. The purity of thyroid cell preparations was ascertained by immunohistochemical staining for the epithelial antigen KL-1, and their viability by measuring the synthesis of thyroglobulin in vitro. The cells were incubated with 0.8-1.5 MBq FDG/ml uptake medium for 1 h. FDG uptake in thyroid cells was quantified as percent of whole FDG activity per well (% ID) or as % ID in relation to total protein mass. This experimental protocol was subsequently varied to study the effect of incubation time, glucose dependency and TSH. Furthermore, radio-thin layer chromatography was used to identify intracellular FDG metabolites. FDG accumulated in the thyroid cells linearly with time, doubling roughly every 20 min. Uptake was competitively inhibited by unlabelled glucose and decreased to approximately 70% at 100 mg/dl glucose compared to the value measured in glucose-free medium. FDG was intracellularly trapped as FDG-6 phosphate and FDG-1,6-diphosphate. TSH significantly increased FDG uptake in vitro in a time- and concentration-dependent manner: Cells cultured at a TSH concentration of 50 μU/ ml doubled FDG uptake compared to TSH-free conditions, and uptake after 72 h of TSH pre-incubation was approximately 300% of that without TSH pre-incubation. TSH stimulates FDG uptake by benign thyroid cells in a time- and concentration-dependent manner. This supports the clinical evidence that in well-differentiated thyroid carcinomas, most of which are still TSH-sensitive, FDG-PET is more accurate at high levels of

TSH elevations as the first laboratory evidence for pseudohypoparathyroidism type Ib (PHP-Ib).

Science.gov (United States)

Molinaro, Angelo; Tiosano, Dov; Takatani, Rieko; Chrysis, Dionisios; Russell, William; Koscielniak, Nikolas; Kottler, Marie-Laure; Agretti, Patrizia; De Marco, Giuseppina; Ahtiainen, Petteri; Christov, Marta; Mäkitie, Outi; Tonacchera, Massimo; Jüppner, Harald

2015-05-01

Hypocalcemia and hyperphosphatemia because of resistance toward parathyroid hormone (PTH) in the proximal renal tubules are the most prominent abnormalities in patients affected by pseudohypoparathyroidism type Ib (PHP-Ib). In this rare disorder, which is caused by GNAS methylation changes, resistance can occur toward other hormones, such as thyroid-stimulating hormone (TSH), that mediate their actions through G protein-coupled receptors. However, these additional laboratory abnormalities are usually not recognized until PTH-resistant hypocalcemia becomes clinically apparent. We now describe four pediatric patients, first diagnosed with subclinical or overt hypothyroidism between the ages of 0.2 and 15 years, who developed overt PTH-resistance 3 to 20 years later. Although anti-thyroperoxidase (anti-TPO) antibodies provided a plausible explanation for hypothyroidism in one of these patients, this and two other patients revealed broad epigenetic GNAS abnormalities, which included loss of methylation (LOM) at exons AS, XL, and A/B, and gain of methylation at exon NESP55; ie, findings consistent with PHP-Ib. LOM at GNAS exon A/B alone led in the fourth patient to the identification of a maternally inherited 3-kb STX16 deletion, a well-established cause of autosomal dominant PHP-Ib. Although GNAS methylation changes were not detected in additional pediatric and adult patients with subclinical hypothyroidism (23 pediatric and 39 adult cases), hypothyroidism can obviously be the initial finding in PHP-Ib patients. One should therefore consider measuring PTH, along with calcium and phosphate, in patients with unexplained hypothyroidism for extended periods of time to avoid hypocalcemia and associated clinical complications. © 2014 American Society for Bone and Mineral Research.

The insulin-like growth axis in patients with autoimmune thyrotoxicosis

DEFF Research Database (Denmark)

Zimmermann-Belsing, T; Juul, A; Juul Holst, J

2004-01-01

Hyperthyroidism is associated with altered growth hormone (GH) secretion. Many patients with thyroid dysfunction experience several poorly described complications such as symptoms and signs also seen in patients with growth hormone deficiency (GHD). We have therefore prospectively evaluated a pos...... years (33-47)), we measured serum thyroxine, triiodothyronine, thyrotropine (TSH), TSH receptor antibodies, anti-thyroid peroxidase, leptin, body composition, body mass index (BMI) and IGF-related peptides at diagnosis and after 12 months of treatment with thiamazol (ATD)....

Serum TSH, thyroglobulin, and thyroidal disorders in atomic bomb survivors exposed in youth: 30-year follow-up study

International Nuclear Information System (INIS)

Morimoto, I.; Yoshimoto, Y.; Sato, K.; Hamilton, H.B.; Kawamoto, S.; Izumi, M.; Nagataki, S.

1987-01-01

Follow-up examinations to determine the frequency of thyroidal disorders were conducted by the Radiation Effects Research Foundation (RERF) on individuals in Hiroshima and Nagasaki who were less than 20 yr of age at the time of exposure to the atomic bomb. Concentrations of serum thyroid stimulating hormone (TSH), thyroglobulin (TG), and anti-TG antibody 30 yr after exposure were also determined. Nontoxic uninodular goiter was found in 13 cases of the 100 + rad exposed group (n = 477) and in three cases of the nonexposed group (n = 501). The prevalence in the 100+ rad exposed group was significantly higher (chi-squared = 6.584, p less than 0.01). Thyroid cancer was found in eight exposed cases, all of whom were in the 100+ rad group, and the prevalence was significantly greater (chi-squared = 7.919, p less than 0.01). Regardless of the presence or absence of thyroid disorders, serum TSH and TG levels were not statistically different between the 100 rad + exposed and nonexposed groups. Although hypothyroidism was found in 23 of the total cases, there was no correlation between its development and exposure to ionizing irradiation

Different mechanisms are involved in the antibody mediated inhibition of ligand binding to the urokinase receptor

DEFF Research Database (Denmark)

List, K; Høyer-Hansen, G; Rønne, E

1999-01-01

Certain monoclonal antibodies are capable of inhibiting the biological binding reactions of their target proteins. At the molecular level, this type of effect may be brought about by completely different mechanisms, such as competition for common binding determinants, steric hindrance or interfer......Certain monoclonal antibodies are capable of inhibiting the biological binding reactions of their target proteins. At the molecular level, this type of effect may be brought about by completely different mechanisms, such as competition for common binding determinants, steric hindrance......) can be employed as a highly useful tool to characterize the inhibitory mechanism of specific antagonist antibodies. Two inhibitory antibodies against uPAR, mAb R3 and mAb R5, were shown to exhibit competitive and non-competitive inhibition, respectively, of ligand binding to the receptor. The former...

TSH-induced hyperthyroidism caused by a pituitary tumor.

Science.gov (United States)

Beck-Peccoz, Paolo; Persani, Luca

2006-09-01

A 45-year-old man presented with frontal headache and visual disturbances to our clinic. For the previous 5 years, he had been receiving treatment for long-lasting mild hyperthyroidism with antithyroid therapy, but therapy had not been carefully followed. During the last 2 years he had also complained of erectile dysfunction and loss of libido. On physical examination, he had a small goiter, normal skin, no Graves' ophthalmopathy, normal BMI, and reduced testis volume and pubic hair. Serum levels of free T3 and T4, serum prolactin, testosterone, serum gonadotropins, insulin-like growth factor 1, adrenocorticotropic hormone, and cortisol were measured. MRI scan, TSH-releasing hormone test, and T3 suppression test were carried out. Levels of pituitary glycoprotein hormone alpha-subunit and sex-hormone-binding protein were also measured. Hyperthyroidism caused by a mixed pituitary adenoma that secretes prolactin and TSH. Trans-sphenoidal resection of the pituitary tumor. After surgery, T3 suppression test failed to completely suppress TSH secretion, which suggested a persistence of residual adenomatous cells. Hyperthyroidism and hypogonadism recurred after 5 years, therefore, treatment with lanreotide was initiated, and resulted in complete resolution of signs and symptoms of the disease.

Comparison of Immunoassay methods for T3, T4 and TSH

International Nuclear Information System (INIS)

Alonso Rodríguez, Celia A.

2016-01-01

Measurements of T3, T4 and TSH have been considered very important in the diagnosis and monitoring of thyroid diseases both overt and subclinical. These subclinical diseases are actively seeking for years, both in healthy patients and hospitalized for other illnesses; and in the population over 35 years, especially women, in health checkups. The active search for these diseases requires the use of rapid and reliable techniques; that can be developed massively, with good level of detectability and comparable. The overall objective is to present the evaluation of different immunoassay techniques with respect to the RIA and IRMA: ELISA, chemiluminescence, Amplified Chemiluminescence, electrochemiluminescence Immunofluorescence. Compare including automatic methods and analyze the cost and feasibility of them for laboratory immunoassay. ELISA colorimetric technique for dosing was comparable to RIA T4, not for T3. Chemiluminescence (AMERLITE) compared to dosing RIA and IRMA T4 to TSH proved to be valid for both. Amplified Chemiluminescence (Immulite) compared to IRMA for TSH was no significant difference. Electrochemiluminescence (Elecsys 2010) compared to T3 and T4 RIA and IRMA for TSH, no significant differences for T4 and TSH; but no variation to T3. Immunofluorescence (AIA-600) used to compare with RIA for T3 and T4, and TSH IRMA, no significant differences for the measured analytes. Benchmarking of automatic methods suggests that the most thrifty of trials is Immunofluorescence the AIA-600, regarding calibration and control, programming time, randomization and the ability to save the value of the fluorescence deferred calculations for tests without valid at the time of realizing calibration. Analyzing the cost and feasibility of these methods for laboratory immunoassay, we must consider that their characteristics electrochemiluminescence is the fastest, but its price is prohibitive for our health systems. The AIA-600 appears to be the method of choice for its

Extended hormone binding site of the human thyroid stimulating hormone receptor: distinctive acidic residues in the hinge region are involved in bovine thyroid stimulating hormone binding and receptor activation.

Science.gov (United States)

Mueller, Sandra; Kleinau, Gunnar; Jaeschke, Holger; Paschke, Ralf; Krause, Gerd

2008-06-27

The human thyroid stimulating hormone receptor (hTSHR) belongs to the glycoprotein hormone receptors that bind the hormones at their large extracellular domain. The extracellular hinge region of the TSHR connects the N-terminal leucine-rich repeat domain with the membrane-spanning serpentine domain. From previous studies we reasoned that apart from hormone binding at the leucine-rich repeat domain, additional multiple hormone contacts might exist at the hinge region of the TSHR by complementary charge-charge recognition. Here we investigated highly conserved charged residues in the hinge region of the TSHR by site-directed mutagenesis to identify amino acids interacting with bovine TSH (bTSH). Indeed, the residues Glu-297, Glu-303, and Asp-382 in the TSHR hinge region are essential for bTSH binding and partially for signal transduction. Side chain substitutions showed that the negative charge of Glu-297 and Asp-382 is necessary for recognition of bTSH by the hTSHR. Multiple combinations of alanine mutants of the identified positions revealed an increased negative effect on hormone binding. An assembled model suggests that the deciphered acidic residues form negatively charged patches at the hinge region resulting in an extended binding mode for bTSH on the hTSHR. Our data indicate that certain positively charged residues of bTSH might be involved in interaction with the identified negatively charged amino acids of the hTSHR hinge region. We demonstrate that the hinge region represents an extracellular intermediate connector for both hormone binding and signal transduction of the hTSHR.

The Isolation of Novel Phage Display-Derived Human Recombinant Antibodies Against CCR5, the Major Co-Receptor of HIV

OpenAIRE

Shimoni, Moria; Herschhorn, Alon; Britan-Rosich, Yelena; Kotler, Moshe; Benhar, Itai; Hizi, Amnon

2013-01-01

Selecting for antibodies against specific cell-surface proteins is a difficult task due to many unrelated proteins that are expressed on the cell surface. Here, we describe a method to screen antibody-presenting phage libraries against native cell-surface proteins. We applied this method to isolate antibodies that selectively recognize CCR5, which is the major co-receptor for HIV entry (consequently, playing a pivotal role in HIV transmission and pathogenesis). We employed a phage screening s...

Preoperative TSH level and risk of thyroid cancer in patients with nodular thyroid disease: nodule size contribution.

Science.gov (United States)

Zafón, Carles; Obiols, Gabriel; Mesa, Jordi

2015-01-01

Many reports have supported the relationship between high preoperative TSH levels and risk of thyroid cancer in nodular thyroid disease (NTD). We investigated whether TSH levels are related to the risk of differentiated thyroid carcinoma (DTC) in patients who have undergone total thyroidectomy for NTD. The relationship between TSH and size of malignant nodule was investigated. Finally, we assessed whether TSH levels are related to DTC and presence of additional benign nodules. A retrospective study of 980 patients was conducted. Variables included age at diagnosis, TSH level, nodule size, gender, final histology (benign versus DTC), and type of malignancy. Malignancy was present in 261 (26.6%) patients. These patients had higher median TSH levels as compared to those with no malignancy (1.61 mU/L (0.9-2.5) versus 0.9 mU/L (0.3-1.6); p-value<0.001). TSH was higher in patients with DTC in whom the largest nodule was malignant than in patients in whom the largest nodule was benign (1.80 mU/L (1.1-2.6) versus 1.38 mU/L (0.7-2.1) respectively; p-value=0.025). A significant correlation was seen between malignant nodule size and TSH level, but not between TSH levels and size of the largest benign nodule. Our study supported an association between preoperative TSH levels and risk of DTC in patients with NTD. There was also a direct relationship between malignant nodule size and TSH levels. By contrast, no relationship was found between the size of benign nodules and TSH levels. Copyright © 2014 SEEN. Published by Elsevier Espana. All rights reserved.

Enraizamento e crescimento de estacas herbáceas do cacaueiro (clones Cepec 42, tsh 516 e tsh 1188 em função da aplicação do ácido indolbutírico (AIB

Directory of Open Access Journals (Sweden)

Faria José Cláudio

2003-01-01

Full Text Available Estacas apicais herbáceas de ramos plagiotrópicos do cacaueiro (clones CEPEC 42, TSH 516 e TSH 1188 foram tratadas com 0 e 6.000 mg.kg-1 do ácido indolbutírico (AIB e estaqueadas em tubetes de 288 cm³ contendo como substrato uma mistura de Plantmax® e fibra de coco triturada (1:1, enriquecido com Osmocote® (19-06-20 e PG mix® (14-16-18. Os tubetes foram acondicionados em bandejas e estas foram mantidas em câmaras de nebulização. Na avaliação, realizada aos 78 dias após o estaqueamento, verificou-se que, independentemente da aplicação de AIB, as estacas dos clones avaliados apresentaram índices de enraizamento superiores a 87%, mas o tratamento das estacas com AIB aumentou os índices de sobrevivência e de estacas enraizadas de todos os clones, número de raízes (clones TSH 516 e TSH 1188, matéria seca de raízes (Clones CEPEC 42 e TSH 516 e matéria seca da parte aérea (Clones TSH 566 e TSH 1188.

Multiple metals predict prolactin and thyrotropin (TSH) levels in men

Energy Technology Data Exchange (ETDEWEB)

Meeker, John D., E-mail: meekerj@umich.edu [Department of Environmental Health Sciences, University of Michigan School of Public Health, 6635 SPH Tower, 109 S. Observatory St., Ann Arbor, MI 48109 (United States); Rossano, Mary G. [Department of Animal and Food Sciences, University of Kentucky, Lexington, KY (United States); Protas, Bridget [Department of Epidemiology, Michigan State University, East Lansing, MI (United States); Diamond, Michael P.; Puscheck, Elizabeth [Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI (United States); Daly, Douglas [Grand Rapids Fertility and IVF, Grand Rapids, MI (United States); Paneth, Nigel [Department of Obstetrics and Gynecology, Michigan State University, East Lansing, MI (United States); Wirth, Julia J. [Department of Epidemiology, Michigan State University, East Lansing, MI (United States); Department of Obstetrics and Gynecology, Michigan State University, East Lansing, MI (United States)

2009-10-15

Exposure to a number of metals can affect neuroendocrine and thyroid signaling, which can result in adverse effects on development, behavior, metabolism, reproduction, and other functions. The present study assessed the relationship between metal concentrations in blood and serum prolactin (PRL) and thyrotropin (TSH) levels, markers of dopaminergic, and thyroid function, respectively, among men participating in a study of environmental influences on male reproductive health. Blood samples from 219 men were analyzed for concentrations of 11 metals and serum levels of PRL and TSH. In multiple linear regression models adjusted for age, BMI and smoking, PRL was inversely associated with arsenic, cadmium, copper, lead, manganese, molybdenum, and zinc, but positively associated with chromium. Several of these associations (Cd, Pb, Mo) are consistent with limited studies in humans or animals, and a number of the relationships (Cr, Cu, Pb, Mo) remained when additionally considering multiple metals in the model. Lead and copper were associated with non-monotonic decrease in TSH, while arsenic was associated with a dose-dependent increase in TSH. For arsenic these findings were consistent with recent experimental studies where arsenic inhibited enzymes involved in thyroid hormone synthesis and signaling. More research is needed for a better understanding of the role of metals in neuroendocrine and thyroid function and related health implications.

Multiple metals predict prolactin and thyrotropin (TSH) levels in men

International Nuclear Information System (INIS)

Meeker, John D.; Rossano, Mary G.; Protas, Bridget; Diamond, Michael P.; Puscheck, Elizabeth; Daly, Douglas; Paneth, Nigel; Wirth, Julia J.

2009-01-01

Exposure to a number of metals can affect neuroendocrine and thyroid signaling, which can result in adverse effects on development, behavior, metabolism, reproduction, and other functions. The present study assessed the relationship between metal concentrations in blood and serum prolactin (PRL) and thyrotropin (TSH) levels, markers of dopaminergic, and thyroid function, respectively, among men participating in a study of environmental influences on male reproductive health. Blood samples from 219 men were analyzed for concentrations of 11 metals and serum levels of PRL and TSH. In multiple linear regression models adjusted for age, BMI and smoking, PRL was inversely associated with arsenic, cadmium, copper, lead, manganese, molybdenum, and zinc, but positively associated with chromium. Several of these associations (Cd, Pb, Mo) are consistent with limited studies in humans or animals, and a number of the relationships (Cr, Cu, Pb, Mo) remained when additionally considering multiple metals in the model. Lead and copper were associated with non-monotonic decrease in TSH, while arsenic was associated with a dose-dependent increase in TSH. For arsenic these findings were consistent with recent experimental studies where arsenic inhibited enzymes involved in thyroid hormone synthesis and signaling. More research is needed for a better understanding of the role of metals in neuroendocrine and thyroid function and related health implications.

Methylation of the thyroid stimulating hormone receptor: diagnostic marker of malignity in thyroid cancer

International Nuclear Information System (INIS)

Marrero Rodriguez, Maria Teresa

2007-01-01

The methylation state of the gene promoter for the receptor of the thyroid stimulating hormone (TSH) in the diagnosis of thyroid tumors of epithelial origin was analyzed. The study was conducted in thyroid tissue obtained from paraffin blocks of different thyroid pathologies (papillary, follicular and undifferentiated carcinoma and follicular adenomas). The work was done by using the DNA modification technique with sodium bisulfite, and polymerase chain reaction was applied to analyze the gene methylation state. Methylation of the promoter for the gene of the TSH receptor was found in the papillary carcinomas (33 of 40; 82.5 %), in 10 undifferentiated carcinomas (100 %), and in 10 of the 15 follicular carcinomas analyzed (66.6 %). No methylation was observed in the 8 follicular adenomas under study. The methylation of the gene for the TSH receptor was proposed as a new diagnostic marker of malignity and as a basis for using demethylating agents together with radioiodine therapy in patients with thyroid cancer of epithelial origin that do not respond to therapy. (Author)

The 11th quality control survey for radioisotopes in vitro tests in Japan, 1989

Energy Technology Data Exchange (ETDEWEB)

1990-10-01

This report presents the results of the 11th quality control nationwide survey. Of 730 facilities performing radioisotopes in vitro tests in November 1989, 422 facilities (60.5%) participated in the present survey. The following 23 items were examined: adrenocorticotropic hormone (ACTH), albumin, carbohydrate antigen 125 (CA 125), carbohydrate antigen 19-9 (CA 19-9), carcinoembryonic antigen (CEA), calcitonin, cortisol, estradiol, ferritin, free thyroxine (FT{sub 4}), follicle stimulating hormone (FSH), gastrine, cholylglycine, glucagon, insulin, anti-DNA antibody, luteinizing hormone (LH), neuron specific enolase (NSE), parathyroid hormone (PTH), squamous cell carcinoma associated antigen (SCC), thyroxine (T{sub 4}), thyroxine binding globulin (TBG), and antithyroid stimulating hormone (TSH) receptor antibody. 'Within kit variation' between facilities showed large coefficient of variation for ACTH, CA125, CEA, estradiol, ferritin, FSH, glucagon, anti-DNA antibody, LH, PTH, and TSH receptor antibody. Both 'within kit variation' and 'between kit variation' showed small coefficient of variation for cortisol, free T{sub 4}, NSE, SCC, T{sub 4}, and TBG. The present survey was characterized by using immunoradiometric assay (IRMA) and non-isotope techniques, as well as radioimmunoassay. Kits for IRMA greatly varied from facility to facility. (N.K.).

Use of a cytochemical bioassay for determination of thyroid stimulating hormone (TSH) in clinical investigation

International Nuclear Information System (INIS)

Doehler, K.D.; Hashimoto, T.; Zur Muehlen, A. von

1977-01-01

Recently a highly sensitive cytochemical bioassay (CBA) for the determination of human TSH has been developed. We could show that this assay is specific for TSH and measurements done on plasma of normal euthyroid persons agree well with radioimmunological findings. Due to the extreme sensitivity of the CBA we were able to detect low but measurable TSH levels in patients with primary hyperthyroidism, which were not increased by TRH treatment before therapeutic treatment. After therapeutic treatment, TRH application was able to stimulate additional biologically active TSH release which, however, barely reached the lowest limit of detection by RIA. In certain pathological cases we were able to detect elevated plasma TSH levels, which were active immunologically but inactive biologically. (orig.) [de

[Particular evolution of the thyroid state in Grave's disease: two cases].

