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Biomedical subjects

J Orgiazzi

Publications and source records attributed to J Orgiazzi.

At least 37 records · Page 2Linked to original sources
PubMed2001

Clinical validity of a new commercial method for detection of TSH-receptor binding antibodies in sera from patients with Graves' disease treated with antithyroid drugs.

In this work, we compared the activities of TSH binding inhibitory immunoglobulin (TBII) results obtained with a new human TBII assay (h-TBII) using the human recombinant TSH receptor with thyroid stimulating antibodies (TSAbs). Sera were obtained from 90 patients with Graves' disease before and after therapy with carbimazole (1-methyl-2-thio-3-carbethoxyimidazole). Before treatment, h-TBII were detected in 89/90 patients (98.9%) whereas TSAb activity was positive in 88/90 patients (97.7%). The two parameters fell during therapy. At the end of treatment, only h-TBII levels were significantly different between patients in remission and those in relapse (Z=-2.212; P=0.0270). The relapse rate in the patients with positive antibodies at drug withdrawal was significantly increased (chi(2)=6.057; P=0.0139 for h-TBII and chi(2)=8.988; P=0.0021 for TSAb). Most of patients (76%) relapsed during the 2 years following drug withdrawal. h-TBII or TSAb values were positive in 84.6% or in 80.8% of patients at the time of relapse. There was a significant correlation between the two antibody measurement methods before treatment, at drug withdrawal and at the time of relapse. These results indicate that the new TBII assay using human TSH receptor is as sensitive as the TSAb assay. Because of its much easier performance, it may advantageously replace TSAb measurement especially for the Graves' disease diagnosis and in the prediction of short-term relapse at the end of treatment.

Adult↗
PubMed2000

Postmenopause hormone treatment in women with NIDDM or impaired glucose tolerance: the MEDIA randomized clinical trial.

OBJECTIVE: To assess the biological safety of four hormone replacement treatment (HRT) combinations in women with non insulin dependent diabetes mellitus (NIDDM) or impaired glucose tolerance (IGT). SUBJECTS AND METHODS: Randomized, double-blind, placebo-controlled trial to analyze the variation of fibrinogen, factor VII, PAI1, and TG blood levels in women (n=99), with NIDDM or IGT, receiving a 3-month course of either oral oestradiol (1 or 2 mg) combined with Chlormadinone Acetate 5 mg, or transdermal oestradiol 50 microg/24 h in association with Norethisterone Acetate (11.2 or 22.4 mg), or placebo. Follow-up lasted 3 months. RESULTS: Ninety nine patients, mean age 56 years (SD 5), mean diabetes duration 7 years (S.D. 7), mean glycated hemoglobin (7.3%) were enrolled. There was no significant difference between the groups for any of the primary hemostasis criteria (n=77). Triglycerides (TG) variation significantly differed between groups, P=0.01, from -21% in the large patch group, to +22% in the placebo group (n=82). Treatment administration routes did not significantly differ for any of the criteria. There was a significant difference in the total cholesterol variation between groups, from +8.7% in the placebo group to -10.8% in the oral 1 mg group (P=0.001). CONCLUSION: The treatments had no highly deleterious effect in these patients with NIDDM or with IGT. Long-term trials can be performed with such patients, and an hormone treatment can be prescribed to relieve symptoms. Since these patients had a well-controlled NIDDM, results might be different in less well-controlled diabetes. The data do not support the hypothesis of an impaired oestrogen effect in patients with NIDDM.

Biomarkers↗
PubMed2000

Management of fetal thyroid goitres: a report of 11 cases in a single perinatal unit.

Fetal thyroid goitres may reveal hormonal imbalance. This can jeopardize neurological development and fetal outcome even when early postnatal treatment is provided. We report a series of 11 goitres diagnosed antenatally in women with past or present thyroid disorders or discovered fortuitously on ultrasound scan. Fetuses presented with hyperthyroidism in three cases and hypothyroidism in eight. Hypothyroidism was iatrogenic in five cases, due to maternal anti-thyroid drugs. Hyperthyroidism was induced by transplacental transfer of thyroid stimulating antibodies (TSHrab). Accurate diagnosis of fetal thyroid status was obtained by fetal blood sampling but this invasive method was deemed necessary only in four cases as maternal clinical and biological data and ultrasound signs provided sufficient information to infer the type of thyroid disorder in the remaining patients. Fetal therapy relied on reduction of maternal antithyroid medication and, in selected cases, intra-amniotic injection of levothyroxin in hypothyroidism, and on administration of antithyroid drugs in hyperthyroidism. All newborns were healthy and none displayed consequences of severe thyroid imbalance. No caesarean section was performed for dystocia. Fetal thyroid goitres can be managed successfully with selected use of invasive diagnostic and therapeutic techniques.