Science.gov (United States)

Cherif, Lotfi; Ben Abdallah, Néjib; Khairi, Karima; Hadj Ali, Inçaf; Turki, Sami; Ben Maïz, Hédi

2003-09-01

We report two cases of Grave's disease (GD) caracterized by the succession of hypothyroid and hyperthyroid states. Case 1: A 32 years old woman, has presented initially a typical GD with hyperthyroidism. Grave's ophtalmopathy and homogenous goiter. Four months later, she presented a spontaneous hypothyroidism necessiting treatment with thyroxine and a severe myasthenia gravis. More later (6 months), she experienced symptoms of hyperthyroidism after thymectomy. The level of anti-thyrotropin-receptor antibodies (TSab) was very high (141 UI/I, NV < 10). Case 2: A 29 years old woman has been treated by thyroxine (150 microg/day) for a primary hypothyroidism. Ten months later, she presented symptoms of hyperthyroidism even after stoppage of thyroxine. TSH value was decreased (TSH < 0.05 microU/ml) and FT4 level was raised (FT4 = 25.5 pmol/l). The thyroid antibodies were positive. We discuss, after review of the litterature, the physiopathological mecanisms of these changes in the thyroid state, particularly the role of the blocking and stimulating anti-thyrotropin-receptor antibodies.

Metilación del receptor de la hormona estimulante del tiroides: marcador diagnóstico de malignidad en cáncer de tiroides Methylation of the thyroid stimulating hormone receptor: diagnostic marker of malignity in thyroid cancer

Directory of Open Access Journals (Sweden)

María Teresa Marrero Rodríguez

2007-12-01

Full Text Available Se analizó el estado de metilación del promotor del gen para el receptor de la hormona estimulante del tiroides (TSH en el diagnóstico de tumores tiroideos de origen epitelial. El estudio se realizó en tejido tiroideo obtenido de bloques de parafina de diferentes patologías tiroideas (carcinoma papilar, folicular e indiferenciado, y adenomas foliculares. El trabajo se realizó empleando la técnica de modificación del ADN con bisulfito de sodio y el análisis del estado de la metilación del gen RTSH se realizó por el método de reacción en cadena de la polimerasa específica para metilación. Encontramos metilación del promotor para el gen del receptor de TSH en los carcinomas papilares (33 de 40; 82,5 %, en los 10 carcinomas indiferenciados (100 % y en 10 de los 15 carcinomas foliculares analizados (66,6 %. En cambio, no se observó metilación en los 8 adenomas foliculares analizados. Se propone la metilación del gen para el receptor de TSH como un nuevo marcador diagnóstico de malignidad, y una base para emplear agentes desmetilantes conjuntamente con la terapia con radioyodo, en los pacientes con cáncer de tiroides de origen epitelial que no respondan a la terapia.The methylation state of the gene promoter for the receptor of the thyroid stimulating hormone (TSH in the diagnosis of thyroid tumors of epithelial origin was analyzed. The study was conducted in thyroid tissue obtained from paraffin blocks of different thyroid pathologies (papillary, follicular and undifferentiated carcinoma and follicular adenomas. The work was done by using the DNA modification technique with sodium bisulfite, and polymerase chain reaction was applied to analyze the gene methylation state. Methylation of the promoter for the gene of the TSH receptor was found in the papillary carcinomas (33 of 40; 82.5 %, in 10 undifferentiated carcinomas (100 %, and in 10 of the 15 follicular carcinomas analyzed (66.6 %. No methylation was observed in the 8

A panel of recombinant monoclonal antibodies against zebrafish neural receptors and secreted proteins suitable for wholemount immunostaining.

Science.gov (United States)

Staudt, Nicole; Müller-Sienerth, Nicole; Fane-Dremucheva, Alla; Yusaf, Shahnaz P; Millrine, David; Wright, Gavin J

2015-01-02

Cell surface receptors and secreted proteins play important roles in neural recognition processes, but because their site of action can be a long distance from neuron cell bodies, antibodies that label these proteins are valuable to understand their function. The zebrafish embryo is a popular vertebrate model for neurobiology, but suffers from a paucity of validated antibody reagents. Here, we use the entire ectodomain of neural zebrafish cell surface or secreted proteins expressed in mammalian cells to select monoclonal antibodies to ten different antigens. The antibodies were characterised by Western blotting and the sensitivity of their epitopes to formalin fixation was determined. The rearranged antigen binding regions of the antibodies were amplified and cloned which enabled expression in a recombinant form from a single plasmid. All ten antibodies gave specific staining patterns within formalin-treated embryonic zebrafish brains, demonstrating that this generalised approach is particularly efficient to elicit antibodies that stain native antigen in fixed wholemount tissue. Finally, we show that additional tags can be easily added to the recombinant antibodies for convenient multiplex staining. The antibodies and the approaches described here will help to address the lack of well-defined antibody reagents in zebrafish research. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Challenges in interpretation of thyroid function tests in pregnant women with autoimmune thyroid disease

DEFF Research Database (Denmark)

Feldt-Rasmussen, Ulla; Bliddal, Sofie; Rasmussen, Åse Krogh

2011-01-01

Physiological changes during gestation are important to be aware of in measurement and interpretation of thyroid function tests in women with autoimmune thyroid diseases. Thyroid autoimmune activity is decreasing in pregnancy. Measurement of serum TSH is the first-line screening variable....... Measurement of antithyroperoxidase and/or TSH receptor antibodies adds to the differential diagnosis of autoimmune and nonautoimmune thyroid diseases....... for thyroid dysfunction also in pregnancy. However, using serum TSH for control of treatment of maternal thyroid autoimmunity infers a risk for compromised foetal development. Peripheral thyroid hormone values are highly different among laboratories, and there is a need for laboratory-specific gestational age...

Potent neutralization of VEGF biological activities with a fully human antibody Fab fragment directed against VEGF receptor 2

International Nuclear Information System (INIS)

Miao, H.-Q.; Hu, Kun; Jimenez, Xenia; Navarro, Elizabeth; Zhang, Haifan; Lu Dan; Ludwig, Dale L.; Balderes, Paul; Zhu Zhenping

2006-01-01

Compelling evidence suggest that vascular endothelial growth factor (VEGF) and its receptors, especially receptor 2 (VEGFR2, or kinase insert domain-containing receptor, KDR), play a critical role in angiogenesis under both physiological and pathological conditions, including cancer and angiogenic retinopathies such as age-related macular degeneration (AMD). To this end, inhibition of angiogenesis with antagonists to either VEGF or KDR has yielded significant therapeutic efficacy both in preclinical studies in animal models and in clinical trials in patients with cancer and AMD. We previously reported the identification of a high affinity, fully human anti-KDR antibody fragment, 1121B Fab, through a highly stringent affinity maturation process with a Fab originally isolated from a naive human antibody phage display library. In this study, we demonstrate that 1121B Fab is able to strongly block KDR/VEGF interaction, resulting in potent inhibition of an array of biological activities of VEGF, including activation of the receptor and its signaling pathway, intracellular calcium mobilization, and migration and proliferation of endothelial cells. Taken together, our data lend strong support to the further development of 1121B Fab fragment as an anti-angiogenesis agent in both cancer and angiogenic retinopathies

Long-term efficacy of modified-release recombinant human TSH (MRrhTSH) augmented radioiodine (131I) therapy for benign multinodular goiter. Results from a multicenter international, randomized, placebo-controlled dose-selection study

DEFF Research Database (Denmark)

Fast, Søren; Hegedus, Laszlo; Pacini, Furio

2014-01-01

with 131I-therapy. Methods: In this phase II, single-blinded, placebo-controlled study, 95 patients (57.2±9.6 years old, 85% women, 83% Caucasians) with MNG (median size 96.0 ml (31.9 - 242.2 ml)) were randomized to receive placebo (n=32), 0.01 mg MRrhTSH (n=30) or 0.03 mg MRrhTSH (n=33), 24 hours before...... a calculated 131I activity. Thyroid volume (TV) and smallest cross-sectional area of trachea (SCAT) were measured (by CT-scan) at baseline, month 6 and month 36. Thyroid function and quality of life (QoL) was evaluated at 3 month and yearly intervals, respectively. Results: At 6 months, TV reduction...... was enhanced in the 0.03 mg MRrhTSH group (32.9% versus 23.1% in the placebo group, p=0.03), but not in the 0.01 mg MRrhTSH group. At month 36 the mean percent TV reduction from baseline was 44 ± 12.7% (SD) in the placebo group, 41 ± 21.0% in the 0.01 mg MRrhTSH-group and 53 ± 18.6% in the 0.03 mg MRrh...

Can neonatal TSH screening reflect trends in population iodine intake?

LENUS (Irish Health Repository)

Burns, Robert

2008-08-01

The distribution of neonatal blood thyroid-stimulating hormone (TSH) concentrations has been used as an index reflecting population dietary iodine intake, with higher concentrations being indicative of lower iodine intake. We examined this distribution in neonates born in Ireland, where the pregnant population has shown a recent decline in urinary iodine (UI) excretion. Our objectives were to determine if any alteration was observed in the percentage of values > 5.0 mIU\\/L and whether a trend in neonatal blood TSH was apparent.

Is serum TSH a biomarker of thyroid carcinoma in patients residing in a mildly iodine-deficient area?

DEFF Research Database (Denmark)

Swan, Kristine Zøylner; Nielsen, Viveque Egsgaard; Godballe, Christian

2018-01-01

Purpose: To investigate the association between the pre-operative serum TSH (s-TSH) level and differentiated thyroid carcinoma (DTC) in a mildly iodine-deficient area. Methods: Patients undergoing surgery for thyroid nodular disease (TND) were included from three tertiary surgical departments. Da......-TSH between patients with benign and malignant TND, s-TSH is not suitable as a biomarker of DTC in a clinical setting....

An MHC-restricted antibody-based chimeric antigen receptor requires TCR-like affinity to maintain antigen specificity

Directory of Open Access Journals (Sweden)

Marcela V Maus

2016-01-01

Full Text Available Chimeric antigen receptors (CARs are synthetic receptors that usually redirect T cells to surface antigens independent of human leukocyte antigen (HLA. Here, we investigated a T cell receptor-like CAR based on an antibody that recognizes HLA-A*0201 presenting a peptide epitope derived from the cancer-testis antigen NY-ESO-1. We hypothesized that this CAR would efficiently redirect transduced T cells in an HLA-restricted, antigen-specific manner. However, we found that despite the specificity of the soluble Fab, the same antibody in the form of a CAR caused moderate lysis of HLA-A2 expressing targets independent of antigen owing to T cell avidity. We hypothesized that lowering the affinity of the CAR for HLA-A2 would improve its specificity. We undertook a rational approach of mutating residues that, in the crystal structure, were predicted to stabilize binding to HLA-A2. We found that one mutation (DN lowered the affinity of the Fab to T cell receptor-range and restored the epitope specificity of the CAR. DN CAR T cells lysed native tumor targets in vitro, and, in a xenogeneic mouse model implanted with two human melanoma lines (A2+/NYESO+ and A2+/NYESO−, DN CAR T cells specifically migrated to, and delayed progression of, only the HLA-A2+/NY-ESO-1+ melanoma. Thus, although maintaining MHC-restricted antigen specificity required T cell receptor-like affinity that decreased potency, there is exciting potential for CARs to expand their repertoire to include a broad range of intracellular antigens.

TSH Response to the Intravenous Administration of Synthetic TRH in Various Thyroid Diseases

Energy Technology Data Exchange (ETDEWEB)

Choi, Sung Jae; Kim, Kwang Won; Lee, Mun Ho [Seoul National University College of Medicine, Seoul (Korea, Republic of)

1980-03-15

Serum TSH levels were ,measured by radioimmunoassay before and after intravenous administration of synthetic thyrotropin-releasing hormone(TRH) to 15 normal subjects and 55 patients with primary thyroid disease (14 patients with euthyroidism, 24 patients with thyrotoxicosis and 17 patients with hypothyroidism) to evaluate pituitary TSH reserve and its diagnostic availability. The observed results were as follows. 1) In normal subjects, serum TSH responses to synthetic TRH were 3.2+-1.0 at 0 min (baseline TSH level), 8.0+-4.0 at 10 min, 11.7+-5.0 at 20 min, 13.7+-7.1 at 80 min, 9.7+-5.0 at 60 min., 5.2+-2.0 at 120 min. and 3.6+-0.4 muU/ml at 180 min. Serum TSH peaked at 20-30 minutes and returned nearly to baseline at 180 minutes. 2) In euthyroid group, serum TSH responses to synthetic TRH were 3.3+-1.6 at 0 min, 8.6+-8.0 at 10 min, 10.9+-8. 5 at 20 min, 12.5+-8.4 at 30 min, 9.0+-5.9 at 60 min, 5.6+-2.6 at 120 min and 3.5+-1.3 muU/ml at 180 min. No significant difference revealed between euthyroid group and normal subjects(p>0.05). 3) In hyperthyroid group, serum TSH responses to synthetic TRH were 1.5+-0.6 at 0 min, 2.2+-0.8 at 10 min., 2.3+-1.0 at 20 min., 2.4+-1.5 at 30 min., 2.1+-1.1 at 60 min,, 1.9+-0.2 at 120 min, and 1. 5+-0.8 muU/ml, at 180 min., No response to TRH showed. 4) In hypothyroid group, mean values of serum TSH response to synthetic TRH were 42.0 at 0 min., 60.6 at 10 min., 124.8 at 20 min., 123.0 at 30 min. 101.6 at 60 min., 64.3 at 120 min. and 15.5 muU/ml at 180 min., Patients with primary hypothyroidism showed an exaggerated TSH response to synthetic TRH despite their high basal TSH. 5) Side effects attending synthetic TRH administration were transient nausea (59.0%), desire to micturate (59.0%), feeling of flushing (19.7%), dizziness (45.9%), metallic taste (9.8%) and headache (19.7%). Any side effect didn't show in 16.4%. These symptoms began almost immediately after TRH intravenous injection and lasted several minutes, and not related

Molecular and Therapeutic Characterization of Anti-ectodysplasin A Receptor (EDAR) Agonist Monoclonal Antibodies*

Science.gov (United States)

Kowalczyk, Christine; Dunkel, Nathalie; Willen, Laure; Casal, Margret L.; Mauldin, Elizabeth A.; Gaide, Olivier; Tardivel, Aubry; Badic, Giovanna; Etter, Anne-Lise; Favre, Manuel; Jefferson, Douglas M.; Headon, Denis J.; Demotz, Stéphane; Schneider, Pascal

2011-01-01

The TNF family ligand ectodysplasin A (EDA) and its receptor EDAR are required for proper development of skin appendages such as hair, teeth, and eccrine sweat glands. Loss of function mutations in the Eda gene cause X-linked hypohidrotic ectodermal dysplasia (XLHED), a condition that can be ameliorated in mice and dogs by timely administration of recombinant EDA. In this study, several agonist anti-EDAR monoclonal antibodies were generated that cross-react with the extracellular domains of human, dog, rat, mouse, and chicken EDAR. Their half-life in adult mice was about 11 days. They induced tail hair and sweat gland formation when administered to newborn EDA-deficient Tabby mice, with an EC50 of 0.1 to 0.7 mg/kg. Divalency was necessary and sufficient for this therapeutic activity. Only some antibodies were also agonists in an in vitro surrogate activity assay based on the activation of the apoptotic Fas pathway. Activity in this assay correlated with small dissociation constants. When administered in utero in mice or at birth in dogs, agonist antibodies reverted several ectodermal dysplasia features, including tooth morphology. These antibodies are therefore predicted to efficiently trigger EDAR signaling in many vertebrate species and will be particularly suited for long term treatments. PMID:21730053

Receptor-binding domain of SARS-CoV spike protein induces highly potent neutralizing antibodies: implication for developing subunit vaccine

International Nuclear Information System (INIS)

He Yuxian; Zhou Yusen; Liu Shuwen; Kou Zhihua; Li Wenhui; Farzan, Michael; Jiang Shibo

2004-01-01

The spike (S) protein of severe acute respiratory syndrome (SARS) coronavirus (CoV), a type I transmembrane envelope glycoprotein, consists of S1 and S2 domains responsible for virus binding and fusion, respectively. The S1 contains a receptor-binding domain (RBD) that can specifically bind to angiotensin-converting enzyme 2 (ACE2), the receptor on target cells. Here we show that a recombinant fusion protein (designated RBD-Fc) containing 193-amino acid RBD (residues 318-510) and a human IgG1 Fc fragment can induce highly potent antibody responses in the immunized rabbits. The antibodies recognized RBD on S1 domain and completely inhibited SARS-CoV infection at a serum dilution of 1:10,240. Rabbit antisera effectively blocked binding of S1, which contains RBD, to ACE2. This suggests that RBD can induce highly potent neutralizing antibody responses and has potential to be developed as an effective and safe subunit vaccine for prevention of SARS

Molecular sampling of the allosteric binding pocket of the TSH receptor provides discriminative pharmacophores for antagonist and agonists.

Science.gov (United States)

Hoyer, Inna; Haas, Ann-Karin; Kreuchwig, Annika; Schülein, Ralf; Krause, Gerd

2013-02-01

The TSHR (thyrotropin receptor) is activated endogenously by the large hormone thyrotropin and activated pathologically by auto-antibodies. Both activate and bind at the extracellular domain. Recently, SMLs (small-molecule ligands) have been identified, which bind in an allosteric binding pocket within the transmembrane domain. Modelling driven site-directed mutagenesis of amino acids lining this pocket led to the delineation of activation and inactivation sensitive residues. Modified residues showing CAMs (constitutively activating mutations) indicate signalling-sensitive positions and mark potential trigger points for agonists. Silencing mutations lead to an impairment of basal activity and mark contact points for antagonists. Mapping these residues on to a structural model of TSHR indicates locations where an SML may switch the receptor to an inactive or active conformation. In the present article, we report the effects of SMLs on these signalling-sensitive amino acids at the TSHR. Surprisingly, the antagonistic effect of SML compound 52 was reversed to an agonistic effect, when tested at the CAM Y667A. Switching agonism to antagonism and the reverse by changing either SMLs or residues covering the binding pocket provides detailed knowledge about discriminative pharmacophores. It prepares the basis for rational optimization of new high-affinity antagonists to interfere with the pathogenic activation of the TSHR.

The clinical value of serum thyrotrophin receptor antibody level in patients with Graves ophthalmopathy

International Nuclear Information System (INIS)

Wang Chaodian; Shi Yuhong; Yan Bing

2013-01-01

Objective: To explore the value of serum thyrotrophin receptor antibody (TRAb) on the pathological mechanism of Graves ophthalmopathy. Methods: Two hundred and nineteen newly diagnosed Graves disease patients who were divided into Graves ophthalmopathy group (n=121) and without Graves ophthalmopathy group (n=98) were tested serum concentration with thyroid function, thyroperoxidase antibodies (TPOAb), thyroglobulin antibodies (TgAb) and TRAb. According to the consensus statement of the European Group on Graves ophthalmopathy, clinical activity score (CAS) and severity evaluation were carried out on Graves ophthalmopathy patients. Results: There was no significant difference in serum concentration of free thyroxine (FT 4 ), free triiodothyronine (FT 3 ), TPOAb and TRAb between the Graves ophthalmopathy group and the without Graves ophthalmopathy group. Serum concentration of TRAb was not correlated with the severity and CAS of Graves ophthalmopathy. Conclusions: The CAS and the severity of Graves ophthalmopathy were irrelevant to the serum concentration of TRAb. Therefore, the correlation between TRAb and Graves ophthalmopathy still needs further study. (authors)

Monoclonal antibody to the type I insulin-like growth factor (IGF-I) receptor blocks IGF-I receptor-mediated DNA synthesis: clarification of the mitogenic mechanisms of IGF-I and insulin in human skin fibroblasts

International Nuclear Information System (INIS)

Flier, J.S.; Usher, P.; Moses, A.C.

1986-01-01

Insulin and insulin-like growth factor type I (IGF-I) stimulate an overlapping spectrum of biological responses in human skin fibroblasts. Although insulin and IGF-I are known to stimulate the incorporation of [ 3 H]thymidine into DNA in these cells, the identify of the receptor(s) that mediates this effect has not been fully clarified. The mouse anti-human IGF-I receptor antibody αIR-3 binds with specificity to IGF-I but not to insulin receptors in human placental membranes; it also specifically inhibits the binding of 125 I-labeled IGF-I but not 125 I-labeled insulin to suspensions of human skin fibroblasts in a dose-dependent manner. αIR-3 competitively inhibits IGF-I-mediated stimulation of [ 3 H]thymidine incorporation into DNA. This inhibition is dependent on the concentration of αIR-3 and in the presence of a fixed antibody concentration can be partially overcome by high concentrations of IGF-I. In contrast, at concentrations of 3 H]thymidine incorporation is not inhibited by αIR-3. However, the incremental effects of higher concentrations (> 1 μg/ml) of insulin on [ 3 H]thymidine incorporation are inhibited by αIR-3. αIR-3 is a highly specific antagonist of IGF-I receptor-mediated mitogenesis in human skin fibroblasts. By using this antibody, it is shown directly that insulin can act through the IGF-I receptor to stimulate DNA synthesis but can also activate this effect through the insulin receptor itself

FcγRII-binding Centyrins mediate agonism and antibody-dependent cellular phagocytosis when fused to an anti-OX40 antibody.

Science.gov (United States)

Zhang, Di; Whitaker, Brian; Derebe, Mehabaw G; Chiu, Mark L

2018-04-01

Immunostimulatory antibodies against the tumor necrosis factor receptors (TNFR) are emerging as promising cancer immunotherapies. The agonism activity of such antibodies depends on crosslinking to Fc gamma RIIB receptor (FcγRIIB) to enable the antibody multimerization that drives TNFR activation. Previously, Fc engineering was used to enhance the binding of such antibodies to Fcγ receptors. Here, we report the identification of Centyrins as alternative scaffold proteins with binding affinities to homologous FcγRIIB and FcγRIIA, but not to other types of Fcγ receptors. One Centyrin, S29, was engineered at distinct positions of an anti-OX40 SF2 antibody to generate bispecific and tetravalent molecules named as mAbtyrins. Regardless of the position of S29 on the SF2 antibody, SF2-S29 mAbtyrins could bind FcγRIIB and FcγRIIA specifically while maintaining binding to OX40 receptors. In a NFκB reporter assay, attachment of S29 Centyrin molecules at the C-termini, but not the N-termini, resulted in SF2 antibodies with increased agonism owing to FcγRIIB crosslinking. The mAbtyrins also showed agonism in T-cell activation assays with immobilized FcγRIIB and FcγRIIA, but this activity was confined to mAbtyrins with S29 specifically at the C-termini of antibody heavy chains. Furthermore, regardless of the position of the molecule, S29 Centyrin could equip an otherwise Fc-silent antibody with antibody-dependent cellular phagocytosis activity without affecting the antibody's intrinsic antibody-dependent cell-meditated cytotoxicity and complement-dependent cytotoxicity. In summary, the appropriate adoption FcγRII-binding Centyrins as functional modules represents a novel strategy to engineer therapeutic antibodies with improved functionalities.

Evaluation of the specificity of antibodies raised against cannabinoid receptor type 2 in the mouse retina

DEFF Research Database (Denmark)

Cécyre, Bruno; Thomas, Sébastien; Ptito, Maurice

2014-01-01

Cannabinoid receptors (CB1R and CB2R) are among the most abundant G protein-coupled receptors in the central nervous system. The endocannabinoid system is an attractive therapeutic target for immune system modulation and peripheral pain management. While CB1R is distributed in the nervous system......, CB2R has traditionally been associated to the immune system. This dogma is currently a subject of debate since the discovery of CB2R expression in neurons using antibody-based methods. The localization of CB2R in the central nervous system (CNS) could have a significant impact on drug development...... because it would mean that in addition to its effects on the peripheral pain pathway, CB2R could also mediate some central effects of cannabinoids. In an attempt to clarify the debate over CB2R expression in the CNS, we tested several commercially or academically produced CB2R antibodies using Western...

Cetuximab in combination with anti-human IgG antibodies efficiently down-regulates the EGF receptor by macropinocytosis

International Nuclear Information System (INIS)

Berger, Christian; Madshus, Inger Helene; Stang, Espen

2012-01-01

The monoclonal antibody C225 (Cetuximab) blocks binding of ligand to the epidermal growth factor receptor (EGFR). In addition, it is known that incubation with C225 induces endocytosis of the EGFR. This endocytosis has previously been shown to be increased when C225 is combined with an additional monoclonal anti-EGFR antibody. However, the effects of antibody combinations on EGFR activation, endocytosis, trafficking and degradation have been unclear. By binding a secondary antibody to the C225-EGFR complex, we here demonstrate that a combination of antibodies can efficiently internalize and degrade the EGFR. Although the combination of antibodies activated the EGFR kinase and induced ubiquitination of the EGFR, the kinase activity was not required for internalization of the EGFR. In contrast to EGF-induced EGFR down-regulation, the antibody combination efficiently degraded the EGFR without initiating downstream proliferative signaling. The antibody-induced internalization of EGFR was found not to depend on clathrin and/or dynamin, but depended on actin polymerization, suggesting induction of macropinocytosis. Macropinocytosis may cause internalization of large membrane areas, and this could explain the highly efficient internalization of the EGFR induced by combination of antibodies. -- Highlight: ► Cetuximab induced endocytosis of EGFR increases upon combination with anti-human IgG. ► Antibody combination causes internalization of EGFR by macropinocytosis. ► Antibody-induced internalization of EGFR is independent of EGFR kinase activity. ► Antibody combination may have a zipper effect and cross-link EGFRs on neighboring cells.

25-Hydroxyvitamin D and TSH as Risk Factors or Prognostic Markers in Thyroid Carcinoma

Science.gov (United States)

Danilovic, Debora Lucia Seguro; Ferraz-de-Souza, Bruno; Fabri, Amanda Wictky; Santana, Nathalie Oliveira; Kulcsar, Marco Aurelio; Cernea, Claudio Roberto; Marui, Suemi; Hoff, Ana Oliveira

2016-01-01

Objective The increasing incidence of thyroid nodules demands identification of risk factors for malignant disease. Several studies suggested the association of higher TSH levels with cancer, but influence of 25-hydroxyvitamin D (25OHD) is controversial. This study aimed to identify the relationship of thyroid cancer with higher TSH levels and hypovitaminosis D and to evaluate their influence on prognostic characteristics of papillary thyroid carcinomas (PTC). Methods We retrospectively evaluated 433 patients submitted to thyroidectomy for thyroid nodules. Patients were categorized according to quartiles of TSH and 25OHD levels. Clinicopathological features were analyzed. Results Subjects with thyroid carcinomas were more frequently male and younger compared to those with benign disease. Their median TSH levels were higher and adjusted odds-ratio (OR) for cancer in the highest-quartile of TSH (> 2.4 mUI/mL) was 2.36 (1.36–4.09). Although vitamin D deficiency/insufficiency was prevalent in our cohort (84%), no significant differences in 25OHD levels or quartile distribution were observed between benign and malignant cases. Among 187 patients with PTC, analyses of prognostic features revealed increased risk of lymph nodes metastases for subjects with highest-quartile TSH levels (OR = 3.7, p = 0.029). Decreased 25OHD levels were not overtly associated with poor prognosis in PTC. Conclusions In this cross-sectional cohort, higher TSH levels increased the risk of cancer in thyroid nodules and influenced its prognosis, particularly favoring lymph nodes metastases. On the other hand, no association was found between 25OHD levels and thyroid carcinoma risk or prognosis, suggesting that serum 25OHD determination may not contribute to risk assessment workup of thyroid nodules. PMID:27737011

Association of TSH Elevation with All-Cause Mortality in Elderly Patients with Chronic Kidney Disease.

Directory of Open Access Journals (Sweden)

Mei-Hsing Chuang

Full Text Available Chronic kidney disease (CKD is a widespread condition in the global population and is more common in the elderly. Thyroid-stimulating hormone (TSH level increases with aging, and hypothyroidism is highly prevalent in CKD patients. However, the relationship between low thyroid function and mortality in CKD patients is unclear. Therefore, we conducted a retrospective cohort study to examine the relationship between TSH elevation and all-cause mortality in elderly patients with CKD. This retrospective cohort study included individuals ≥65 years old with CKD (n = 23,786 in Taipei City. Health examination data from 2005 to 2010 were provided by the Taipei Databank for Public Health Analysis. Subjects were categorized according to thyroid-stimulating hormone (TSH level as follows: low normal (0.34<TSH<1.074 mIU/L, middle normal (1.074≤TSH≤2.46 mIU/L, high normal (2.46<TSH<5.2 mIU/L, elevated I (5.2≤TSH<10 mIU/L, and elevated II (TSH≥10 mIU/L. Risk of mortality was evaluated using a Cox proportional hazard regression model adjusted for sex, age, hypertension, diabetes mellitus, CKD stage, serum albumin, high-density lipoprotein cholesterol, uric acid, hemoglobin, body mass index, glutamic-pyruvic transaminase, smoking, alcohol consumption, and history of cardiovascular disease (coronary artery disease, congestive heart failure, cerebral vascular disease, history of cancer, and history of chronic obstructive pulmonary disease. Our results showed that compared to the reference group (middle normal TSH, the risk of all-cause mortality was increased in the elevated I group (hazard ratio [HR], 1.21; 95% confidence interval [CI], 1.02-1.45 and elevated II group (HR, 1.30; 95% CI, 1.00-1.69. We found a significant association between TSH elevation and all-cause mortality in this cohort of elderly persons with CKD. However, determining the benefit of treatment for moderately elevated TSH level (5.2-10 mIU/L in elderly patients with CKD will require a

A noncognate interaction with anti-receptor antibody-activated helper T cells induces small resting murine B cells to proliferate and to secrete antibody

DEFF Research Database (Denmark)

Owens, T

1988-01-01

on resting B cells (even in the presence of intact F23.1 antibody), but could induce antibody secretion by anti-Ig-preactivated B cells. Both F23.1+ clones (E9.D4 and 4.35F2) and one F23.1- clone (D2.2) could synergize with supernatants from activated E9.D4 T cells to induce B cell activation. F(ab')2......Culture of small resting allogeneic B cells (of an irrelevant haplotype) with two clones of T helper (Th) cells that were activated by the F23.1 anti-T cell receptor antibody led to the activation of B cells to proliferate and to secrete antibody. Th cell supernatants by themselves had no effect...... fragments of F23.1 induced E9.D4 to activate B cells as efficiently as intact F23.1 and B cell populations that had been incubated with F23.1 were not activated when cultured with E9.D4, although T cells recognized cell-presented F23.1 and were weakly activated. Reduction of the density of F23.1 adsorbed...

Usefulness of recombinant human TSH aided radioiodine doses administered in patients with differentiated thyroid carcinoma

International Nuclear Information System (INIS)

Pitoia, Fabian; El Tamer, Elias; Schere, Daniel B.; Passerieu, Mariano; Bruno, Oscar D.; Niepominiszcze, Hugo

2006-01-01

The published studies confirming the safety and efficacy of rh TSH for diagnostic purposes have led to an increased interest in its use for preparation for radioiodine (RI) dose administration in patients with recurrent or persistent differentiated thyroid carcinoma (DTC). In order to establish the efficacy of RI therapy after rh TSH, we have reviewed 39 rh TSH-aided radioiodine treatments in a series of 28 DTC patients. Patients were divided into two groups: GI (n=17), with previous thyroid bed uptake and undetectable thyroglobulin (Tg) levels under levothyroxine treatment and GII (n=11), with proven metastatic local or distant disease. Median follow-up after the first rh TSH-aided radioiodine treatment was 32 ± 13 months (range 8 to 54 months). Sixteen patients (94%) in GI were rendered disease free and one patient was shown to have persistent disease. In GII, the post therapy whole body scan showed pathological uptakes in all cases: in four patients in lungs, in four in mediastinum and in three in lateral neck. In two patients with mediastinum uptake, Tg levels were undetectable after rh TSH. In the follow-up, two patients with lateral neck uptake were rendered disease free, four patients died (three due to thyroid cancer) and five out of the remaining patients have persistent disease. In conclusion, rh TSH aided therapy was helpful to eliminate normal thyroid bed remnants in 16/17 (94%) patients (GI). rh TSH stimulated Tg was undetectable in two patients with mediastinal metastasis. We believe that rh TSH is a good alternative to levothyroxine withdrawal for the treatment of DTC with radioactive iodine, increasing the quality of life in these patients. Caution should be recommended in the follow-up of unselected DTC patients only with stimulated Tg levels. (author) [es

TSH Response to the Intravenous Administration of Synthetic TRH in Various Thyroid Diseases

International Nuclear Information System (INIS)

Choi, Sung Jae; Kim, Kwang Won; Lee, Mun Ho

1980-01-01

Serum TSH levels were ,measured by radioimmunoassay before and after intravenous administration of synthetic thyrotropin-releasing hormone(TRH) to 15 normal subjects and 55 patients with primary thyroid disease (14 patients with euthyroidism, 24 patients with thyrotoxicosis and 17 patients with hypothyroidism) to evaluate pituitary TSH reserve and its diagnostic availability. The observed results were as follows. 1) In normal subjects, serum TSH responses to synthetic TRH were 3.2±1.0 at 0 min (baseline TSH level), 8.0±4.0 at 10 min, 11.7±5.0 at 20 min, 13.7±7.1 at 80 min, 9.7±5.0 at 60 min., 5.2±2.0 at 120 min. and 3.6±0.4 μU/ml at 180 min. Serum TSH peaked at 20-30 minutes and returned nearly to baseline at 180 minutes. 2) In euthyroid group, serum TSH responses to synthetic TRH were 3.3±1.6 at 0 min, 8.6±8.0 at 10 min, 10.9±8. 5 at 20 min, 12.5±8.4 at 30 min, 9.0±5.9 at 60 min, 5.6±2.6 at 120 min and 3.5±1.3 μU/ml at 180 min. No significant difference revealed between euthyroid group and normal subjects(p>0.05). 3) In hyperthyroid group, serum TSH responses to synthetic TRH were 1.5±0.6 at 0 min, 2.2±0.8 at 10 min., 2.3±1.0 at 20 min., 2.4±1.5 at 30 min., 2.1±1.1 at 60 min,, 1.9±0.2 at 120 min, and 1. 5±0.8 μU/ml, at 180 min., No response to TRH showed. 4) In hypothyroid group, mean values of serum TSH response to synthetic TRH were 42.0 at 0 min., 60.6 at 10 min., 124.8 at 20 min., 123.0 at 30 min. 101.6 at 60 min., 64.3 at 120 min. and 15.5 μU/ml at 180 min., Patients with primary hypothyroidism showed an exaggerated TSH response to synthetic TRH despite their high basal TSH. 5) Side effects attending synthetic TRH administration were transient nausea (59.0%), desire to micturate (59.0%), feeling of flushing (19.7%), dizziness (45.9%), metallic taste (9.8%) and headache (19.7%). Any side effect didn't show in 16.4%. These symptoms began almost immediately after TRH intravenous injection and lasted several minutes, and not related to

Ah receptor mediated suppression of the antibody response in mice is primarily dependent on the Ah phenotype of lymphoid tissue

International Nuclear Information System (INIS)

Silkworth, J.B.; Antrim, L.A.; Sack, G.

1986-01-01

Halogenated aromatic hydrocarbons act through the aromatic hydrocarbon (Ah) receptor in mice to produce a series of toxic effects of the immune system. The receptor protein is a product of the Ah gene locus. Ah responsive (Ahb/Ahb) mice express a high affinity receptor in both lymphoid and nonlymphoid tissues whereas nonresponsive Ahd/Ahd mice express a poor affinity receptor. To determine the role of the Ah receptor of lymphoid tissue relative to that of nonlymphoid tissue in the induction of immune impairment, bone marrow was used to reconstitute lethally irradiated mice of the same or opposite Ah phenotype. All mice were given 3,3',4,4'-tetrachlorobiphenyl (35 and 350 mumol/kg) ip 2 days before immunization with sheep erythrocytes (SRBC). The immune response to this T dependent antigen and organ weights were determined 5 or 7 days later in normal or chimeric mice, respectively. Monoclonal Lyt 1.1 and Lyt 1.2 antibodies were used to establish the origin of the cells which repopulated the chimeric thymuses. The immune responses of both BALB/cBy (Ahb/Ahb) and the BALB/cBy X DBA/2 hybrid, CByD2F1 (Ahb/Ahd), were significantly suppressed but DBA/2 mice were unaffected. The immune responses of chimeric BALB/cBy----BALB/cBy and BALB/cBy----DBA/2 (donor----recipient) mice were also significantly suppressed and thymic atrophy was observed in both cases. The serum anti-SRBC antibody titers of DBA/2----BALB/cBy chimeras were also significantly decreased although not to the same extent as in BALB/cBy----DBA/2 mice. Chimeric DBA/2----DBA/2 mice were not affected. These results indicate that the sensitivity to Ah receptor mediated suppression of the antibody response is primarily determined by the Ah phenotype of the lymphoid tissue

Automated immunoradiometric assay of thyrotrophin (TSH) in dried blood filter paper spots

Energy Technology Data Exchange (ETDEWEB)

John, R.; Woodhead, J.S. (Welsh National School of Medicine, Cardiff (UK))

1982-11-10

An immunoradiometric two-site assay for thyrotrophin (TSH) in dried blood filter paper spots is described. The assay is automated by means of the Kemtek 3000 automated immunoassay system. The technique uses a 6.0 mm disc punched from the dried blood samples collected as part of the screening programme for phenylketonuria. The method is sensitive and precise, and results correlate well with those obtained in TSH assays of serum samples. The procedure is rapid, results being available within 24 h of receipt of samples. Of 25204 specimens so far screened by this assay, 99.9% have TSH levels less than 15 mU/l. One false positive result has been obtained and six confirmed cases of neonatal hypothyroidism detected, giving a prevalence of 1 in 4200.

The PD-1/PD-L1 complex resembles the antigen-binding Fv domains of antibodies and T cell receptors

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Lin, David Yin-wei; Tanaka, Yoshimasa; Iwasaki, Masashi; Gittis, Apostolos G.; Su, Hua-Poo; Mikami, Bunzo; Okazaki, Taku; Honjo, Tasuku; Minato, Nagahiro; Garboczi, David N. (NIH); (Kyoto)

2008-07-29

Signaling through the programmed death 1 (PD-1) inhibitory receptor upon binding its ligand, PD-L1, suppresses immune responses against autoantigens and tumors and plays an important role in the maintenance of peripheral immune tolerance. Release from PD-1 inhibitory signaling revives 'exhausted' virus-specific T cells in chronic viral infections. Here we present the crystal structure of murine PD-1 in complex with human PD-L1. PD-1 and PD-L1 interact through the conserved front and side of their Ig variable (IgV) domains, as do the IgV domains of antibodies and T cell receptors. This places the loops at the ends of the IgV domains on the same side of the PD-1/PD-L1 complex, forming a surface that is similar to the antigen-binding surface of antibodies and T cell receptors. Mapping conserved residues allowed the identification of residues that are important in forming the PD-1/PD-L1 interface. Based on the structure, we show that some reported loss-of-binding mutations involve the PD-1/PD-L1 interaction but that others compromise protein folding. The PD-1/PD-L1 interaction described here may be blocked by antibodies or by designed small-molecule drugs to lower inhibitory signaling that results in a stronger immune response. The immune receptor-like loops offer a new surface for further study and potentially the design of molecules that would affect PD-1/PD-L1 complex formation and thereby modulate the immune response.

Nodding syndrome in Tanzania may not be associated with circulating anti-NMDA-and anti-VGKC receptor antibodies or decreased pyridoxal phosphate serum levels-a pilot study.

Science.gov (United States)

Dietmann, Anelia; Wallner, Bernd; König, Rebekka; Friedrich, Katrin; Pfausler, Bettina; Deisenhammer, Florian; Griesmacher, Andrea; Seger, Christoph; Matuja, William; JilekAall, Louise; Winkler, Andrea S; Schmutzhard, Erich

2014-06-01

Nodding syndrome (NS) is a seemingly progressive epilepsy disorder of unknown underlying cause. We investigated association of pyridoxal-phosphate serum levels and occurrence of anti-neuronal antibodies against N-methyl-D-aspartate (NMDA) receptor and voltage gated potassium channel (VGKC) complex in NS patients. Sera of a Tanzanian cohort of epilepsy and NS patients and community controls were tested for the presence of anti-NMDA-receptor and anti-VGKC complex antibodies by indirect immunofluorescence assay. Furthermore pyridoxal-phosphate levels were measured. Auto-antibodies against NMDA receptor or VGKC (LG1 or Caspr2) complex were not detected in sera of patients suffering from NS (n=6), NS plus other seizure types (n=16), primary generalized epilepsy (n=1) and community controls without epilepsy (n=7). Median Pyridoxal-phosphate levels in patients with NS compared to patients with primary generalized seizures and community controls were not significantly different. However, these median pyridoxal-phosphate levels are significantly lower compared to the range considered normal in Europeans. In this pilot study NS was not associated with serum anti-NMDA receptor or anti-VGKC complex antibodies and no association to pyridoxal-phosphate serum levels was found.

Downregulation of transferrin receptor surface expression by intracellular antibody

International Nuclear Information System (INIS)

Peng Jilin; Wu Sha; Zhao Xiaoping; Wang Min; Li Wenhan; Shen Xin; Liu Jing; Lei Ping; Zhu Huifen; Shen Guanxin

2007-01-01

To deplete cellular iron uptake, and consequently inhibit the proliferation of tumor cells, we attempt to block surface expression of transferrin receptor (TfR) by intracellular antibody technology. We constructed two expression plasmids (scFv-HAK and scFv-HA) coding for intracellular single-chain antibody against TfR with or without endoplasmic reticulum (ER) retention signal, respectively. Then they were transfected tumor cells MCF-7 by liposome. Applying RT-PCR, Western blotting, immunofluorescence microscopy and immunoelectron microscope experiments, we insure that scFv-HAK intrabody was successfully expressed and retained in ER contrasted to the secreted expression of scFv-HA. Flow cytometric analysis confirmed that the TfR surface expression was markedly decreased approximately 83.4 ± 2.5% in scFv-HAK transfected cells, while there was not significantly decrease in scFv-HA transfected cells. Further cell growth and apoptosis characteristics were evaluated by cell cycle analysis, nuclei staining and MTT assay. Results indicated that expression of scFv-HAK can dramatically induce cell cycle G1 phase arrest and apoptosis of tumor cells, and consequently significantly suppress proliferation of tumor cells compared with other control groups. For First time this study demonstrates the potential usage of anti-TfR scFv-intrabody as a growth inhibitor of TfR overexpressing tumors

Development of therapeutic antibodies to G protein-coupled receptors and ion channels: Opportunities, challenges and their therapeutic potential in respiratory diseases.

Science.gov (United States)

Douthwaite, Julie A; Finch, Donna K; Mustelin, Tomas; Wilkinson, Trevor C I

2017-01-01

The development of recombinant antibody therapeutics continues to be a significant area of growth in the pharmaceutical industry with almost 50 approved monoclonal antibodies on the market in the US and Europe. Therapeutic drug targets such as soluble cytokines, growth factors and single transmembrane spanning receptors have been successfully targeted by recombinant monoclonal antibodies and the development of new product candidates continues. Despite this growth, however, certain classes of important disease targets have remained intractable to therapeutic antibodies due to the complexity of the target molecules. These complex target molecules include G protein-coupled receptors and ion channels which represent a large target class for therapeutic intervention with monoclonal antibodies. Although these targets have typically been addressed by small molecule approaches, the exquisite specificity of antibodies provides a significant opportunity to provide selective modulation of these important regulators of cell function. Given this opportunity, a significant effort has been applied to address the challenges of targeting these complex molecules and a number of targets are linked to the pathophysiology of respiratory diseases. In this review, we provide a summary of the importance of GPCRs and ion channels involved in respiratory disease and discuss advantages offered by antibodies as therapeutics at these targets. We highlight some recent GPCRs and ion channels linked to respiratory disease mechanisms and describe in detail recent progress made in the strategies for discovery of functional antibodies against challenging membrane protein targets such as GPCRs and ion channels. Copyright © 2016 Elsevier Inc. All rights reserved.

Evidence That Graves' Ophthalmopathy Immunoglobulins Do Not Directly Activate IGF-1 Receptors.