Female↗
PubMed2000

Anti-TSH receptor antibodies in clinical practice.

Anti-thyroid stimulating hormone receptor antibodies are pathophysiologic and clinical indicators in autoimmune thyroid diseases, not only in Graves' disease. The detection of these antibodies is useful for diagnostic and management purposes. The presence and titers of anti-TSH receptor antibodies, however, have to be interpreted in light of the clinical and other biological characteristics of each patient. Newer, more sensitive assays of anti-TSH receptor antibodies may increase their significance in the diagnosis and management of autoimmune thyroid diseases and Graves' disease.

Adolescent↗
PubMed1999

The screening for mutations in the thyroglobulin cDNA from six patients with congenital hypothyroidism.

The six patients described in this study were clinically diagnosed with congenital hypothyroidism. Based on clinical and pathophysiological parameters, the cause of the thyroid dyshormonogenesis was suspected to be a defect in the synthesis of thyroglobulin, the matrix protein for thyroid hormone synthesis in the thyroid gland. After RNA isolation from six goitrous tissues and control thyroid tissues, RT-PCR was used to amplify 20 overlapping thyroglobulin (TG) cDNA fragments. Two alternative splice transcripts were identified: a transcript with a deletion of nucleotides 177-274 and a transcript with a deletion of nucleotides 3430-3736 that result in frame shifts and the introduction of premature stop codons. Two alternatively spliced transcripts not changing the reading frame were also identified: a transcript containing a deletion of nucleotides 4529-4699 and a transcript with a deletion of nucleotides 7301-7561. All these transcripts were expressed in thyroid tissue of both patients and controls. Nucleotide sequence analysis and comparison to the revised TG sequence (1997) revealed one revision and eight polymorphisms that did not result in amino acid changes and four polymorphisms that did change amino acid codons. In three patients a homozygous mutation was present at nucleotide position 229, causing a glycine to serine amino acid substitution. The clinical description 'thyroglobulin synthesis defect' in this population cannot be explained by major mutations in the coding region of the TG gene. Furthermore, the presence and level of expression of the alternatively spliced transcripts do not co-segregate with thyroid dyshormonogenesis, since in normal thyroid tissue the same alternatively spliced transcripts are present.

Adolescent↗
PubMed1999

T cell response pattern to glutamic acid decarboxylase 65 (GAD65) peptides of newly diagnosed type 1 diabetic patients sharing susceptible HLA haplotypes.

Autoantibodies and autoreactive T lymphocytes directed against several pancreatic beta cell proteins such as GAD65 have been identified in the circulation before and at the onset of clinical type 1 (insulin-dependent) diabetes. Using GAD65 synthetic peptides, we studied the proliferative response of peripheral blood mononuclear cells (PBMC) either from recently diagnosed type 1 diabetic patients, of whom the majority share the disease-associated HLA class II haplotype (DR4-DQB1*0201 or DR3-DQB1*0302), or from HLA-matched control subjects. We found that 67% (14/21) of the type 1 diabetic patients and 39% (9/23) of the control subjects exhibited a positive proliferative response. Compared with control subjects, however, PBMC from diabetic patients proliferated more frequently (P < 0.05) in the presence of peptide pools from the C-terminal region of GAD65 (amino acids 379-585). Diabetic patients with the same HLA-DQ or HLA-DR alleles showed partially identical T cell reactivity, but no clear correlation could be made between MHC class II specificity and T cell epitopes because of multiple combinations of class II alleles. In addition, by flow cytometry, we studied the direct binding of GAD65 peptides to MHC class II molecules of Epstein-Barr virus (EBV)-transformed B (EBV-B) cells obtained from a diabetic patient. We found that 11 GAD peptides were able to bind to the highly susceptible haplotype DRB1*0301/0401-DQA1*0301/0501-DQB1*0302/0201 on the surface of EBV-B cells in partial correlation with the results obtained in the proliferation assays.

Adolescent↗
PubMed1999

Autoantibodies interacting with purified native thyrotropin receptor.