Science.gov (United States)

Marcus-Samuels, Bernice; Krieger, Christine C; Boutin, Alisa; Kahaly, George J; Neumann, Susanne; Gershengorn, Marvin C

2018-05-01

Graves' ophthalmopathy (GO) pathogenesis involves thyrotropin (TSH) receptor (TSHR)-stimulating autoantibodies. Whether there are autoantibodies that directly stimulate insulin-like growth factor 1 receptors (IGF-1Rs), stimulating insulin-like growth factor receptor antibodies (IGFRAbs), remains controversial. This study attempted to determine whether there are stimulating IGFRAbs in patients with GO. Immunoglobulins (Igs) were purified from normal volunteers (NV-Igs) and patients with GO (GO-Igs). The effects of TSH, IGF-1, NV-Igs, and GO-Igs on pAKT and pERK1/2, members of pathways used by IGF-1R and TSHR, were compared in orbital fibroblasts from GO patients (GOFs) and U2OS-TSHR cells overexpressing TSHRs, and U2OS cells that express TSHRs at very low endogenous levels. U2OS-TSHR and U2OS cells were used because GOFs are not easily manipulated using molecular techniques such as transfection, and U2OS cells because they express TSHRs at levels that do not measurably stimulate signaling. Thus, comparing U2OS-TSHR and U2OS cells permits specifically distinguishing signaling mediated by the TSHR and IGF-1R. In GOFs, all GO-Igs stimulated pERK1/2 formation and 69% stimulated pAKT. In U2OS-TSHR cells, 15% of NV-IGs and 83% of GO-Igs stimulated increases in pERK1/2, whereas all NV-Igs and GO-Igs stimulated increases in pAKT. In U2OS cells, 70% of GO-Igs stimulated small increases in pAKT. Knockdown of IGF-1R caused a 65 ± 6.3% decrease in IGF-1-stimulated pAKT but had no effect on GO-Igs stimulation of pAKT. Thus, GO-Igs contain factor(s) that stimulate pAKT formation. However, this factor(s) does not directly activate IGF-1R. Based on the findings analyzing these two signaling pathways, it is concluded there is no evidence of stimulating IGFRAbs in GO patients.

Cetuximab in combination with anti-human IgG antibodies efficiently down-regulates the EGF receptor by macropinocytosis

Energy Technology Data Exchange (ETDEWEB)

Berger, Christian [Department of Pathology, Oslo University Hospital, Rikshospitalet, Post box 4950 Nydalen, 0424 Oslo (Norway); Madshus, Inger Helene [Institute of Pathology, University of Oslo, Rikshospitalet, 0027 Oslo (Norway); Department of Pathology, Oslo University Hospital, Rikshospitalet, Post box 4950 Nydalen, 0424 Oslo (Norway); Stang, Espen, E-mail: espsta@rr-research.no [Department of Pathology, Oslo University Hospital, Rikshospitalet, Post box 4950 Nydalen, 0424 Oslo (Norway)

2012-12-10

The monoclonal antibody C225 (Cetuximab) blocks binding of ligand to the epidermal growth factor receptor (EGFR). In addition, it is known that incubation with C225 induces endocytosis of the EGFR. This endocytosis has previously been shown to be increased when C225 is combined with an additional monoclonal anti-EGFR antibody. However, the effects of antibody combinations on EGFR activation, endocytosis, trafficking and degradation have been unclear. By binding a secondary antibody to the C225-EGFR complex, we here demonstrate that a combination of antibodies can efficiently internalize and degrade the EGFR. Although the combination of antibodies activated the EGFR kinase and induced ubiquitination of the EGFR, the kinase activity was not required for internalization of the EGFR. In contrast to EGF-induced EGFR down-regulation, the antibody combination efficiently degraded the EGFR without initiating downstream proliferative signaling. The antibody-induced internalization of EGFR was found not to depend on clathrin and/or dynamin, but depended on actin polymerization, suggesting induction of macropinocytosis. Macropinocytosis may cause internalization of large membrane areas, and this could explain the highly efficient internalization of the EGFR induced by combination of antibodies. -- Highlight: Black-Right-Pointing-Pointer Cetuximab induced endocytosis of EGFR increases upon combination with anti-human IgG. Black-Right-Pointing-Pointer Antibody combination causes internalization of EGFR by macropinocytosis. Black-Right-Pointing-Pointer Antibody-induced internalization of EGFR is independent of EGFR kinase activity. Black-Right-Pointing-Pointer Antibody combination may have a zipper effect and cross-link EGFRs on neighboring cells.

Fcγ-receptor IIa-mediated Src Signaling Pathway Is Essential for the Antibody-Dependent Enhancement of Ebola Virus Infection.

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Wakako Furuyama

2016-12-01

Full Text Available Antibody-dependent enhancement (ADE of Ebola virus (EBOV infection has been demonstrated in vitro, raising concerns about the detrimental potential of some anti-EBOV antibodies. ADE has been described for many viruses and mostly depends on the cross-linking of virus-antibody complexes to cell surface Fc receptors, leading to enhanced infection. However, little is known about the molecular mechanisms underlying this phenomenon. Here we show that Fcγ-receptor IIa (FcγRIIa-mediated intracellular signaling through Src family protein tyrosine kinases (PTKs is required for ADE of EBOV infection. We found that deletion of the FcγRIIa cytoplasmic tail abolished EBOV ADE due to decreased virus uptake into cellular endosomes. Furthermore, EBOV ADE, but not non-ADE infection, was significantly reduced by inhibition of the Src family protein PTK pathway, which was also found to be important to promote phagocytosis/macropinocytosis for viral uptake into endosomes. We further confirmed a significant increase of the Src phosphorylation mediated by ADE. These data suggest that antibody-EBOV complexes bound to the cell surface FcγRIIa activate the Src signaling pathway that leads to enhanced viral entry into cells, providing a novel perspective for the general understanding of ADE of virus infection.

Radioimmunoassay of serum T3, T4 and TSH during anesthesia and operation

International Nuclear Information System (INIS)

Gosheva-Antonova, Ts.; Zakharieva, B.; Kurtev, I.

1987-01-01

The serum concentrations of thyroxine (T 3 ), triiodothyronine (T 4 ) and thyroid-stimulating hormone (TSH) were determined in 31 partients before and during urologic operations on the 30th and 60th minute since the onset of the operation, performed under endotracheal halotane or neuroleptanesthesia (NLA) in assisted breathing and intravenous drip anesthesia with ketalar-diazepam in spontaneous breathing. There was statistically significant rise in T 4 level, decrease in T 3 and negligible changes in TSH level, in patients operated under halotane anesthesia. In those operated under NLA, T 4 tended initially to be elevated, with subseguent fall to starting level, with a tendency toward rise in TSH and stable unchanged T 3 level. Ketalar-diazepam anesthesia was applied only to patients subjected to transurethral resections. T 4 in them tended to be decreased, while T 3 and TSH showed negligible changes. Since the operations of patients anesthesized with halotane and NLA had similar localizations and severity, the differences in the thyroid hormone reactions could be associated with the type of anesthesia. The negligible changes in TSH are highly suggestive that this hormone is not influenced by the operation stress and anesthetics, and does hot exert regulating effect upon the thyroid status under these conditions. The milder reactions in patients operated under ketalar-diazepam anestesia may largely be associated with the milder operation stress in transurethal resection

T cell receptor-like recognition of tumor in vivo by synthetic antibody fragment.

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Keith R Miller

Full Text Available A major difficulty in treating cancer is the inability to differentiate between normal and tumor cells. The immune system differentiates tumor from normal cells by T cell receptor (TCR binding of tumor-associated peptides bound to Major Histocompatibility Complex (pMHC molecules. The peptides, derived from the tumor-specific proteins, are presented by MHC proteins, which then serve as cancer markers. The TCR is a difficult protein to use as a recombinant protein because of production issues and has poor affinity for pMHC; therefore, it is not a good choice for use as a tumor identifier outside of the immune system. We constructed a synthetic antibody-fragment (Fab library in the phage-display format and isolated antibody-fragments that bind pMHC with high affinity and specificity. One Fab, fE75, recognizes our model cancer marker, the Human Epidermal growth factor Receptor 2 (HER2/neu peptide, E75, bound to the MHC called Human Leukocyte Antigen-A2 (HLA-A2, with nanomolar affinity. The fE75 bound selectively to E75/HLA-A2 positive cancer cell lines in vitro. The fE75 Fab conjugated with (64Cu selectively accumulated in E75/HLA-A2 positive tumors and not in E75/HLA-A2 negative tumors in an HLA-A2 transgenic mouse as probed using positron emission tomography/computed tomography (PET/CT imaging. Considering that hundreds to thousands of different peptides bound to HLA-A2 are present on the surface of each cell, the fact that fE75 arrives at the tumor at all shows extraordinary specificity. These antibody fragments have great potential for diagnosis and targeted drug delivery in cancer.

TSH and Thyrotropic Agonists: Key Actors in Thyroid Homeostasis

Science.gov (United States)

Dietrich, Johannes W.; Landgrafe, Gabi; Fotiadou, Elisavet H.

2012-01-01

This paper provides the reader with an overview of our current knowledge of hypothalamic-pituitary-thyroid feedback from a cybernetic standpoint. Over the past decades we have gained a plethora of information from biochemical, clinical, and epidemiological investigation, especially on the role of TSH and other thyrotropic agonists as critical components of this complex relationship. Integrating these data into a systems perspective delivers new insights into static and dynamic behaviour of thyroid homeostasis. Explicit usage of this information with mathematical methods promises to deliver a better understanding of thyrotropic feedback control and new options for personalised diagnosis of thyroid dysfunction and targeted therapy, also by permitting a new perspective on the conundrum of the TSH reference range. PMID:23365787

Thyroid storm induced by TSH-secreting pituitary adenoma: a case report.

Science.gov (United States)

Fujio, Shingo; Ashari; Habu, Mika; Yamahata, Hitoshi; Moinuddin, F M; Bohara, Manoj; Arimura, Hiroshi; Nishijima, Yui; Arita, Kazunori

2014-01-01

Thyroid stimulating hormone-secreting pituitary adenomas (TSHomas) are uncommon tumors of the anterior pituitary gland. Patients with TSHomas may present with hyperthyroidism, but the incidence of thyroid storm due to TSHomas has yet to be determined. We report a rare case of thyroid storm caused by TSHoma in a 54-year-old woman. Preoperatively she had symptoms of excessive sweating and palpitation. Blood tests showed inappropriate secretion of TSH with blood TSH 6.86 μ U/mL, fT3 19.8 pg/mL, and fT4 5.95 ng/dL. Magnetic resonance imaging (MRI) revealed a pituitary tumor with maximum diameter of 13 mm that was extirpated through transsphenoidal route. After operation the patient was stuporous and thyroid storm occurred presenting with hyperthermia, hypertension, and tachycardia. It was well managed with nicardipine, midazolam, steroids, and potassium iodide. Immunohistochemical staining of tumor specimen was positive for TSH and growth hormone (GH). One year after operation, fT3 and fT4 levels were still high. As her tumor was diagnosed to be GH- and TSH-producing adenoma, octreotide injection therapy was started, which normalized thyroid hormone levels. This is the second reported case with thyroid storm due to TSHoma and emphasizes the importance of strategies with interdisciplinary cooperation for prevention of such emergency conditions.

Congenital Neonatal Hyperthyroidism Caused by Germline Mutations in the TSH Receptor Gene: Case Report and Review of the Literature

Science.gov (United States)

Chester, Jeremy; Rotenstein, Deborah; Ringkananont, Usanee; Steuer, Guy; Carlin, Beatrice; Stewart, Lindsay; Grasberger, Helmut; Refetoff, Samuel

2018-01-01

Neonatal hyperthyroidism, a rare and serious disorder occurs in two forms. An autoimmune form associated with maternal Graves’ disease, resulting from transplacental passage of maternal thyroid-stimulating antibodies, and a nonautoimmune form, resulting from mutations in the stimulatory G protein or the thyrotropin receptor (TSHR) causing constitutive activation of intracellular signaling cascades. To date, 29 separate cases of thyrotoxicosis caused by germline mutations of the TSHR have been documented. These cases have expressed themselves in a range of clinical consequences. This report describes a new case of a newborn with nonautoimmune hyperthyroidism secondary to a constitutively active TSHR mutation (S281N) whose clinical course was complicated by severe respiratory compromise. Typical clinical findings in this disorder are discussed by a review of all previously published cases. PMID:18655531

Antibody immobilized on Fe3O4 particles and its application to RIAs

International Nuclear Information System (INIS)

Shen Rongsen; Xing Ruiyun

1997-01-01

A magnetic particle second antibody (MSA-I) was prepared by means of immobilizing donkey anti-rabbit antiserum on Fe 3 O 4 particles 10.8 nm +- 34% in diameter. Effects of some factors, such as pH of buffer used for immobilizing antiserum, amount of antiserum, time of immobilizing antiserum and blocking buffer on specific and nonspecific binding of MSA-I in RIAs were studied. The MSA-I was successfully applied to RIAs of T 3 , T 4 and TSH. The advantages of the magnetic second antibody were simplicity and time-saving in preparation and low cost

The Comparison Of TSH IRMA Serum Level With TRH Test Value In Healthy People Who Are Suspected To Have Hyperthyroidism

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Keshavarz zirak A

2005-06-01

Full Text Available Background: Sub clinical hyperthyroidism is a state of subnormal serum TSH and T3,T4 within normal range, although usually without overt clinical manifestation but many disastrous complications especially in senile patient. In Iranian people, serum TSH is generally assayed by IRMA method. This study is aimed to determine the value of low serum TSH in these patients, better management and decision when encountered. Materials and Methods: The populations under study are guys with serum TSH lower than 0.5mu/l and normal thyroid hormones without known thyroidal and non-thyroidal illness. A basal serum TSH and TSH 30 minutes after TRH injection intra venous were sampled and correlation of clinical signs and symptoms and basal TSH with sub clinical hyperthyroidism was considered. Results: The population under study was categorized into five groups and prevalence of sub clinical hyperthyroidism was noted. In patients with b.TSH equal or lower than 0.1mu/l, 100%, 0.1-0.2mu/l, 75%, 0.2-0.3mu/l, 38.5%, 0.3-0.4mu/l, 14.3% and TSH levels greater than 0.4mu/l, were all normal. After analyzing of these data and determination of sensitivity and specificity of IRMA, it was concluded that IRMA is not sufficient to distinguish sub clinical hyperthyroidism, although there is a good linear (r=0.68; P<0.001 and cubic (r=0.79; P<0.001 relationship between b.TSH and d.TSH. Conclusion: Since TRH test is not cost effective for all cases, TSH levels lower than 0.25mu/l, can be considered as sub clinical hyperthyroidism and levels more than 0.4mu/l, as normal. In cases with TSH level between 0.25 and 0.4mu/l, TRH test is needed in high-risk patients.

Valence of acetylcholine-receptor-antibody-titers in myasthenia gravis

International Nuclear Information System (INIS)

Zeitlhofer, J.; Maida, E.M.; Mamoli, B.; Mayr, N.

1986-01-01

In a retrospective study in 47 patients with myasthenia gravis acetylcholine-receptor-antibody-titers (AChR-AB) were correlated with the severity of the disease. In 18 patients the course of titers was studied and two groups of patients could be differentiated: patients with relative constant and patients with fluctuating titers. Age, age of begin of myasthenia and sex did not influence the titers. Also the duration of the disease and the severity of symptoms did not influence the level of AChR-AB-titers. In this retrospective study the influence of immunsuppressive therapy on the intra-individual course of AB-titers and their correlation with the clinical symptoms could not be judged. Measurement of AChR-AB is of value for the diagnosis of myasthenia gravis and important for judging the clinical course and the effect of therapy. (Author)

Comparison between thyroid hormone withdrawal and recombinant human TSH administration before radioiodine treatment for advanced thyroid cancer

International Nuclear Information System (INIS)

Coelho, Sabrina M.; Corbo, Rossana; Buescu, Alexandru; Carvalho, Denise P.; Vaisman, Mario

2005-01-01

Full text: Radioiodine treatment is traditionally performed after thyroid hormone withdrawal. However, induction of hypothyroidism is associated with physical and psychological symptoms and a possible induction of tumor growth. This is particularly harmful in patients with advanced thyroid cancer (ATC). The objective of this study was to compare the thyroxine withdrawal and the recombinant human TSH (rh TSH) administration in patients with non-radioiodine responsive ATC after retinoic acid (RA) therapy for induction of iodine uptake. Patients were treated with isotretinoin (1.0 to 1.5 mg/kg/d) for 5 weeks, then, thyroxine (LT 4 ) was discontinued 4 weeks before therapeutic dose (150 mCi). Based on the presence of a satisfactory response to RA (increased iodine uptake, reduction of serum thyroglobulin and tumor regression), another cycle of RA was offered, then rh TSH was used (0.9 mg in two consecutive days). A total of 8 patients (1 follicular, 1 poorly differentiated and 6 papillary carcinomas) were treated. In a patient with pituitary adenoma the endogenous TSH did not rise after T 4 withdrawal, and rh TSH was administered before radioiodine therapy. Although an increase in iodine uptake was observed after RA therapy in the patient with poorly differentiated cancer, the tumor continued to progress and patient died of respiratory insufficiency. Four out of 7 patients had at least a partial response and were selected for re-treatment. Post-therapeutic whole body scan was similar using both protocols, but patients had fewer side effects with rh TSH. One patient who had no compressive symptoms during LT 4 withdrawal did present dysphagia and dysphonia secondary to tumor swelling, 6 hours after the last rh TSH injection. Glucocorticoid was administered and symptoms were reversed after 10 days. Conclusion: Radioiodine uptake using rh TSH was comparable to T 4 withdrawal and is particularly useful when endogenous TSH cannot rise. However, the possibility of compressive

A genomic point mutation in the extracellular domain of the thyrotropin receptor in patients with Graves` ophthalmopathy

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Bahn, R.S.; Dutton, C.M.; Heufelder, A.E.; Sarkar, G. [Mayo Clinic/Foundation, Rochester, MN (United States)]|[Ludwig-Maximilians-Universitat, Munich (Germany)

1994-02-01

Orbital and pretibial fibroblasts are targets of autoimmune attack in Graves` ophthalmopathy (GO) and pretibial dermopathy (PTD). The fibroblast autoantigen involved in these peripheral manifestations of Graves` disease and the reason for the association of GO and PTD with hyperthyroidism are unknown. RNA encoding the full-length extracellular domain of the TSH receptor has been demonstrated in orbital and dermal fibroblasts from patients with GO and normal subjects, suggesting a possible antigenic link between fibroblasts and thyrocytes. RNA was isolated from cultured orbital, pretibial, and abdominal fibroblasts obtained from patients with severe GO (n = 22) and normal subjects (n = 5). RNA was reverse transcribed, and the resulting cDNA was amplified by the polymerase chain reaction, using primers spanning overlapping regions of the entire extracellular domain of the TSH receptor. Nucleotide sequence analysis showed an A for C substitution in the first position of codon 52 in 2 of the patients, both of whom had GO, PTD, and acropachy. Genomic DNA isolated from the 2 affected patients, and not from an additional 12 normal subjects, revealed the codon 52 mutation by direct sequencing and AciI restriction enzyme digestions. In conclusion, the authors have demonstrated the presence of a genomic point mutation, leading to a threonine for proline amino acid shift in the predicted peptide, in the extracellular domain of the TSH receptor in two patients with severe GO, PTD, acropachy, and high thyroid-stimulating immunoglobulin levels. RNA encoding this mutant product was demonstrated in the fibroblasts of these patients. They suggest that the TSH receptor may be an important fibroblast autoantigen in GO and PTD, and that this mutant form of the receptor may have unique immunogenic properties. 28 refs., 3 figs., 2 tabs.

HUBUNGAN KADAR TIROGLOBULIN, TSH DAN fT4 SERUM PADA ANAK USIA SEKOLAH DI TIGA KABUPATEN DENGAN TINGKAT ENDEMISITAS DEFISIENSI-IODIUM BERBEDA (ASSOCIATION BETWEEN THE SERUM THYROGLOBULIN, TSH, AND fT4 AMONG SCHOOL-AGED CHILDREN IN THREE DISTRICTS WITH DIF

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Agus Wibowo

2013-06-01

Full Text Available ABSTRACT Iodine deficiency lowers circulating thyroxine (T4 and raises serum Thyroid Stimulating Hormone (TSH, where free T4 (fT4 and TSH have strong corelation with thyroglobulin (Tg. The results from population studies indicate, Tg appears to be a valuable indicator of thyroid status, but it has yet to be fully explored. This study aimed to measure the association between serum Tg with TSH and fT4 as alternatif indicators thyroid status in school-aged children. This was a cross-sectional study of sample of 398 schoolchildren aged 10-12 years in three districts with different iodine-deficiency endemicity level, i.e. Pati as a mild endemic district, Purbalingga as a moderate endemic district, and Malang as a severe endemic district. Children’s blood have taken 3 cc as a sample for the determination of Tg, TSH, and fT4. Enzyme-Linked Immunosorbent Assay (ELISA was used to determine Tg, TSH and fT4. Mean of serum Tg 14.3 ± 11.1 ng/mL (cut-off 2-50 ng/mL, TSH 3.7 ± 2.2 µIU/mL (cut-off 0.3-6.2, fT4 1.4 ± 0.4 ng/dL (cut-off 0.8-2.0 ng/dL. Correlation analysis was showed the significance of Tg and TSH (p< 0.05 and Tg with fT4 (p< 0.05. The significance analysis of Tg with TSH and fT4 may be evaluated as indicator  for thyroid function in school-aged children in iodine-deficiency endemic areas.   Keywords: thyroglobulin (Tg, Thyroid Stimulating Hormone (TSH, free thyroxine (fT4, school-aged children ABSTRAK Defisiensi iodium menurunkan tiroksin (T4 yang beredar dalam darah dan meningkatkan Thyroid Stimulating Hormone (TSH, di mana T4 bebas (fT4 dan TSH memiliki hubungan erat dengan tiroglobulin (Tg. Hasil studi populasi menunjukkan, Tg tampak menjadi indikator berharga untuk status tiroid di daerah endemik defisiensi iodium, tetapi belum sepenuhnya dieksplorasi. Penelitian ini bertujuan mengukur hubungan antara kadar Tg serum dengan kadar TSH dan fT4 sebagai indikator alternatif status tiroid pada anak usia sekolah. Ini merupakan penelitian

Serum TSH, thyroglobulin, and thyroid disorders in atomic bomb survivors exposed in youth: a study 30 years after exposure

International Nuclear Information System (INIS)

Morimoto, Isao; Yoshimoto, Yasuhiko; Sato, Kenshi; Hamilton, H.B.; Kawamoto, Sadahisa; Izumi, Motomori; Nagataki, Shigenobu.

1986-08-01

A study of individuals in Hiroshima and Nagasaki who were under 20 years of age at the time of atomic bomb exposure and who had been exposed to 100+ rad was conducted to determine the frequency of thyroid disorders as well as the levels of serum thyroid stimulating hormone (TSH), antithyroglobulin antibody, and thyroglobulin (TG), 30 years after exposure. Thyroid disorders were detected in 56 of the 477 subjects of the 100+ rad exposed group and in 39 of the 501 subjects of the 0 rad exposed group, the prevalence being significantly higher in the former group (X 2 = 3.872, P = 0.049). This increased prevalence of thyroid disorders in the 100+ rad exposed group was due to the increased occurrence of thyroid cancer and nontoxic uninodular goiter. Thyroid cancer was found in eight exposed individuals, all of whom belonged to the 100+ rad group; statistically, the prevalence was significantly higher (X 2 = 7.919, P = 0.005). Nontoxic uninodular goiter was observed in 13 cases of the 100+ rad exposed group and 3 cases of the 0 rad exposed group, the prevalence in the 100+ rad exposed group being significantly higher (X 2 = 6.584, P = 0.010). In these cases no increase of serum TSH or TG levels was observed. Mean serum TSH levels in individuals without thyroid disorders were 1.64 ± 1.89 μU/ml (n = 421) in the 100+ rad exposed group and 1.54 ± 1.86 μU/ml (n = 462) in the 0 rad exposed group. Mean serum TG levels were 13.49 ± 13.88 ng/ml (n = 421) in the 100+ rad exposed group and 14.76 ± 15.69 ng/ml (n = 462) in the 0 rad exposed group. Thus, these differences between the two groups were not significant. Also, no significant differences were observed between the 100+ rad and 0 rad exposed groups in the mean serum TSH and TG levels of the subjects who had thyroid diseases but had not been treated for the diseases, and the subjects who had no thyroid diseases. (J.P.N.)

Neonatal hypothyroidism: detection by estimation of TSH in dried blood eluate

International Nuclear Information System (INIS)

Daver, A.; Chassevent, A.; Larra, F.; Guittet, J.; Berthelot, J.; Larget Piet, L.

1978-01-01

The micromethod for the estimation of TSH was used in a group of 3173 newborn. At the same time, TSH curves during the first six days were established. One case of hypothyroidism was detected and treated during the neonatal period and then regularly followed-up using the micromethod. The existence of a recall level of 5 per cent in the statistics is discussed. Technical modifications are envisaged with the aim of reducing the percentage of specimens in which it is impossible to perform an estimation [fr

TSH and Thyrotropic Agonists: Key Actors in Thyroid Homeostasis

Directory of Open Access Journals (Sweden)

Johannes W. Dietrich

2012-01-01

Full Text Available This paper provides the reader with an overview of our current knowledge of hypothalamic-pituitary-thyroid feedback from a cybernetic standpoint. Over the past decades we have gained a plethora of information from biochemical, clinical, and epidemiological investigation, especially on the role of TSH and other thyrotropic agonists as critical components of this complex relationship. Integrating these data into a systems perspective delivers new insights into static and dynamic behaviour of thyroid homeostasis. Explicit usage of this information with mathematical methods promises to deliver a better understanding of thyrotropic feedback control and new options for personalised diagnosis of thyroid dysfunction and targeted therapy, also by permitting a new perspective on the conundrum of the TSH reference range.

Labelled antibody techniques in glycoprotein estimation

International Nuclear Information System (INIS)

Hazra, D.K.; Ekins, R.P.; Edwards, R.; Williams, E.S.

1977-01-01

The problems in the radioimmunoassay of the glycoprotein hormones (pituitary LH, FSH and TSH and human chlorionic gonadotrophin HGG) are reviewed viz: limited specificity and sensitivity in the clinical context, interpretation of disparity between bioassay and radioimmunoassay, and interlaboratory variability. The advantages and limitations of the labelled antibody techniques - classical immonoradiometric methods and 2-site or 125 I-anti-IgG indirect labelling modifications are reviewed in general, and their theoretical potential in glycoprotein assays examined in the light of previous work. Preliminary experiments in the development of coated tube 2-site assay for glycoproteins using 125 I anti-IgG labelling are described, including conditions for maximizing solid phase extraction of the antigen, iodination of anti-IgG, and assay conditions such as effects of temperature of incubation with antigen 'hormonefree serum', heterologous serum and detergent washing. Experiments with extraction and antigen-specific antisera raised in the same or different species are described as exemplified by LH and TSH assay systems, the latter apparently promising greater sensitivity than radioimmunoassay. Proposed experimental and mathematical optimisation and validation of the method as an assay system is outlined, and the areas for further work delineated. (orig.) [de

A TSHβ Variant with Impaired Immunoreactivity but Intact Biological Activity and Its Clinical Implications

DEFF Research Database (Denmark)

Pappa, Theodora; Johannesen, Jesper; Scherberg, Neal

2015-01-01

BACKGROUND: Thyrotropin (TSH) deficiency caused by TSHβ gene mutations is a rare form of congenital central hypothyroidism. Nine different TSHβ gene mutations have been reported, all with clinical manifestations. The aim was to identify the genetic cause of undetectable TSH levels in two siblings......). This variant was found in 12 out of 5008 alleles in the 1000 Genomes project (all South Asian). Serum TSH of the two brothers was undetectable in two of five platforms, both produced by Siemens, whereas TSH levels of the heterozygous brother and mother were half compared to the other three platforms (Roche...

Rapid iterative stimulation (IS) of endogenous TSH (En-TSH) utilizing thyrotropin releasing hormone (TRH) in patients with differentiated thyroid carcinoma (DTC)

International Nuclear Information System (INIS)

Degrossi, Osvaldo J.; Degrossi, Elina B.; Barmasch, Martha; Lopart, Iris; Mignogna, A.; Garcia del Rio, H.; Alvarez, Liliana; Pena, Marta

2007-01-01

In the follow up (F) of patients with DTC it is necessary to obtain high figures of serum TSH for determination of serum Tg and 131 I scan (WBS). For this object, the method, for a long time, was to withdrawal thyroid hormone therapy (generally l-T4) that produced hypothyroidism with the inconvenient for the patients, dramatics in certain cases. Our objective was to increase TSH by IS to shortening time of L-T4 withdrawal for F, ablation (A) or treatment (T) with 131 I. In 37 patients with DTC (G-1), aged 19-78 years, 34 with papillary DTC and 3 with follicular forms, 25 females, 12 males, 43 studies were carried out; 6 p carried 2 studies. The group was divided in 2 sub-groups: G-1A, 7 patients derived for A; G-1 B 36 patients for F or T with 131 I. Six patients carried out 2 studies; 4 of them for A and for F and 2 realizes 2 times F. All patients treated with I-T4 replaced this hormone for T3 during 3 weeks that was withdrawal the day before IS. In G-1A, between 8/10 days after surgery they begin IS. IS: At days 1, 3, 5 and 6, the patients were injected i.v. with 200 mcg of TRH; at 30 minutes of the 3rd injection blood TSH determination; immediately 370 MBq of 99m T was administered and at 30 minutes a WBS was carried out. At 30 minutes of the 4th injection blood figures of TSH, Tg and Tg-ab were determined; immediately the activity of 131 I indicated for each group was given to the patients; in G-1A, at 8 days and in G1-B, at 48 hours WBS were carried out. As a control group (G-2) 41 studies in 35 DTC patients that withdrawal-T4 for 4/5 weeks, were studied, aged 18-81 years, 31 females and 4 males; 32 with papillary and 3 follicular form; 18 for A (G-2A) and 23 for F (G-2B); 6 p carried out 2 studies. One for A and the second as the first control. In G-1, TSH values obtained were 26-360 UI/L (83 ± 54. In G-1A : 137 ± 109 and in G-1B 7, 62 ± 52). The 2 tracers 131 I and 99m Tc-Tc, produces show similar figures. In G-1A all p present thyroid remnants and

Engineering chimeric human and mouse major histocompatibility complex (MHC) class I tetramers for the production of T-cell receptor (TCR) mimic antibodies

Science.gov (United States)

Bentley, Carol; Yates, Jenna; Salimi, Maryam; Greig, Jenny; Wiblin, Sarah; Hassanali, Tasneem; Banham, Alison H.

2017-01-01

Therapeutic monoclonal antibodies targeting cell surface or secreted antigens are among the most effective classes of novel immunotherapies. However, the majority of human proteins and established cancer biomarkers are intracellular. Peptides derived from these intracellular proteins are presented on the cell surface by major histocompatibility complex class I (MHC-I) and can be targeted by a novel class of T-cell receptor mimic (TCRm) antibodies that recognise similar epitopes to T-cell receptors. Humoural immune responses to MHC-I tetramers rarely generate TCRm antibodies and many antibodies recognise the α3 domain of MHC-I and β2 microglobulin (β2m) that are not directly involved in presenting the target peptide. Here we describe the production of functional chimeric human-murine HLA-A2-H2Dd tetramers and modifications that increase their bacterial expression and refolding efficiency. These chimeric tetramers were successfully used to generate TCRm antibodies against two epitopes derived from wild type tumour suppressor p53 (RMPEAAPPV and GLAPPQHLIRV) that have been used in vaccination studies. Immunisation with chimeric tetramers yielded no antibodies recognising the human α3 domain and β2m and generated TCRm antibodies capable of specifically recognising the target peptide/MHC-I complex in fully human tetramers and on the cell surface of peptide pulsed T2 cells. Chimeric tetramers represent novel immunogens for TCRm antibody production and may also improve the yield of tetramers for groups using these reagents to monitor CD8 T-cell immune responses in HLA-A2 transgenic mouse models of immunotherapy. PMID:28448627

TITERS OF ANTIBODIES TO Β1-ADRENOCEPTOR AND M2 CHOLINERGIC RECEPTORS IN PATIENTS WITH VENTRICULAR ARRHYTHMIAS WITHOUT AN ORGANIC CARDIOVASCULAR DISEASE AND THEIR POSSIBLE CLINICAL SIGNIFICANCE

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M. M. Rogova

2012-01-01

Full Text Available Aim. To identify the most promising epitopes that simulate various sites β1-adrenergic and M2-cholinergic receptors, and to evaluate their possible contribution to the development and maintenance of cardiac arrhythmias, particularly idiopathic ventricular arrhythmia. Material and methods. Patients with ventricular arrhythmias without organic cardiovascular disease (the study group; n=70 were included in the study. The control group consisted of 20 healthy volunteers. Evaluation of levels of antibodies to antigenic determinants, modeling various sites β1-adrenergic and M2-cholinergic performed in all patients. Causal treatment with clarithromycin and valacyclovir performed in part of patients. Results. Antibodies to different peptide sequences of β1-adrenergic and M2-cholinergic receptors have been identified in 25% of main group patients. A direct correlation between the frequency of episodes of ventricular tachycardia and IgG levels to MRI-MRIV (p=0.02 revealed. Increase in titre of antibodies to β1-adrenoceptors, to a peptide sequence β8 (p=0.02, and lower titers of antibodies to the M2 acetylcholine receptor — chimera MRI-MRIV IgM (p=0.06 and ARI-MRIV IgM (p=0.07 were observed when assessing the efficacy of the therapy in the causal dynamics in the group of "untreated" patients. IgG titer reduction of ARI-MRIV (p=0.02, which is 4 times out of 10 with reduction of ventricular ectopic activity , recorded after valacyclovir therapy. Clarithromycin therapy on the level of antibodies exerted no significant effect. Conclusion. Possible involvement of antibodies to β1-adrenoceptor and M2-cholinergic receptors in the development of idiopathic ventricular arrhythmias demonstrated. The relationship between the frequency of episodes of ventricular tachycardia and levels of antibody titers to M2-cholinergic receptors found. Attempt of causal treatment, depending on the possible mechanisms of the autoimmune process is executed. Further studies to

Sonographic decreased echogenicity of thyroid parenchyma in asymptomatic population: Correction with thyroid function and thyroid autoimmune activity

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Park, Ji Yeon; Park, Noh Hyuck; Park, Chan Sub; Lee, Ji Ye [Dept. of Radiology, Myongji Hospital, Seonam University College of Medicine, Goyang (Korea, Republic of); Chun, Kyung Ah [Dept. of Radiology, Catholic Kwandong University School of Medicine, Gangneung (Korea, Republic of); Yi, Seong Yoon [Div. of Hematology-Oncology, Dept. of Internal Medicine, Inje University Ilsan Paik Hospital, Goyang (Korea, Republic of); Park, Hee Jin [Dept. of of Radiology, Sungkyunkwan University School of Medicine, Kangbuk Samsung Hospital, Seoul (Korea, Republic of)

2016-09-15

The aim of the study was to evaluate the correlation between decreased echogenicity of thyroid and thyroid hormones or autoantibodies. From January 2009 to December 2011, 543 patients with decreased parenchymal echogenicity [M:F = 133:410, median age: 42 years (range: 9-82 years)], who did not have solid nodule, symptom or medication related to thyroid and underwent thyroid function test were retrospectively reviewed. Images were classified based on the degree of hypoechogenicity, heterogenicity or thyroid size. 1) Group A: mild decreased echogenicity, group B: marked decreased echogenicity, 2) group Ho: homogeneous echogenicity, group He: heterogeneous echogenicity, 3) group 1: decreased size, group 2: normal size, group 3: increased size. Differences in triiodiothyronyne (T3), free-thyroxine (fT4), thyrotropin (TSH), anti-thyroglobulin antibody (TgAb), thyroid peroxidase antibody (TPOAb), and anti-TSH receptor antibody (TSH-rAb) were evaluated among groups. T3, fT4, and TSH levels differed between groups A and B (p < 0.001, p = 0.001, p < 0.001). TgAb and TPOAb of group B were higher than group A (p = 0.006, p < 0.001). TPOAb of group He was higher than group Ho (p < 0.001). TSH-rAb and TPOAb of group 3 were higher than group 2 (p = 0.017, p < 0.001). The patients with findings of markedly decreased, heterogeneous echogenicity or thyroid enlargement may have abnormal thyroid function and autoantibodies. These may facilitate the physicians' decision to order tests for thyroid function and autoimmune activity.

Modulation of the virus-receptor interaction by mutations in the V5 loop of feline immunodeficiency virus (FIV following in vivo escape from neutralising antibody

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Samman Ayman

2010-04-01

Full Text Available Abstract Background In the acute phase of infection with feline immunodeficiency virus (FIV, the virus targets activated CD4+ T cells by utilising CD134 (OX40 as a primary attachment receptor and CXCR4 as a co-receptor. The nature of the virus-receptor interaction varies between isolates; strains such as GL8 and CPGammer recognise a "complex" determinant on CD134 formed by cysteine-rich domains (CRDs 1 and 2 of the molecule while strains such as PPR and B2542 require a more "simple" determinant comprising CRD1 only for infection. These differences in receptor recognition manifest as variations in sensitivity to receptor antagonists. In this study, we ask whether the nature of the virus-receptor interaction evolves in vivo. Results Following infection with a homogeneous viral population derived from a pathogenic molecular clone, a quasispecies emerged comprising variants with distinct sensitivities to neutralising antibody and displaying evidence of conversion from a "complex" to a "simple" interaction with CD134. Escape from neutralising antibody was mediated primarily by length and sequence polymorphisms in the V5 region of Env, and these alterations in V5 modulated the virus-receptor interaction as indicated by altered sensitivities to antagonism by both anti-CD134 antibody and soluble CD134. Conclusions The FIV-receptor interaction evolves under the selective pressure of the host humoral immune response, and the V5 loop contributes to the virus-receptor interaction. Our data are consistent with a model whereby viruses with distinct biological properties are present in early versus late infection and with a shift from a "complex" to a "simple" interaction with CD134 with time post-infection.

Modulation of the virus-receptor interaction by mutations in the V5 loop of feline immunodeficiency virus (FIV) following in vivo escape from neutralising antibody.

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Willett, Brian J; Kraase, Martin; Logan, Nicola; McMonagle, Elizabeth L; Samman, Ayman; Hosie, Margaret J

2010-04-26

In the acute phase of infection with feline immunodeficiency virus (FIV), the virus targets activated CD4+ T cells by utilising CD134 (OX40) as a primary attachment receptor and CXCR4 as a co-receptor. The nature of the virus-receptor interaction varies between isolates; strains such as GL8 and CPGammer recognise a "complex" determinant on CD134 formed by cysteine-rich domains (CRDs) 1 and 2 of the molecule while strains such as PPR and B2542 require a more "simple" determinant comprising CRD1 only for infection. These differences in receptor recognition manifest as variations in sensitivity to receptor antagonists. In this study, we ask whether the nature of the virus-receptor interaction evolves in vivo. Following infection with a homogeneous viral population derived from a pathogenic molecular clone, a quasispecies emerged comprising variants with distinct sensitivities to neutralising antibody and displaying evidence of conversion from a "complex" to a "simple" interaction with CD134. Escape from neutralising antibody was mediated primarily by length and sequence polymorphisms in the V5 region of Env, and these alterations in V5 modulated the virus-receptor interaction as indicated by altered sensitivities to antagonism by both anti-CD134 antibody and soluble CD134. The FIV-receptor interaction evolves under the selective pressure of the host humoral immune response, and the V5 loop contributes to the virus-receptor interaction. Our data are consistent with a model whereby viruses with distinct biological properties are present in early versus late infection and with a shift from a "complex" to a "simple" interaction with CD134 with time post-infection.

Did hypocretin receptor 2 autoantibodies cause narcolepsy with hypocretin deficiency in Pandemrix-vaccinated children? Comment on “Antibodies to influenza nucleoprotein cross-react with human hypocretin receptor 2”

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Vassalli Anne

2015-01-01

Abstract Did hypocretin receptor 2 auto antibodies cause narcolepsy with hypocretin deficiency in Pandemrix vaccinated children as suggested by Ahmed et al.? Using newly developed mouse models to report and inactivate hypocretin receptor expression Vassalli et al. now show that hypocretin neurons (whose loss causes narcolepsy) do not express hypocretin autoreceptors raising questions to the interpretation of Ahmed et al.’s findings. Mouse Genome Informatics: www.informatics.jax.org/reference/...

[Low levels of TSH measured by a sensitive assay: do they reflect hyperthyroidism? A critical analysis of 580 cases].

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Rohmer, V; Ligeard-Ducoroy, A; Perdrisot, R; Beldent, V; Jallet, P; Bigorgne, J C

1990-05-12

Highly sensitive TSH assays make it easier to diagnose thyroid diseases. During one year, we performed 5,300 sensitive TSH assays (normal range: 0.15-4 mU/l) in various patients. The purpose of this work was to test the value of the low TSH plasma concentrations found in 580 patients. In 99.7 percent of the cases, low TSH levels were the consequence of a thyroid disorder or a treatment by thyroid hormones; non thyroidal illnesses were detected in only 0.3 percent. However, not all TSH values below 0.15 mU/l were associated with overt or occult thyrotoxicosis. When TSH was undetectable (less than 0.04 mU/l), and excluding thyroid hormone-treated patients, thyrotoxicosis was present in 97 percent of the cases. On the other hand, when TSH values were between 0.04 and 0.15 mU/l, 41 percent of the patients failed to show any sign or symptom of hyperthyroidism, although they had functioning thyroid nodules, multinodular goitre or iodine overload, or they received thyroid hormones.

Pretreatment with betamethasone of patients with Graves' disease given radioiodine therapy: thyroid autoantibody responses and outcome of therapy

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Gamstedt, A.; Karlsson, A.

1991-01-01

The effects of betamethasone on thyroid autoantibody responses and outcome of radioiodine therapy were determined over a period of 1 yr in a prospective randomized study of 40 patients with Graves' disease. Twenty patients were given placebo tablets, and 20 patients were treated with betamethasone from 3 weeks before until 4 weeks after 131 I therapy. At the time of inclusion in the study, the mean serum concentrations of TSH receptor antibodies, thyroid peroxidase antibodies, and thyroglobulin antibodies (TgAb) were increased in both groups. Three weeks of treatment with betamethasone reduced the thyroid peroxidase antibody and TgAb titers as well as the serum concentrations of thyroid hormones. A decrease in the TSH receptor antibody level was not statistically significant. After radioiodine therapy, transient increases in thyroid autoantibody levels were observed. The titers of the different antibodies generally changed in parallel. In some patients a detectable level of a given antibody was found only after the radioiodine treatment, and in two cases, TgAb did not appear at all, although the two other antibodies increased temporarily. Betamethasone delayed, but did not abolish, the 131 I-induced antibody peaks. Betamethasone also caused a reduction in the total serum immunoglobulin G, a reduction which persisted throughout the study period. When the study ended, 17 patients given placebo and 9 patients given betamethasone were receiving replacement therapy due to the development of hypothyroidism. These patients at this point in time had lower antibody levels than those not requiring T4. The results of this study demonstrate that betamethasone reduces and modifies the thyroid autoantibody responses as well as the outcome of radioiodine therapy in patients with Graves' disease

Investigating the Interaction between the Neonatal Fc Receptor and Monoclonal Antibody Variants by Hydrogen/Deuterium Exchange Mass Spectrometry

DEFF Research Database (Denmark)

Jensen, Pernille Foged; Larraillet, Vincent; Schlothauer, Tilman

2015-01-01

The recycling of immunoglobulins by the neonatal Fc receptor (FcRn) is of crucial importance in the maintenance of antibody levels in plasma and is responsible for the long half-lives of endogenous and recombinant monoclonal antibodies. From a therapeutic point of view there is great interest...... in understanding and modulating the IgG-FcRn interaction to optimize antibody pharmacokinetics and ultimately improve efficacy and safety. Here we studied the interaction between a full-length human IgG1 and human FcRn via hydrogen/deuterium exchange mass spectrometry and targeted electron transfer dissociation...... to map sites perturbed by binding on both partners of the IgG-FcRn complex. Several regions in the antibody Fc region and the FcRn were protected from exchange upon complex formation, in good agreement with previous crystallographic studies of FcRn in complex with the Fc fragment. Interestingly, we found...