Native thyrotropin receptor (TSHR) was purified by immunoaffinity chromatography from membrane extracts of stably transfected L cells. An ELISA test was devised to study anti-TSHR autoantibodies directly. Comparison of native TSHR with bacterially expressed, denatured TSHR showed that the latter was not recognized by the autoantibodies, suggesting that they bind to conformational epitopes only present on the native receptor. The use of deglycosylated TSHR and of purified receptor ectodomain (alpha-subunit) showed that the autoantibodies recognized only the protein backbone moiety of the receptor and that their epitopes were localized entirely in its ectodomain. Autoantibodies were detected in 45 of 48 subjects with untreated Graves' disease and in 26 of 47 healthy volunteers. The affinity for the receptor was similar in the two groups (Kd = 0.25-1 x 10-10 M) and the autoantibodies belonged to the IgG class in all cases. Although the concentration of autoantibodies was higher in Graves' disease patients (3.50 +/- 0.36 mg.L-1) than in control subjects (1.76 +/- 0.21) (mean +/- SEM), there was an overlap between the groups. Receptor-stimulating autoantibodies (TSAb) were studied by measuring cAMP synthesis in stably transfected HEK 293 cells. Their characteristics (recognition of alpha-subunit, of deglycosylated TSHR, nonrecognition of bacterially expressed denatured receptor) were similar to those of the antibodies detected by the ELISA test. TSAb were only found in individuals with Graves' disease. The ELISA test measures total anti-TSHR antibodies, whereas the test using adenylate cyclase stimulation measures antibodies that recognize specific epitopes involved in receptor activation. Our observations thus disprove the hypothesis according to which Graves' disease is related to the appearance of anti-TSHR antibodies not present in normal subjects. Actually, anti-TSHR antibodies exist in many euthyroid subjects, in some cases even at concentrations higher than those found in patients with Graves' disease. What distinguishes the latter from normal subjects is the existence of subpopulation(s) of antibodies directed against specific epitope(s) of the receptor involved in its activation.

Animals↗
PubMed1999

The relationship between peripheral T cell reactivity to insulin, clinical remissions and cytokine production in type 1 (insulin-dependent) diabetes mellitus.

Antigenic proliferative responses of peripheral blood mononuclear cells (PBMC) to insulin were studied in 44 type 1 new-onset diabetic subjects. Of them, 14 (32%) had a stimulation index (> or =3) above the mean + 3 SD of 39 healthy controls and of 7 of 15 (47%) diabetic patients of long duration (P = 0.001). Responses to insulin were not dictated by specific major histocompatibility complex class II association and were not observed in normal subjects with diabetes-associated human leukocyte antigen-DR/DQ alleles. Whereas no relation of PBMC reactivity with insulin autoantibodies was found, there was a positive correlation with the presence of at least one of the four autoantibodies tested and with IA-2 antibody. An interesting finding was that the proportion of patients with subsequent low insulin requirement, up to 24 months, was significantly higher in patients who showed PBMC reactivity to insulin (8 of 8) than in those who did not (10 of 24, 42%; P = 0.004). The former had a higher mean stimulation index than the latter (3.3+/-2.6 vs. 1.5+/-0.6; P = 0.006). Furthermore, interleukin-4 (IL-4) production was lower in type 1 diabetic patients who proliferated to insulin than in those who did not (23+/-15 vs. 64+/-47 pg/mL; P = 0.04), but interferon-gamma, IL-2, and IL-10 productions were similar. In conclusion, these results suggest that proliferation to insulin may reflect the presence of an higher residual beta-cell mass.

Adolescent↗
PubMed1999

[Multinodular goiter: natural history].

Despite its high prevalence, at least in areas with even mild iodine deficiency, the aetiopathogenesis of multinodular goitre is poorly understood. The combination of genetic and environmental factors, the likely involvement of endocrine para and autocrine goitrogenic agents and the remarkable heterogenicity of thyroid tissue complicate elucidation of the mechanisms involved. Multinodular goitre follows an initial phase of hyperplastic goitre or results from the generation of several individual nodules. Alterations of the stromal and vascular tissues as well as the occurrence of somatic mutations are contributing factors. In many instances, multinodular goitres become autonomous in the long term.

Adolescent↗
PubMed1996

Four IgG anti-islet human monoclonal antibodies isolated from a type 1 diabetes patient recognize distinct epitopes of glutamic acid decarboxylase 65 and are somatically mutated.

The selective destruction by an autoimmune process of the beta cells in the pancreas is the hallmark of the type 1 insulin-dependent diabetes mellitus. What triggers islet cell-specific autoreactive T and B cells, however, remains unclear. Identification of the targets of the anti-islet cell autoantibodies frequently found in insulin-dependent diabetes mellitus patients and analysis of their sequences should provide some insights into the nature of this disease. We have combined EBV transformation with CD40 activation of peripheral B cells from one patient with insulin-dependent diabetes mellitus to isolate four B cell clones that secrete islet cell-specific autoantibodies, These four human monoclonal autoantibodies are of the IgG1 isotype, and they each recognize a different epitope of the glutamic acid decarboxylase enzyme. Analysis of their variable gene sequences shows that, while clonally unrelated, three of the four human monoclonal autoantibodies use a member of the VH4 family, and two have rearranged the same delta light chain variable gene. The IgG1 isotype of the four autoantibodies as well as the presence of somatic mutations in both heavy and light chain genes provide concrete evidence for their derivation by a T cell-dependent immune response.

Adult↗