Usefulness of recombinant human TSH-aided radioiodine doses administered in patients with differentiated thyroid carcinoma Administración de dosis terapéuticas de radioyodo luego de TSH recombinante en pacientes con carcinoma diferenciado de tiroides

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Fabián Pitoia

2006-04-01

Full Text Available The published studies confirming the safety and efficacy of rhTSH for diagnostic purposes have led to an increased interest in its use for preparation for radioiodine (RI dose administration in patients with recurrent or persistent differentiated thyroid carcinoma (DTC. In order to establish the efficacy of RI therapy after rhTSH, we have reviewed 39 rhTSH-aided radioiodine treatment in a series of 28 DTC patients. Patients were divided into two groups: GI (n=17, with previous thyroid bed uptake and undetectable thyroglobulin (Tg levels under levothyroxine treatment and GII (n=11, with proven metastatic local or distant disease. Median follow-up after the first rhTSH-aided radioiodine treatment was 32 ± 13 months (range 8 to 54 months. Sixteen patients (94% in GI were rendered disease free and one patient was shown to have persistent disease. In GII, the post therapy whole body scan showed pathological uptakes in all cases: in four patients in lungs, in four in mediastinum and in three in lateral neck. In two patients with mediastinum uptake, Tg levels were undetectable after rhTSH. In the follow-up, two patients with lateral neck uptake were rendered disease free, four patients died (three due to thyroid cancer and five out of the remaining patients have persistent disease. In conclusion, rhTSH aided therapy was helpful to eliminate normal thyroid bed remnants in 16/17 (94% patients (GI. rhTSH stimulated Tg was undetectable in two patients with mediastinal metastasis. We believe that rhTSH is a good alternative to levothyroxine withdrawal for the treatment of DTC with radioactive iodine, increasing the quality of life in these patients. Caution should be recommended in the follow-up of unselected DTC patients only with stimulated Tg levels.Los estudios publicados que confirman la seguridad y eficacia de la TSH recombinante (rhTSH llevaron a un incremento en el interés para su uso como adyuvante terapéutico en el CDT (ablación o tratamiento

CARbodies: Human Antibodies Against Cell Surface Tumor Antigens Selected From Repertoires Displayed on T Cell Chimeric Antigen Receptors

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Vanesa Alonso-Camino

2013-01-01

Full Text Available A human single-chain variable fragment (scFv antibody library was expressed on the surface of human T cells after transduction with lentiviral vectors (LVs. The repertoire was fused to a first-generation T cell receptor ζ (TCRζ-based chimeric antigen receptor (CAR. We used this library to isolate antibodies termed CARbodies that recognize antigens expressed on the tumor cell surface in a proof-of-principle system. After three rounds of activation-selection there was a clear repertoire restriction, with the emergence dominant clones. The CARbodies were purified from bacterial cultures as soluble and active proteins. Furthermore, to validate its potential application for adoptive cell therapy, human T cells were transduced with a LV encoding a second-generation costimulatory CAR (CARv2 bearing the selected CARbodies. Transduced human primary T cells expressed significant levels of the CARbodies-based CARv2 fusion protein on the cell surface, and importantly could be specifically activated, after stimulation with tumor cells. This approach is a promising tool for the generation of antibodies fully adapted to the display format (CAR and the selection context (cell synapse, which could extend the scope of current adoptive cell therapy strategies with CAR-redirected T cells.

An automated immunoradiometric assay of thyrotrophin (TSH) in dried blood filter paper spots

International Nuclear Information System (INIS)

John, R.; Woodhead, J.S.

1982-01-01

An immunoradiometric two-site assay for thyrotrophin (TSH) in dried blood filter paper spots is described. The assay is automated by means of the Kemtek 3000 automated immunoassay system. The technique uses a 6.0 mm disc punched from the dried blood samples collected as part of the screening programme for phenylketonuria. The method is sensitive and precise, and results correlate well with those obtained in TSH assays of serum samples. The procedure is rapid, results being available within 24 h of receipt of samples. Of 25204 specimens so far screened by this assay, 99.9% have TSH levels less than 15 mU/l. One false positive result has been obtained and six confirmed cases of neonatal hypothyroidism detected, giving a prevalence of 1 in 4200. (Auth.)

Seasonal variations in TSH serum levels in athyreotic patients under L-thyroxine replacement monotherapy.

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Gullo, Damiano; Latina, Adele; Frasca, Francesco; Squatrito, Sebastiano; Belfiore, Antonino; Vigneri, Riccardo

2017-08-01

Whether serum TSH undergoes seasonal fluctuations in euthyroid and hypothyroid residents of temperate climates is controversial. Monthly TSH and thyroid hormone levels were cross-sectionally analysed in a large cohort of euthyroid subjects (n=11 806) and L-thyroxine (L-T4)-treated athyreotic patients (n=3 934). Moreover, in a small group (n=119) of athyreotic patients treated with an unchanged dosage of L-T4 monotherapy, hormones were measured both in the coldest and in the hottest seasons of the same year (longitudinal study). No seasonal hormone change was observed in the euthyroid subjects except for a small FT3 increase in winter (+2.9%, P<.001). In contrast, the L-T4-treated athyreotic patients had significantly higher serum TSH values in the cold season when the FT4 values were significantly lower. The differences were more notable in the longitudinal series (TSH, 0.80 vs. 0.20 mU/L and FT4, 16.3 vs. 17.8 pmol/L in December-March vs. June-September, respectively). In these patients also serum FT3 values significantly decreased in winter (in the longitudinal series, 3.80 in winter vs 4.07 pmol/L in summer). Regression analysis showed that in athyreotic subjects, a greater FT4 change is required to obtain a TSH change similar to that of euthyroid controls and that this effect is more pronounced in the summer. Athyreotic patients undergoing L-T4 monotherapy have abnormal seasonal variations in TSH. These changes are secondary to the FT4 and FT3 serum decreases in winter, which occur in spite of the constant treatment. The underlying mechanisms are unclear, but in some cases, these changes may be clinically relevant. © 2017 John Wiley & Sons Ltd.

The anti-thyroid antibody and I-131 uptake in thyroid disorder patient

International Nuclear Information System (INIS)

Faridul Alam; Fatema Sultana Haque; Mohammad Abdul Karim; Liaquat Ali; Omer Faruque; Azad Khan, A.K.

2004-01-01

The problem of thyroid disorder is extensive in Bangladesh, even more than that of other developing countries. The high incidence rate of goiter is reduced after universal iodine supplement. This study has been undertaken to study the an-thyroid anti-body level among the thyroid disorder population (anti-TPO and anti-thyrogobulin antibody) and TSAb among Graves' disease and sub-acute thyroiditis. This study was performed over 300 persons of them 150 have some type of thyroid (patient) disorder and 150 have got no clinical thyroid disorder (volunteer). We also studied TSH receptor anti-body (TSAb) in 112 Graves' disease patients and 86 patients with sub-acute thyroiditis. All the patient had I-131 Uptake in 24 hours. Among the patient 42(28%) had elevated anti-TPO, 12(8%) had borderline and 96(64%) had normal anti-TPO. It was found the uptake percentage of this group of patient hade slight lower than average uptake of our population. 13±5% It was found that 28(18.6%) had elevated anti thyrogobulin anti-body, 9 (6.2%) had borderline and 113(75.3%) had normal level anti thyrogobulin anti-body. It was also that found the uptake percentage of this group of patient had slight lower than average uptake of our population. We also found that 21% patient had elevated both the antibodies. Among the normal volunteer 24(16%) had elevated anti-TPO, 8 (5.3%) had borderline and 118(78.7%) had normal level of anti-TPO. Thyroid 1-131 uptake was 15±4%. It was found that 14(9.3%) had elevated anti thyrogobulin anti-body, 6(4.1%) had borderline and 130 (76.6%) had normal level of anti thyrogobulin anti-body. Among the normal volunteer 6% had elevated both the antibodies. It was found 91% patient Graves' disease had positive TSAb and 92% of' sub-acute thyroiditis has negative TSAb, I-131 uptake was 31±8% among this group of patient.. Thyroid stimulating antibody is found in 91% of Graves' disease and very few patient with sub-acute thyroiditis. The uptake of I-131 in sub

Study of serum TSH content in functioning thyroid gland adenoma by 'supersensitive' immunoradiometric assay

International Nuclear Information System (INIS)

Foeldes, Janos; Banos, Csaba; Csillag, Jozsef; Lakatos, Peter; Tarjan, Gabor; 2546970HU)

1987-01-01

Determinations of serum TSH levels by immunoradiometric assay (IRMA)-math TSH (Mallinckrodt) kit and of the thyroid function by scintiscanning using 99m Tc-pertechnetate (20-40 MBq) were carried out paralelly in euthyroid and hyperthyroid patients. A comparison of the two tests allowed a better distinction of preclinical hyperthyreosis from toxic adenomas. (L.E.)

Inhibition of fibroblast growth factor receptor 3-dependent lung adenocarcinoma with a human monoclonal antibody

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Yongjun Yin

2016-05-01

Full Text Available Activating mutations in fibroblast growth factor receptor 3 (FGFR3 have been identified in multiple types of human cancer and in congenital birth defects. In human lung cancer, fibroblast growth factor 9 (FGF9, a high-affinity ligand for FGFR3, is overexpressed in 10% of primary resected non-small cell lung cancer (NSCLC specimens. Furthermore, in a mouse model where FGF9 can be induced in lung epithelial cells, epithelial proliferation and ensuing tumorigenesis is dependent on FGFR3. To develop new customized therapies for cancers that are dependent on FGFR3 activation, we have used this mouse model to evaluate a human monoclonal antibody (D11 with specificity for the extracellular ligand-binding domain of FGFR3, that recognizes both human and mouse forms of the receptor. Here, we show that D11 effectively inhibits signaling through FGFR3 in vitro, inhibits the growth of FGFR3-dependent FGF9-induced lung adenocarcinoma in mice, and reduces tumor-associated morbidity. Given the potency of FGF9 in this mouse model and the absolute requirement for signaling through FGFR3, this study validates the D11 antibody as a potentially useful and effective reagent for treating human cancers or other pathologies that are dependent on activation of FGFR3.

Radioiodine therapy of benign thyroid diseases: Graves' disease - current aspects; Radioiodtherapie gutartiger Schilddruesenerkrankungen: Morbus Basedow - aktuelle Aspekte

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Reinhardt, M.J. [Klinik und Poliklinik fuer Nuklearmedizin, Univ. Bonn (Germany)

2005-06-01

Radioiodine therapy is a reliable and cost-effective alternative to medical treatment of Graves' hyperthyroidism. Current recommendations favour a risk-adapted therapeutic procedure. Medical treatment is preferred in patients with a low risk of relapse which are characterised by the combination of female gender, age of onset above 40 years, thyroid volume below 40 ml and TSH-receptor antibodies below 10 U/l. Because of the poor remission rate with medical treatment in patients at less than 40 years of age, male gender, thyroid volume above 40 ml and TSH receptor antibodies above 10 U/l, it is suggested that definitive treatment with radioiodine or surgery should be considered soon after disease presentation. Analysis of cost-effectiveness clearly favour ablative radioiodine treatment. Ablative treatment is even more favourable in terms of early resumption of a normal life style of the hyperthyroid patient. Recent publications suggest further an adaptation of the tissue-absorbed dose to the pre-treatment thyroid volume using Marinelli's formula to achieve thyroid ablation with a single radioiodine treatment. (orig.)

Antibodies to watch in 2014.

Science.gov (United States)

Reichert, Janice M

2014-01-01

Since 2010, mAbs has documented the biopharmaceutical industry's progress in transitioning antibody therapeutics to first Phase 3 clinical studies and regulatory review, and its success at gaining first marketing approvals for antibody-based products. This installment of the "Antibodies to watch" series outlines events anticipated to occur between December 2013 and the end of 2014, including first regulatory actions on marketing applications for vedolizumab, siltuximab, and ramucirumab, as well as the Fc fusion proteins Factor IX-Fc and Factor VIII-Fc; and the submission of first marketing applications for up to five therapeutics (secukinumab, ch14.18, onartuzumab, necitumumab, gevokizumab). Antibody therapeutics in Phase 3 studies are described, with an emphasis on those with study completion dates in 2014, including antibodies targeting interleukin-17a or the interleukin-17a receptor (secukinumab, ixekizumab, brodalumab), proprotein convertase subtilisin/kexin type 9 (alirocumab, evolocumab, bococizumab), and programmed death 1 receptor (lambrolizumab, nivolumab). Five antibodies with US Food and Drug Administration's Breakthrough Therapy designation (obinutuzumab, ofatumumab, lambrolizumab, bimagrumab, daratumumab) are also discussed.

Clinical significance of detection of antibodies to fetal and adult acetylcholine receptors in myasthenia gravis

Institute of Scientific and Technical Information of China (English)

Qi-Guang Shi; Zhi-Hong Wang; Xiao-Wei Ma; Da-Qi Zhang; Chun-Sheng Yang; Fu-Dong Shi; Li Yang

2012-01-01

Objective To evaluate the frequency,distribution and clinical significance of the antibodies to the fetal and/or adult acetylcholine receptor (AChR) in patients with myasthenia gravis (MG).Methods AChR antibodies were detected by cell-based assay in the serum of ocular MG (OMG) (n =90) and generalized MG (GMG) patients (n =110).The fetaltype (2α∶ β∶ γ∶ δ) and adult-type (2α∶ β∶ ε∶ δ) AChR were used as antigens,and their relevance to disease presentation was assessed.Results The overall frequencies of anti-adult and anti-fetal AChR antibodies were similar in all 200 patients examined,with 14 having serum specific to the AChR-γ subunit,and 22 to the AChR-ε subunit.The overall sensitivity when using the fetal and adult AChR antibodies was higher than that when using the fetal AChR antibody only (P =0.015).Compared with OMG patients,the mean age at disease onset and the positive ratio of antibodies to both isoforms of the AChR were significantly higher in patients who subsequently progressed to GMG.Older patients and patients with both anti-fetal and anti-adult AChR antibodies had a greater risk for developing generalized disease [odds ratio (OR),1.03;95％ confidence interval (CI),1.01-1.06 and OR,5.09;95％ CI,2.23-11.62].Conclusion Using both fetal-and adulttype AChRs as the antigens may be more sensitive than using either subtype.Patients with serum specific to both isoforms are at a greater risk of progressing to GMG.Patients with disease onset at an advanced age appear to have a higher frequency of GMG conversion.

Isolation of a human anti-epidermal growth factor receptor Fab antibody, EG-19-11, with subnanomolar affinity from naïve immunoglobulin repertoires using a hierarchical antibody library system.

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Hur, Byung-ung; Yoon, Jae-bong; Liu, Li-Kun; Cha, Sang-hoon

2010-11-30

Specific antibodies that possess a subnanomolar affinity are very difficult to obtain from human naïve immunoglobulin repertoires without the use of lengthy affinity optimization procedures. Here, we designed a hierarchical phage-displayed antibody library system to generate an enormous diversity of combinatorial Fab fragments (6×10(17)) and attempted to isolate high-affinity Fabs against the human epidermal growth factor receptor (EGFR). A primary antibody library, designated HuDVFab-8L, comprising 4.5×10(9) human naïve heavy chains and eight unspecified human naïve light chains was selected against the EGFR-Fc protein by biopanning, and four anti-EGFR Fab clones were isolated. Because one of the Fab clones, denoted EG-L2-11, recognized a native EGFR expressed on A431 cells, the heavy chain of the Fab was shuffled with a human naïve light chain repertoire with a diversity of 1.4×10(8) and selected a second time against the EGFR-Fc protein again. One EG-L2-11 variant, denoted EG-19-11, recognized an EGFR epitope that was almost the same as that bound by cetuximab and had a K(D) of approximately 540 pM for soluble EGFR, which is about 7-fold higher than that of the FabC225 derived from cetuximab. This variant was also internalized by A431 cells, likely via receptor-mediated endocytosis, and it efficiently inhibited EGF-mediated tyrosine phosphorylation of the EGFR. These results demonstrate that the use of our hierarchical antibody library system is advantageous in generating fully human antibodies especially with a therapeutic purpose. Copyright © 2010 Elsevier B.V. All rights reserved.

A generalized quantitative antibody homeostasis model: maintenance of global antibody equilibrium by effector functions.

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Prechl, József

2017-11-01

The homeostasis of antibodies can be characterized as a balanced production, target-binding and receptor-mediated elimination regulated by an interaction network, which controls B-cell development and selection. Recently, we proposed a quantitative model to describe how the concentration and affinity of interacting partners generates a network. Here we argue that this physical, quantitative approach can be extended for the interpretation of effector functions of antibodies. We define global antibody equilibrium as the zone of molar equivalence of free antibody, free antigen and immune complex concentrations and of dissociation constant of apparent affinity: [Ab]=[Ag]=[AbAg]= K D . This zone corresponds to the biologically relevant K D range of reversible interactions. We show that thermodynamic and kinetic properties of antibody-antigen interactions correlate with immunological functions. The formation of stable, long-lived immune complexes correspond to a decrease of entropy and is a prerequisite for the generation of higher-order complexes. As the energy of formation of complexes increases, we observe a gradual shift from silent clearance to inflammatory reactions. These rules can also be applied to complement activation-related immune effector processes, linking the physicochemical principles of innate and adaptive humoral responses. Affinity of the receptors mediating effector functions shows a wide range of affinities, allowing the continuous sampling of antibody-bound antigen over the complete range of concentrations. The generation of multivalent, multicomponent complexes triggers effector functions by crosslinking these receptors on effector cells with increasing enzymatic degradation potential. Thus, antibody homeostasis is a thermodynamic system with complex network properties, nested into the host organism by proper immunoregulatory and effector pathways. Maintenance of global antibody equilibrium is achieved by innate qualitative signals modulating a

An FSH and TSH pituitary adenoma, presenting with precocious puberty and central hyperthyroidism

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Guadalupe Vargas

2017-07-01

Full Text Available A 19-year-old woman with a history of isosexual precocious puberty and bilateral oophorectomy at age 10 years because of giant ovarian cysts, presents with headaches and mild symptoms and signs of hyperthyroidism. Hormonal evaluation revealed elevated FSH and LH levels in the postmenopausal range and free hyperthyroxinemia with an inappropriately normal TSH. Pituitary MRI showed a 2-cm macroadenoma with suprasellar extension. She underwent successful surgical resection of the pituitary tumor, which proved to be composed of two distinct populations of cells, each of them strongly immunoreactive for FSH and TSH, respectively. This mixed adenoma resulted in two different hormonal hypersecretion syndromes: the first one during childhood and consisting of central precocious puberty and ovarian hyperstimulation due to the excessive secretion of biologically active FSH and which was not investigated in detail and 10 years later, central hyperthyroidism due to inappropriate secretion of biologically active TSH. Although infrequent, two cases of isosexual central precocious puberty in girls due to biologically active FSH secreted by a pituitary adenoma have been previously reported in the literature. However, this is the first reported case of a mixed adenoma capable of secreting both, biologically active FSH and TSH.

Epitope mapping of the alpha-chain of the insulin-like growth factor I receptor using antipeptide antibodies.

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Delafontaine, P; Ku, L; Ververis, J J; Cohen, C; Runge, M S; Alexander, R W

1994-12-01

Insulin-like growth factor I (IGF I) is an important mitogen for vascular smooth muscle cells (VSMC). The IGF I receptor (IGF IR) is a heterotetramer composed of two cross-linked extracellular alpha-chains and two membrane-spanning beta-chains that contain a tyrosine-kinase domain. It has a high degree of sequence similarity to the insulin receptor (IR), and the putative ligand-specific binding site has been localized to a cysteine-rich region (CRR) of the alpha-chain. To obtain insights into antigenic determinants of the IGF IR, we raised a panel of site-specific polyclonal antibodies against short peptide sequences N-terminal to and within the CRR. Several antibodies raised against linear epitopes within the CRR bound to solubilized and native rat and human IGF IR by ELISA, did not cross-react with IR, but unexpectedly failed to inhibit 125I-IGF I binding. A polyclonal antibody directed against a 48-amino acid synthetic peptide, corresponding to a region of the CRR postulated to be essential for ligand binding, failed to react with either solubilized, reduced or intact IGF IR. Three antibodies specific for the N-terminus of the alpha-chain reacted with solubilized and native IGF IR. One of these, RAB 6, directed against amino acids 38-44 of the IGF IR, inhibited 125I-IGF I binding to rat aortic smooth muscle cells (RASM) and to IGF IR/3T3 cells (overexpressing human IGF IR) by up to 45%. Immunohistochemical analysis revealed strong IGF IR staining in the medial smooth muscle cell layer of rat aorta. These findings are consistent with a model wherein conformational epitopes within the CRR and linear epitopes within the N-terminus of the alpha-chain contribute to the IGF I binding pocket. These antibodies should provide a valuable tool to study structure-function relationships and in vivo regulation of the IGF IR.

Heterophilic antibody interference affecting multiple hormone assays: Is it due to rheumatoid factor?

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Mongolu, Shiva; Armston, Annie E; Mozley, Erin; Nasruddin, Azraai

2016-01-01

Assay interference with heterophilic antibodies has been well described in literature. Rheumatoid factor is known to cause similar interference leading to falsely elevated hormone levels when measured by immunometric methods like enzyme-linked immunosorbent assay (ELISA) or multiplex immunoasays (MIA). We report a case of a 60-year-old male patient with a history of rheumatoid arthritis referred to our endocrine clinic for investigation of hypogonadism and was found to have high serum levels of LH, FSH, SHBG, Prolactin, HCG and TSH. We suspected assay interference and further tests were performed. We used Heteroblock tubes and PEG precipitation to eliminate the interference and the hormone levels post treatment were in the normal range. We believe the interference was caused by high serum levels of rheumatoid factor. Although he was treated with thyroxine for 3 years, we believe he may have been treated inappropriately as his Free T4 level was always normal despite high TSH due to assay interference. Our case illustrates the phenomenon of heterophilic antibody interference likely due to high levels of rheumatoid factor. It is essential for clinicians and endocrinologists in particular to be aware of this possibility when making treatment decisions in these groups of patients.

The value of recombinant human TSH-aided 131I treatment in differentiated thyroid carcinoma patients

International Nuclear Information System (INIS)

Ding Yong; Long Yahong; Tian Jiahe; Xu Baixuan; Xing Jialiu; Fang Yi; Wei Lijing; Zong Zhaoyi

2013-01-01

Objective: To evaluate the efficacy and safety of recombinant human TSH(rhTSH)-aided 131 I treatment for DTC. Methods: A total of 144 patients with DTC who underwent total or near total thyroidectomy were retrospectively analyzed. The rhTSH-aided 131 I treatment of 3.7 GBq was performed in 72 cases (Group Ⅰ: euthyroid). Another 72 cases received radioiodine ablation treatment of 3.7 GBq after 4 to 6 weeks of thyroxine withdrawal (Group Ⅱ: hypothyroidism). Serum endogenous TSH, FT 3 , FT 4 and Tg were measured. The life qualities of both groups were observed, such as intolerance to cold, weight gain, constipation, motor retardation, skin dryness, periorbital edema and bone pain. Absence of visible uptake or uptake rate less than 1% was taken as complete ablation. The efficacy of 131 I treatment was evaluated. The life quality of both groups was evaluated by χ 2 test, and the effect of 131 I treatment was analyzed by t test. Results: Serum TSH was effectively improved in both groups before 131 I treatment. In group Ⅰ, TSH was higher than that of group Ⅱ ((141.26 ± 27.30) mU/L vs (70.57 ± 51.13) mU/L; t=2.435, P<0.05), and FT 3 , FT 4 were not significantly different before or after the injection of rhTSH. Tg was well stimulated in both groups with no statistical difference. Group Ⅱ exhibited more side effects, which included intolerance to cold 80.56% (58/72), weight gain 86.11% (62/72), constipation 15.28% (11/72), motor retardation 22.22% (16/72), skin dryness 56.94% (41/72), bone pain 2.78% (2/72), and no periorbital edema was found. Group Ⅰ had a higher quality of life than group Ⅱ, only few side effects were observed including dizziness and nausea 2.78% (2/72), bone pain 2.78% (2/72), and transient tachycardia 1.39% (1/72). The effect of 131 I treatment was evaluated by whole body scans with a diagnostic dose of 131 I. The complete ablation rate was 70.83% (51/72) in group Ⅰ and 66.67% (48/72) in group Ⅱ (χ 2 =0.58, P>0.05). Conclusion: The

A monoclonal antibody against PDGF B-chain inhibits PDGF-induced DNA synthesis in C3H fibroblasts and prevents binding of PDGF to its receptor.

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Vassbotn, F S; Langeland, N; Hagen, I; Holmsen, H

1990-09-01

A monoclonal antibody (MAb 6D11) against platelet-derived growth factor (PDGF) was studied. We found that the MAb 6D11 in concentrations equimolar to PDGF blocked the [3H]thymidine incorporation in C3H/10T1/2 C18 fibroblasts stimulated by PDGF B-B and PDGF A-B. This inhibition was overcome by high doses of PDGF. The [3H]thymidine incorporation stimulated by other growth factors (aFGF, bFGF and bombesin) was not inhibited by the antibody. The MAb 6D11 blocked receptor binding of PDGF B-B, but not PDGF A-A. These findings suggest that the MAb 6D11 abolishes PDGF-induced DNA synthesis by blocking PDGF receptor binding. In this communication we demonstrate an isoform-specific monoclonal antibody against PDGF.

TSH alone is not sufficient to exclude all patients with a functioning thyroid nodule from undergoing testing to exclude thyroid cancer

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Hurtado-Lopez, Luis-Mauricio; Monroy-Lozano, Blanca-Estela [General Hospital of Mexico, Mexico City (Mexico); Martinez-Duncker, Carlos [Hospital Infantil de Mexico Federico Gomez, Medicina Nuclear Molecular, Mexico City, DF (Mexico)

2008-06-15

The purpose of the study was to analyze whether the thyroid-stimulating hormone (TSH) alone avoids tests to exclude malignancy in all patients with functional thyroid nodules (FTN). Sixty-nine patients with FTN on {sup 99m}Tc scintigraphy, radioiodine uptake test (RIU), {sup 99m}Tc thyroid uptake, TSH assay, T3, and T4 obtained within 48 h were retrospectively identified out of 2,356 thyroid scans performed from January 2000 to April 2007. FTNs were classified as causing total, partial, or no inhibition of the thyroid as group 1, 2, or 3, respectively. TSH was subnormal in 21 of 69 (30.43%) patients. In group 1 (N = 23, 33.3%), TSH was subnormal, normal, and high in eight, nine, and six patients; in group 2 (N = 17, 24.6%), TSH was subnormal, normal, and high in four, six, and seven patients, and in group 3 (N = 29, 42%), TSH was subnormal, normal, and high in 9, 13, and 7 patients, respectively. TSH was significantly lower in group 1. In T3, T4, {sup 99m}Tc thyroid uptake, and RIU, there were no differences between the three groups. Only 30.43% of patients had subnormal TSH. TSH alone cannot avoid tests to exclude malignancy in all patients with FTN. FTN existence can only be accurately assessed by thyroid scintigraphy. The current incidence of FTN may be unknown because scintigraphy is not routinely performed in all patients with thyroid nodules. Thyroid scintigraphy of patients with high TSH can detect diseases such as Hashimoto's thyroiditis and identify patients with FTN in whom no further diagnostic procedures would be needed in patients with normal TSH levels with nondiagnostic fine-needle aspiration results. (orig.)

Recombinant human TSH-aided radioiodine treatment of advanced differentiated thyroid carcinoma: a single-centre study of 54 patients

International Nuclear Information System (INIS)

Jarzab, Barbara; Handkiewicz-Junak, Daria; Roskosz, Jozef; Puch, Zbigniew; Wygoda, Zbigniew; Kukulska, Aleksandra; Jurecka-Lubieniecka, Beata; Hasse-Lazar, Kornelia; Turska, Maria; Zajusz, Aleksander

2003-01-01

In 54 consecutive patients who had retained bulky metastatic and/or locoregional lesions of DTC despite the exhaustion of other therapeutic options, we gave one to four courses of two consecutive daily intramuscular injections of rhTSH, 0.9 mg, followed by a therapeutic activity of 131 I per os on day 3. Fifty patients had received prior radioiodine treatment aided by l-thyroxine (T 4 ) withdrawal. We included in the study 23 patients who had received a trial of isotretinoin therapy for re-differentiation of confirmed de-differentiated metastases. In a blinded, within-patient comparison of post-therapy whole-body scans after the first rhTSH-aided and latest withdrawal-aided treatments in patients with functional metastases at baseline, 18 of 27 (67%) scan pairs were concordant, four (15%) were discordant in favour of the rhTSH-aided scan and five (19%) were discordant in favour of the withdrawal-aided scan. In total, 37 (74%) of 50 paired scans were concordant, eight (16%) favoured rhTSH and five (10%) favoured withdrawal. All differences appeared to be attributable to clinical causes, not to any difference between endogenous and exogenous TSH stimulation. Reflecting the biochemical activity of rhTSH and the release of thyroglobulin (Tg) due to tumour destruction, median serum Tg concentration rose approximately fourfold between baseline and day 6 of the rhTSH-aided treatment course. rhTSH was well tolerated, with mostly minor, transient toxicity, except for neck oedema in three patients with neck infiltrates and pathological spine fracture in one patient with a large vertebral metastasis. At 6 months, complete response occurred in one (2%), partial response in 12 (26%) and disease stabilisation in 19 (40%) of 47 evaluable patients. The rate of complete + partial response was 41% and that of disease stabilisation, 30%, in the 27 evaluable patients with functional metastases at baseline; the corresponding rates were 10% and 55% in the 20 evaluable patients with non

Clinical experience with a radioreceptor assay for TSH-binding inhibiting immunoglobulins (TBII)

International Nuclear Information System (INIS)

Heberling, H.J.; Bierwolf, B.; Lohmann, D.

1988-01-01

The aim was evaluate the clinical value of a commercial kit for determination of TSH-binding inhibiting immunoglobulin (TBII). 47 of 50 patients with untreated hyperthyroid Graves' disease were TBII positive (sensitivity 94%). TBII was in the normal range in all normal volunteers and in patients with simple goiter, thyroid cancer and in most cases of nonimmunogenic hyperthyreoidism (19 of 22). After 12 months antithyroid drug therapy with methimazole of 21 patients the prevalence of positive TBII findings was 28%. In contrast to this, 50 percent of the patients had increased microsomal antibodies at the end of therapy. The determination of TBII by TRAK assay proved to be a sensitive, specific and practical method. The assay can be used to differentiate between hyperthyreoidism of autoimmune or nonimmunogenic origin. Even so this method seems to be helpful for the follow-up during medical treatment of patients with Graves' disease. The results indicate that persistence of increased TBII levels are markers of active Graves' disease and suggest that in this situation ablative measures should be performed. Normalization of TBII on the end of a longstanding antithyroid therapy does not exclude the possibility of relapse in the further course. (author)

Identification of endogenous opioid receptor components in rat brain using a monoclonal antibody

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Bero, L.A.; Roy, S.; Lee, N.M.

1988-11-01

A monoclonal antibody generated against the tertiary structure of a partially purified opioid binding protein was used to probe the structure of the dynorphin and beta-endorphin receptors. The Fab fragment 3B4F11 inhibited completely the binding of 125I-beta-endorphin and (3H)dynorphin to rat brain P2 membranes with IC50 values of 26 ng/ml and 40 ng/ml, respectively. To explore further the interaction of 3B4F11 with the beta-endorphin receptor, the effect of the Fab fragment on 125I-beta-endorphin cross-linking to rat brain membranes was examined. 125I-beta-endorphin was covalently bound to three major species of approximate molecular weights 108,000, 73,000, and 49,000. The delta-selective ligand D-Pen2, D-pen5enkephalin was least effective at inhibiting the cross-linking of beta-endorphin, whereas the micro-selective ligand Tyr-D-Ala-Gly-NMe-Phe-Gly-ol and kappa-selective ligand U50488 inhibited beta-endorphin cross-linking to the 108,000 and 73,000 Da species. Both 3B4F11 and beta-endorphin prevented the covalent binding of 125I-beta-endorphin to all three labeled species. These findings suggest that micro and kappa receptor types might have some structural similarities, whereas the delta receptor type might differ in molecular size. In addition, the micro, kappa, and delta ligands might have different primary sequences, whereas their tertiary structures might share regions of molecular homology with all three receptor constituents labeled by 125I-beta-endorphin. 3B4F11 will be a valuable tool for the purification and isolation of the several components of the beta-endorphin receptor complex.

Excess Mortality in Treated and Untreated Hyperthyroidism Is Related to Cumulative Periods of Low Serum TSH.

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Lillevang-Johansen, Mads; Abrahamsen, Bo; Jørgensen, Henrik Løvendahl; Brix, Thomas Heiberg; Hegedüs, Laszlo

2017-07-01

Cumulative time-dependent excess mortality in hyperthyroid patients has been suggested. However, the effect of antithyroid treatment on mortality, especially in subclinical hyperthyroidism, remains unclarified. We investigated the association between hyperthyroidism and mortality in both treated and untreated hyperthyroid individuals. Register-based cohort study of 235,547 individuals who had at least one serum thyroid-stimulating hormone (TSH) measurement in the period 1995 to 2011 (7.3 years median follow-up). Hyperthyroidism was defined as at least two measurements of low serum TSH. Mortality rates for treated and untreated hyperthyroid subjects compared with euthyroid controls were calculated using multivariate Cox regression analyses, controlling for age, sex, and comorbidities. Cumulative periods of decreased serum TSH were analyzed as a time-dependent covariate. Hazard ratio (HR) for mortality was increased in untreated [1.23; 95% confidence interval (CI), 1.12 to 1.37; P hyperthyroid patients. When including cumulative periods of TSH in the Cox regression analyses, HR for mortality per every 6 months of decreased TSH was 1.11 (95% CI, 1.09 to 1.13; P hyperthyroid patients (n = 1137) and 1.13 (95% CI, 1.11 to 1.15; P hyperthyroidism, respectively. Mortality is increased in hyperthyroidism. Cumulative periods of decreased TSH increased mortality in both treated and untreated hyperthyroidism, implying that excess mortality may not be driven by lack of therapy, but rather inability to keep patients euthyroid. Meticulous follow-up during treatment to maintain biochemical euthyroidism may be warranted. Copyright © 2017 by the Endocrine Society

Hypothyroidism in adults. Levothyroxine if warranted by clinical and laboratory findings, not for simple TSH elevation.

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2015-10-01

Hypothyroidism is a common disorder due to inadequate thyroid hormone secretion. When a patient has signs and symptoms suggestive of hypothyroidism, how is it determined whether thyroid hormone replacement therapy will have a favourable harm-benefit balance? How should treatment be managed? To answer these questions, we conducted a review of the literature using the standard Prescrire methodology. The symptoms of hypothyroidism are due to slow metabolism (constipation, fatigue, sensitivity to cold, weight gain, etc.) and to polysaccharide accumulation in certain tissues, leading to hoarseness, eyelid swelling, etc. A blood TSH concentration of less than 4 or 5 mlU/L rules out peripheral hypothyroidism. TSH levels increase with age. Between 30% and 60% of high TSH levels are not confirmed on a second blood test. In overt hypothyroidism, the TSH level is high and the free T4 (thyroxine) level is low. Most of these patients are symptomatic. So-called subclinical hypothyroidism, which is rarely symptomatic, is characterised by high blood TSH levels and normal free T4 levels. The natural history of hypothyroidism depends on its cause. In chronic autoimmune thyroiditis, the most common form seen in rich countries, hypothyroidism generally worsens over time. However, other situations can lead to transient hypothyroidism that may last several weeks or months. Subclinical hypothyroidism, as the name implies, is usually asymptomatic. The risk of progression to overt hypothyroidism is about 3% to 4% per year overall but increases with the initial TSH level. Treatment guidelines are mainly based on physiological and pharmacological considerations and generally recommend levothyroxine therapy. The adverse effects of levothyroxine are signs of thyrotoxicosis in case of overdose (tachycardia, tremor, sweating, etc.). Even a slight overdose carries a risk of osteoporotic fractures and atrial fibrillation, especially in the elderly. In young adults, levothyroxine is usually started

Thyroid profiles in a patient with resistance to thyroid hormone and episodes of thyrotoxicosis, including repeated painless thyroiditis.

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Taniyama, Matsuo; Otsuka, Fumiko; Tozaki, Teruaki; Ban, Yoshiyuki

2013-07-01

Thyrotoxic disease can be difficult to recognize in patients with resistance to thyroid hormone (RTH) because the clinical symptoms of thyrotoxicosis cannot be observed, and thyrotropin (TSH) may not be suppressed because of hormone resistance. Painless thyroiditis is a relatively common cause of thyrotoxicosis, but its occurrence in RTH has not been reported. We assessed the thyroid profile in a patient with RTH and episodes of thyrotoxicosis who experienced repeated painless thyroiditis. A 44-year-old Japanese woman with RTH, which was confirmed by the presence of a P453A mutation in the thyroid hormone receptor β (TRβ) gene, showed a slight elevation of the basal levels of thyroid hormones, which indicated that her pituitary RTH was mild. She experienced a slight exacerbation of hyperthyroxinemia concomitant with TSH suppression. A diagnosis of painless thyroiditis was made because of the absence of TSH receptor antibodies, low Tc-99m pertechnetate uptake by the thyroid gland, and transient suppression followed by a slight elevation of TSH following the elevation of thyroid hormones. The patient's complaints of general malaise and occasional palpitations did not change throughout the course of painless thyroiditis. Three years later, painless thyroiditis occurred again without any deterioration of the clinical manifestations. Mild pituitary RTH can be overcome by slight exacerbation of hyperthyroxinemia during mild thyrotoxicosis. When pituitary resistance is severe and TSH is not suppressed, thyrotoxicosis may be overlooked.

Clonal heterogeneity of thymic B cells from early-onset myasthenia gravis patients with antibodies against the acetylcholine receptor.

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Vrolix, Kathleen; Fraussen, Judith; Losen, Mario; Stevens, Jo; Lazaridis, Konstantinos; Molenaar, Peter C; Somers, Veerle; Bracho, Maria Alma; Le Panse, Rozen; Stinissen, Piet; Berrih-Aknin, Sonia; Maessen, Jos G; Van Garsse, Leen; Buurman, Wim A; Tzartos, Socrates J; De Baets, Marc H; Martinez-Martinez, Pilar

2014-08-01

Myasthenia gravis (MG) with antibodies against the acetylcholine receptor (AChR-MG) is considered as a prototypic autoimmune disease. The thymus is important in the pathophysiology of the disease since thymus hyperplasia is a characteristic of early-onset AChR-MG and patients often improve after thymectomy. We hypothesized that thymic B cell and antibody repertoires of AChR-MG patients differ intrinsically from those of control individuals. Using immortalization with Epstein-Barr Virus and Toll-like receptor 9 activation, we isolated and characterized monoclonal B cell lines from 5 MG patients and 8 controls. Only 2 of 570 immortalized B cell clones from MG patients produced antibodies against the AChR (both clones were from the same patient), suggesting that AChR-specific B cells are not enriched in the thymus. Surprisingly, many B cell lines from both AChR-MG and control thymus samples displayed reactivity against striated muscle proteins. Striational antibodies were produced by 15% of B cell clones from AChR-MG versus 6% in control thymus. The IgVH gene sequence analysis showed remarkable similarities, concerning VH family gene distribution, mutation frequency and CDR3 composition, between B cells of AChR-MG patients and controls. MG patients showed clear evidence of clonal B cell expansion in contrast to controls. In this latter aspect, MG resembles multiple sclerosis and clinically isolated syndrome, but differs from systemic lupus erythematosus. Our results support an antigen driven immune response in the MG thymus, but the paucity of AChR-specific B cells, in combination with the observed polyclonal expansions suggest a more diverse immune response than expected. Copyright © 2013 Elsevier Ltd. All rights reserved.

Thyroid-Stimulating Hormone (TSH Concentration at Birth in Belgian Neonates and Cognitive Development at Preschool Age

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Caroline Trumpff

2015-11-01

Full Text Available The main objective of the study was to investigate the effect of MID during late pregnancy, assessed by the thyroid-stimulating hormone (TSH concentration at neonatal screening, on cognitive development of preschool children. A retrospective cohort study including 311 Belgian preschool children of 4–6 years old was conducted. Children were selected at random from the total list of neonates screened in 2008, 2009, and 2010 by the Brussels new-born screening center. Infants with congenital hypothyroidism, low birth weight, and/or prematurity were excluded from the selection. The selected children were stratified by gender and TSH-range (0.45–15 mIU/L. Cognitive abilities were assessed using Wechsler Preschool and Primary Scale of Intelligence—third edition. In addition, several socioeconomic, parental, and child confounding factors were assessed. Neonatal TSH concentration—a surrogate marker for MID—was not associated with Full Scale and Performance IQ scores in children. Lower Verbal IQ scores were found in children with neonatal TSH values comprised between 10–15 mIU/L compared to lower TSH levels in univariate analysis but these results did not hold when adjusting for confounding factors. Current levels of iodine deficiency among pregnant Belgian women may not be severe enough to affect the neurodevelopment of preschool children.

The Impact of HLA Class I-Specific Killer Cell Immunoglobulin-Like Receptors on Antibody-Dependent Natural Killer Cell-Mediated Cytotoxicity and Organ Allograft Rejection.

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Rajalingam, Raja

2016-01-01

Natural killer (NK) cells of the innate immune system are cytotoxic lymphocytes that play an important roles following transplantation of solid organs and hematopoietic stem cells. Recognition of self-human leukocyte antigen (HLA) class I molecules by inhibitory killer cell immunoglobulin-like receptors (KIRs) is involved in the calibration of NK cell effector capacities during the developmental stage, allowing the subsequent recognition and elimination of target cells with decreased expression of self-HLA class I (due to virus infection or tumor transformation) or HLA class I disparities (in the setting of allogeneic transplantation). NK cells expressing an inhibitory KIR-binding self-HLA can be activated when confronted with allografts lacking a ligand for the inhibitory receptor. Following the response of the adaptive immune system, NK cells can further destroy allograft endothelium by antibody-dependent cell-mediated cytotoxicity (ADCC), triggered through cross-linking of the CD16 Fc receptor by donor-specific antibodies bound to allograft. Upon recognizing allogeneic target cells, NK cells also secrete cytokines and chemokines that drive maturation of dendritic cells to promote cellular and humoral adaptive immune responses against the allograft. The cumulative activating and inhibitory signals generated by ligation of the receptors regulates mature NK cell killing of target cells and their production of cytokines and chemokines. This review summarizes the role of NK cells in allograft rejection and proposes mechanistic concepts that indicate a prominent role for KIR-HLA interactions in facilitating NK cells for Fc receptor-mediated ADCC effector function involved in antibody-mediated rejection of solid organ transplants.

The impact of HLA class I-specific killer cell immunoglobulin-like receptors on antibody-dependent natural killer cell-mediated cytotoxicity and organ allograft rejection

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Raja Rajalingam

2016-12-01

Full Text Available Natural killer (NK cells of the innate immune system are cytotoxic lymphocytes that play important roles following transplantation of solid organs and hematopoietic stem cells. Recognition of self HLA class I molecules by inhibitory killer cell immunoglobulin-like receptors (KIR is involved in the calibration of NK cell effector capacities during a developmental stage, allowing the subsequent recognition and elimination of target cells with decreased expression of self HLA class I (due to virus infection or tumor transformation or HLA class I disparities (in the setting of allogeneic transplantation. NK cells expressing an inhibitory KIR binding self HLA can be activated when confronted with allografts lacking a ligand for the inhibitory receptor. Following the response of the adaptive immune system, NK cells can further destroy allograft endothelium by antibody-dependent cell-mediated cytotoxicity (ADCC, triggered through cross-linking of the CD16 Fc receptor by donor-specific antibodies bound to allograft. Upon recognizing allogeneic target cells, NK cells also secrete cytokines and chemokines that drive maturation of dendritic cells to promote cellular and humoral adaptive immune responses against the allograft. The cumulative activating and inhibitory signals generated by ligation of the receptors regulates mature NK cell killing of target cells and their production of cytokines and chemokines. This review summarizes the role of NK cells in allograft rejection and proposes mechanistic concepts that indicate a prominent role for KIR-HLA interactions in facilitating NK cells for Fc receptor-mediated ADCC effector function involved in antibody-mediated rejection of solid organ transplants.

Homogeneous plate based antibody internalization assay using pH sensor fluorescent dye.

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Nath, Nidhi; Godat, Becky; Zimprich, Chad; Dwight, Stephen J; Corona, Cesear; McDougall, Mark; Urh, Marjeta

2016-04-01

Receptor-mediated antibody internalization is a key mechanism underlying several anti-cancer antibody therapeutics. Delivering highly toxic drugs to cancer cells, as in the case of antibody drug conjugates (ADCs), efficient removal of surface receptors from cancer cells and changing the pharmacokinetics profile of the antibody drugs are some of key ways that internalization impacts the therapeutic efficacy of the antibodies. Over the years, several techniques have been used to study antibody internalization including radiolabels, fluorescent microscopy, flow cytometry and cellular toxicity assays. While these methods allow analysis of internalization, they have limitations including a multistep process and limited throughput and are generally endpoint assays. Here, we present a new homogeneous method that enables time and concentration dependent measurements of antibody internalization. The method uses a new hydrophilic and bright pH sensor dye (pHAb dye), which is not fluorescent at neutral pH but becomes highly fluorescent at acidic pH. For receptor mediated antibody internalization studies, antibodies against receptors are conjugated with the pHAb dye and incubated with the cells expressing the receptors. Upon binding to the receptor, the dyes conjugated to the antibody are not fluorescent because of the neutral pH of the media, but upon internalization and trafficking into endosomal and lysosomal vesicles the pH drops and dyes become fluorescent. The enabling attributes of the pHAb dyes are the hydrophilic nature to minimize antibody aggregation and bright fluorescence at acidic pH which allows development of simple plate based assays using a fluorescent reader. Using two different therapeutic antibodies--Trastuzumab (anti-HER2) and Cetuximab (anti-EGFR)--we show labeling with pHAb dye using amine and thiol chemistries and impact of chemistry and dye to antibody ration on internalization. We finally present two new approaches using the pHAb dye, which will be

[Autoimmune diseases of the thyroid gland].

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Allelein, S; Feldkamp, J; Schott, M

2017-01-01

Autoimmune diseases of the thyroid gland are considered to be the most frequent cause of thyroid gland disorders. Autoimmune thyroid diseases consist of two subgroups: autoimmune thyroiditis (AIT) and Graves' disease. The AIT is the most common human autoimmune disease. Infiltration of the thyroid gland with cytotoxic T‑cells can lead to an initial thyrotoxicosis und during the course to hypothyroidism due to destruction of the thyroid gland. Substitution with Levothyroxine is indicated for manifest hypothyroidism and subclinical hypothyroidism with increased thyroid antibodies with the intention of normalizing the serum thyroid stimulating hormone (TSH). Graves' disease is characterized by the appearance of stimulating TSH receptor antibodies leading to hyperthyroidism. Endocrine ophthalmopathy may also occur. Ablative therapy with radioiodine therapy or thyroidectomy is administered to patients with Graves' disease without remission after at least 1 year of antithyroid drug therapy.

Myasthenic Crisis Complicated with Myxedema, Positive for Both Anti-acetylcholine Receptor and Anti-muscle-specific Tyrosine Kinase Antibodies.

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Horiuchi, Kazuhiro; Nagai, Azusa; Wakita, Masahiro; Ito, Shotaro; Takamura, Kei; Houzen, Hideki

2018-01-15

We herein report the case of myasthenic crisis occurring in a 51-year-old man. He had experienced ptosis, increased body weight with edema, and fatigue with dyspnea. He presented at our emergency department with disturbed consciousness. He was originally diagnosed with myxedema coma, and he required artificial respiration. Because his weakness persisted and he was positive for anti-acetylcholine receptor antibodies and anti-muscle-specific tyrosine kinase antibodies, we diagnosed myasthenic crisis after various examinations. His clinical response to treatment was good and he was discharged in an ambulatory status 3 months after admission. This case demonstrates that myasthenic crisis may occur in association with myxedema.

Toll-like receptor activation enhances cell-mediated immunity induced by an antibody vaccine targeting human dendritic cells

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Berger Marc A

2007-01-01

Full Text Available Abstract Previously, we have successfully targeted the mannose receptor (MR expressed on monocyte-derived dendritic cells (DCs using a fully human MR-specific antibody, B11, as a vehicle to deliver whole protein tumor antigens such as the human chorionic gonadotropin hormone (hCGβ. Since MRs play a role in bridging innate immunity with adaptive immunity we have explored several toll-like receptor (TLR-specific ligands that may synergize with MR targeting and be applicable as adjuvants in the clinic. We demonstrate that antigen-specific helper and cytolytic T cells from both healthy donors and cancer patients were effectively primed with B11-hCGβ-treated autologous DCs when a combination of one or several TLR ligands is used. Specifically, concomitant signaling of DCs via TLR3 with dsRNA (poly I:C and DC TLR 7/8 with Resiquimod (R-848, respectively, elicited efficient antigen presentation-mediated by MR-targeting. We demonstrate that MR and TLRs contribute towards maturation and activation of DCs by a mechanism that may be driven by a combination of adjuvant and antibody vaccines that specifically deliver antigenic targets to DCs.

Characterization and expression of the human T cell receptor-T3 complex by monoclonal antibody F101.01

DEFF Research Database (Denmark)

Geisler, C; Plesner, T; Pallesen, G

1988-01-01

A murine monoclonal antibody (MoAb) F101.01 reacting with the T cell receptor (TCR)-T3 complex is presented. Immunohistological studies showed that F101.01 specifically stains T-zone lymphocytes in lymph nodes, tonsils, and splenic tissue. Two-colour immunofluorescence and flow cytometry...... demonstrated co-expression of the antigen defined by F101.01 and the pan-T cell antigens defined by CD2, CD3, CD5, and CD7 antibodies. Cells stained with CD4 and CD8 antibodies were both included in the F101.01-positive population, whereas CD16-positive natural killer cells (NK), B cells (CD19 and CD20......), and myeloid cells (CD13 and CD33) were excluded. The target antigen of F101.01 co-modulated with the CD3-defined antigen (T3) and the TCR recognized by the MoAb WT-31. CD3 antibody and WT-31 both blocked binding of F101.01. F101.01 precipitated the TCR-T3 complex from lysates of 125I-labelled peripheral blood...

Interesting coincidence of atypical TSH-secreting pituitary adenoma and chronic lymphocytic leukemia.

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Bolanowski, Marek; Zieliński, Grzegorz; Jawiarczyk-Przybyłowska, Aleksandra; Maksymowicz, Maria; Potoczek, Stanisław; Syrycka, Joanna; Podgórski, Jan K

2014-01-01

Thyrotropin-secreting adenomas (TSH-oma) are very rare pituitary tumours. They are macroadenomas usually presenting with signs and symptoms of hyperthyroidism, and mass effects. They can co-secrete other hormones such as growth hormone or prolactin. Different malignancies, including haematological ones, are reported in patients with pituitary diseases. Chronic lymphocytic leukemia (CLL) occurs mostly in older patients, more often in males. CLL is associated with increased risk of second malignancies such as other blood neoplasms, skin and solid tumours. We present a successful neurosurgical outcome in a patient with an interesting coincidence of atypical TSH-oma and asymptomatic CLL.

A monoclonal antibody TrkB receptor agonist as a potential therapeutic for Huntington's disease.

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Daniel Todd

Full Text Available Huntington's disease (HD is a devastating, genetic neurodegenerative disease caused by a tri-nucleotide expansion in exon 1 of the huntingtin gene. HD is clinically characterized by chorea, emotional and psychiatric disturbances and cognitive deficits with later symptoms including rigidity and dementia. Pathologically, the cortico-striatal pathway is severely dysfunctional as reflected by striatal and cortical atrophy in late-stage disease. Brain-derived neurotrophic factor (BDNF is a neuroprotective, secreted protein that binds with high affinity to the extracellular domain of the tropomyosin-receptor kinase B (TrkB receptor promoting neuronal cell survival by activating the receptor and down-stream signaling proteins. Reduced cortical BDNF production and transport to the striatum have been implicated in HD pathogenesis; the ability to enhance TrkB signaling using a BDNF mimetic might be beneficial in disease progression, so we explored this as a therapeutic strategy for HD. Using recombinant and native assay formats, we report here the evaluation of TrkB antibodies and a panel of reported small molecule TrkB agonists, and identify the best candidate, from those tested, for in vivo proof of concept studies in transgenic HD models.

Thyrotoxic Dysphagia in an 82-Year-Old Male

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Konstantinos Parperis

2011-01-01

Full Text Available Dysphagia is a common problem in elderly patients and a rare manifestation of Graves' disease. We report a case of an 82-year-old male who presented with a 4-week history of dysphagia and weight loss. Workup for his dysphagia with upper endoscopy, MRI brain, electromyography, acetyl-cholinesterase receptor antibodies, and voltage-gated calcium channel antibodies were negative. Modified Barium swallow test showed oropharyngeal dysphagia. Thyroid function tests that revealed hyperthyroidism and antibodies to TSH-receptor were positive. Based on the above findings, we considered Graves' disease as the most likely diagnosis. Patient was treated with methimazole and beta-blockers and subsequently his dysphagia resolved. This paper highlights the importance to clinicians of considering thyrotoxicosis as possible diagnosis in an elderly patient presenting with unexplained dysphagia.

Nonclassical ligands for the thyrotropin receptor: functional studies on thyrostimulin and Graves’ disease immunoglobulins

NARCIS (Netherlands)

van Zeijl, C.J.J.

2011-01-01

Clementine van Zeijl onderzocht twee liganden (verbindingsmoleculen) voor TSHR, de receptor voor schildklierstimulerend hormoon (TSH). Ze bestudeerde bij muizen de rol van thyrostimuline (een recentelijk ontdekt TSHR-stimulerend glycoproteïnehormoon) in de hypothalamus-hypofyse-schildklieras (HPT)

Targeting Malignant Brain Tumors with Antibodies

Directory of Open Access Journals (Sweden)

Rok Razpotnik

2017-09-01

Full Text Available Antibodies have been shown to be a potent therapeutic tool. However, their use for targeting brain diseases, including neurodegenerative diseases and brain cancers, has been limited, particularly because the blood–brain barrier (BBB makes brain tissue hard to access by conventional antibody-targeting strategies. In this review, we summarize new antibody therapeutic approaches to target brain tumors, especially malignant gliomas, as well as their potential drawbacks. Many different brain delivery platforms for antibodies have been studied such as liposomes, nanoparticle-based systems, cell-penetrating peptides (CPPs, and cell-based approaches. We have already shown the successful delivery of single-chain fragment variable (scFv with CPP as a linker between two variable domains in the brain. Antibodies normally face poor penetration through the BBB, with some variants sufficiently passing the barrier on their own. A “Trojan horse” method allows passage of biomolecules, such as antibodies, through the BBB by receptor-mediated transcytosis (RMT. Such examples of therapeutic antibodies are the bispecific antibodies where one binding specificity recognizes and binds a BBB receptor, enabling RMT and where a second binding specificity recognizes an antigen as a therapeutic target. On the other hand, cell-based systems such as stem cells (SCs are a promising delivery system because of their tumor tropism and ability to cross the BBB. Genetically engineered SCs can be used in gene therapy, where they express anti-tumor drugs, including antibodies. Different types and sources of SCs have been studied for the delivery of therapeutics to the brain; both mesenchymal stem cells (MSCs and neural stem cells (NSCs show great potential. Following the success in treatment of leukemias and lymphomas, the adoptive T-cell therapies, especially the chimeric antigen receptor-T cells (CAR-Ts, are making their way into glioma treatment as another type of cell

Iodine excretion during stimulation with rhTSH in differentiated thyroid carcinoma

International Nuclear Information System (INIS)

Loeffler, M.; Weckesser, M.; Franzius, C.; Kies, P.; Schober, O.

2003-01-01

Aim: Elevated iodine intake is a serious problem in the diagnostic and therapeutic application of 131 iodine in patients with differentiated thyroid cancer. Therefore, iodine avoidance is necessary 3 months in advance. Additionally, endogenous stimulation requires withdrawal of thyroid hormone substitution for 4 weeks. Exogenous stimulation using recombinant human TSH (rhTSH) enables the continuous substitution of levothyroxine, which contains 65.4% of its molecular weight in iodine. Thus, a substantial source of iodine intake is maintained during exogenous stimulation. Although this amount of stable iodine is comparable to the iodine intake in regions of normal iodine supply, it may reduce the accumulation of radioiodine in thyroid carcinoma tissue. The aim of this study was to assess the iodine excretion depending on different ways of stimulation. Methods: Iodine excretion was measured in 146 patients in the long term follow up after differentiated thyroid carcinoma. Patients were separated into 2 groups, those on hormone withdrawal (G I) and rhTSH-stimulated patients on hormone substitution (G II). Results: Iodine excretion was significantly lower in hypothyroid patients (G I, median 50 μg/l, range: 25-600 μg/l) than in those under levothyroxine medication (G II, median 75 μg/l, 25-600 μg/l, p [de

Relationship between serum TSH and the responsiveness of toxic solitary autonomous thyroid nodules to radioiodine therapy

DEFF Research Database (Denmark)

Pedersen-Bjergaard, U; Kirkegaard, B C

1998-01-01

hypothyroidism both had detectable serum TSH at the time of 131I treatment. No other clinical parameter seemed to influence the outcome. CONCLUSION: There is no clinically significant effect of circulating TSH on the response of toxic solitary autonomous thyroid nodules to 131I therapy. However, keeping...... the patients subclinically hyperthyroid when receiving 131I treatment may possibly result in a reduced frequency of hypothyroidism.......) were euthyroid, three (8%) had responded insufficiently and required further antithyroid therapy, and two (5%) had developed hypothyroidism. No significant difference in the response pattern between patients with suppressed or detectable serum TSH could be demonstrated. The two patients who developed...

Activating thyrotropin receptor mutations in histologically heterogeneous hyperfunctioning nodules of multinodular goiter.

Science.gov (United States)

Tonacchera, M; Vitti, P; Agretti, P; Giulianetti, B; Mazzi, B; Cavaliere, R; Ceccarini, G; Fiore, E; Viacava, P; Naccarato, A; Pinchera, A; Chiovato, L

1998-07-01

Activating thyrotropin (TSH) receptor mutations have been found in toxic adenomas and in hot nodules contained in toxic multinodular goiter. The typical feature of multinodular goiter is the heterogeneity in morphology and function of different follicles within the same enlarged gland. In this report we describe a patient with a huge multinodular goiter, normal free triiodothyronine (FT3) and free thyroxine (FT4) serum values, and subnormal TSH serum concentration. Thyroid scintiscan showed two hot areas corresponding to the basal and apical nodules of the left lobe. The right lobe was poorly visualized by the radioisotope. The patient underwent thyroidectomy, and histological examination of the tissue was performed. Genomic DNA was extracted from the tissue specimen and direct sequencing of the TSH receptor and Gs alpha genes was done. At histology, one hyperfunctioning nodule had the typical microscopic structure of thyroid adenomas, and the other contained multiple macrofollicular areas not confined by a capsule. In spite of this histological difference, both hyperfunctioning nodules harbored a mutation of the thyrotropin receptor (TSHr) gene: an isoleucine instead of a threonine in position 632 (T632I) in the first nodule and a methionine instead of an isoleucine in position 486 (I486M) in the second nodule. In conclusion, our findings show for the first time that gain-of-function TSHr mutations are not only present in hyperfunctioning thyroid nodules with the histological features of the true thyroid adenomas, but also in hyperfunctioning hyperplastic nodules contained in the same multinodular goiter.

The Isolation of Novel Phage Display-Derived Human Recombinant Antibodies Against CCR5, the Major Co-Receptor of HIV

Science.gov (United States)

Shimoni, Moria; Herschhorn, Alon; Britan-Rosich, Yelena; Kotler, Moshe; Benhar, Itai

2013-01-01

Abstract Selecting for antibodies against specific cell-surface proteins is a difficult task due to many unrelated proteins that are expressed on the cell surface. Here, we describe a method to screen antibody-presenting phage libraries against native cell-surface proteins. We applied this method to isolate antibodies that selectively recognize CCR5, which is the major co-receptor for HIV entry (consequently, playing a pivotal role in HIV transmission and pathogenesis). We employed a phage screening strategy by using cells that co-express GFP and CCR5, along with an excess of control cells that do not express these proteins (and are otherwise identical to the CCR5-expressing cells). These control cells are intended to remove most of the phages that bind the cells nonspecifically; thus leading to an enrichment of the phages presenting anti-CCR5-specific antibodies. Subsequently, the CCR5-presenting cells were quantitatively sorted by flow cytometry, and the bound phages were eluted, amplified, and used for further successive selection rounds. Several different clones of human single-chain Fv antibodies that interact with CCR5-expressing cells were identified. The most specific monoclonal antibody was converted to a full-length IgG and bound the second extracellular loop of CCR5. The experimental approach presented herein for screening for CCR5-specific antibodies can be applicable to screen antibody-presenting phage libraries against any cell-surface expressed protein of interest. PMID:23941674

Expression analysis and specific blockade of the receptor for human thymic stromal lymphopoietin (TSLP) by novel antibodies to the human TSLPRα receptor chain.

Science.gov (United States)

Borowski, Andreas; Vetter, Tina; Kuepper, Michael; Wohlmann, Andreas; Krause, Sebastian; Lorenzen, Thomas; Virchow, Johann Christian; Luttmann, Werner; Friedrich, Karlheinz

2013-02-01

Thymic stromal lymphopoietin (TSLP) is an interleukin-7 (IL-7)-like cytokine with a pivotal role in development and maintenance of atopic diseases such as allergic asthma and atopic dermatitis. Moreover, recent studies show an involvement of TSLP in the progression of various cancers. TSLP signaling is mediated by the TSLP receptor (TSLPR), a heterodimeric type I cytokine receptor. It consists of the IL-7 receptor alpha chain (IL-7Rα), which is shared with the IL-7 receptor, and the TSLPRα chain as a specific subunit. Blocking signal release by TSLP without affecting IL-7 function is a potentially interesting option for the treatment of atopic diseases or certain tumors. By employing the extracellular domain of human TSLPRα chain (hTSLPRα(ex)) as an antigen, we generated a set of monoclonal antibodies. Several binders to native and/or denatured receptor protein were identified and characterized by cytometry and Western blot analysis. A screen based on a STAT3-driven reporter gene assay in murine pro-B cells expressing a functional hTSLPR yielded two hybridoma clones with specific antagonistic properties towards hTSLP, but not IL-7. Kinetic studies measuring blockade of hTSLP-dependent STAT phosphorylation in a TSLP-responsive cell line revealed an inhibitory constant in the nanomolar range. Copyright © 2012 Elsevier Ltd. All rights reserved.

Visualization of Tumor Angiogenesis Using MR Imaging Contrast Agent Gd-DTPA-anti-VEGF Receptor 2 Antibody Conjugate in a Mouse Tumor Model

International Nuclear Information System (INIS)

Jun, Hong Young; Yin, Hong Hua; Kim, Sun Hee; Park, Seong Hoon; Kim, Hun Soo; Yoon Kwon Ha Yoon

2010-01-01

To visualize tumor angiogenesis using the MRI contrast agent, Gd- DTPA-anti-VEGF receptor 2 antibody conjugate, with a 4.7-Tesla MRI instrument in a mouse model. We designed a tumor angiogenesis-targeting T1 contrast agent that was prepared by the bioconjugation of gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA) and an anti-vascular endothelial growth factor receptor-2 (VEGFR2) antibody. The specific binding of the agent complex to cells that express VEGFR2 was examined in cultured murine endothelial cells (MS-1 cells) with a 4.7-Tesla magnetic resonance imaging scanner. Angiogenesis-specific T1 enhancement was imaged with the Gd-DTPA-anti-VEGFR2 antibody conjugate using a CT-26 adenocarcinoma tumor model in eight mice. As a control, the use of the Gd-DTPA-anti-rat immunoglobulin G (Gd-DTPA-anti-rat IgG) was imaged with a tumor model in eight mice. Statistical significance was assessed using the Mann-Whitney test. Tumor tissue was examined by immunohistochemical analysis. The Gd-DTPA-anti-VEGFR2 antibody conjugate showed predominant binding to cultured endothelial cells that expressed a high level of VEGFR2. Signal enhancement was approximately three-fold for in vivo T1-weighted MR imaging with the use of the Gd-DTPA-anti-VEGFR2 antibody conjugate as compared with the Gd-DTPA-rat IgG in the mouse tumor model (p < 0.05). VEGFR2 expression in CT-26 tumor vessels was demonstrated using immunohistochemical staining. MR imaging using the Gd-DTPA-anti-VEGFR2 antibody conjugate as a contrast agent is useful in visualizing noninvasively tumor angiogenesis in a murine tumor model

Visualization of Tumor Angiogenesis Using MR Imaging Contrast Agent Gd-DTPA-anti-VEGF Receptor 2 Antibody Conjugate in a Mouse Tumor Model

Energy Technology Data Exchange (ETDEWEB)

Jun, Hong Young; Yin, Hong Hua; Kim, Sun Hee; Park, Seong Hoon; Kim, Hun Soo; Yoon Kwon Ha Yoon [Wonkwang University School of Medicine, Iksan (Korea, Republic of)

2010-08-15

To visualize tumor angiogenesis using the MRI contrast agent, Gd- DTPA-anti-VEGF receptor 2 antibody conjugate, with a 4.7-Tesla MRI instrument in a mouse model. We designed a tumor angiogenesis-targeting T1 contrast agent that was prepared by the bioconjugation of gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA) and an anti-vascular endothelial growth factor receptor-2 (VEGFR2) antibody. The specific binding of the agent complex to cells that express VEGFR2 was examined in cultured murine endothelial cells (MS-1 cells) with a 4.7-Tesla magnetic resonance imaging scanner. Angiogenesis-specific T1 enhancement was imaged with the Gd-DTPA-anti-VEGFR2 antibody conjugate using a CT-26 adenocarcinoma tumor model in eight mice. As a control, the use of the Gd-DTPA-anti-rat immunoglobulin G (Gd-DTPA-anti-rat IgG) was imaged with a tumor model in eight mice. Statistical significance was assessed using the Mann-Whitney test. Tumor tissue was examined by immunohistochemical analysis. The Gd-DTPA-anti-VEGFR2 antibody conjugate showed predominant binding to cultured endothelial cells that expressed a high level of VEGFR2. Signal enhancement was approximately three-fold for in vivo T1-weighted MR imaging with the use of the Gd-DTPA-anti-VEGFR2 antibody conjugate as compared with the Gd-DTPA-rat IgG in the mouse tumor model (p < 0.05). VEGFR2 expression in CT-26 tumor vessels was demonstrated using immunohistochemical staining. MR imaging using the Gd-DTPA-anti-VEGFR2 antibody conjugate as a contrast agent is useful in visualizing noninvasively tumor angiogenesis in a murine tumor model