Role of autoimmune and familial factors in goiter prevalence. Studies performed in a moderately endemic area

The goitrogenic role of autoimmune phenomena in endemic goiter is still uncertain. Scanty and discrepant results have been reported in different areas of the world. This prompted us to evaluate the prevalence of circulating thyroid antibodies in an area of North-Western Tuscany during a survey for endemic goiter. The survey was carried out according to the P.A.H.O. criteria in a stable community. In all schoolchildren (n = 142, age range 7-15 yr) and in most of their parents (n = 159), thyroid size was evaluated and urine was collected for iodine determination. Blood was drawn for determination of circulating thyroid microsomal (MAb) and thyroglobulin antibodies (TgAb), TT3, TT4 and TSH. Prevalence of goiter in schoolchildren was 77.9% and 94.8% in their parents. Mean (+/- SD) urinary iodine excretion was 55.0 +/- 2.1 micrograms/24 h. The overall frequency of TgAb and MAb in the adult population was 14.4%, statistically higher than that of control subjects matched for sex and age. The frequency in schoolchildren was 4.3%. The presence of goiter in children was unrelated to the presence of thyroid antibodies in parents, whether goitrous or nongoitrous. A higher prevalence of goiter was found in children with goitrous parents as compared to children with nongoitrous parents (p less than 0.005). In conclusion, the frequency of thyroid autoantibodies in the adult population of the endemic area studied was increased, but showed no relation with the presence of goiter. The prevalence of goiter in children was associated with the presence of goiter but not of thyroid autoantibodies in parents. These data suggest that autoimmune phenomena are of limited importance in the development of endemic goiter.     

Assays of TSH-receptor antibodies in 576 patients with various thyroid disorders: their incidence, significance and clinical usefulness

The incidence and the significance of TSH-receptor antibodies in Graves' disease and in various thyroid disorders have been evaluated. TSH-binding inhibiting antibodies (TBIAb) and thyroid stimulating antibodies (TSAb) were detected in a large proportion of Graves' disease patients (TBIAb in 68.8% and TSAb in 77.8%), in a small number of patients with idiopathic myxoedema or Hashimoto's thyroiditis, and were not detected in patients with endemic euthyroid goitre, differentiated thyroid carcinoma and toxic adenoma. Furthermore, TSH-receptor antibodies were present in some patients with toxic multinodular goitre (TBIAb in 12.7% and TSAb in 15.9%). When TSH-receptor and other thyroid autoantibodies were compared, it was found that 13 of the 15 Graves' patients with negative tests for thyroglobulin and thyroid microsomal antibodies were positive for TSH-receptor antibodies. On the other hand, 9 of the 11 patients with toxic multinodular goitre who had positive TSH-receptor antibody tests, also had serum thyroglobulin and/or thyroid microsomal antibodies. No significant differences in the prevalence of TSH-receptor antibodies were found in Graves' patients irrespective of the presence of ophthalmopathy or pretibial myxoedema. Elevated TBIAb activity at the end of anti-thyroid drug treatment was found in 52.9% of Graves' patients who subsequently relapsed, while in Graves' patients in remission TBIAb was always negative. TSH-receptor antibody results were not predictive of the outcome of radioiodine treatment in Graves' disease. Finally no correlation could be found between TBIAb and TSAb in Graves' disease and Hashimoto's thyroiditis. In conclusion: the high incidence of TSH-receptor antibodies in Graves' disease confirms their pathogenetic role in the development of hyperthyroidism; TSH-receptor antibodies in Graves' disease are not significantly associated with the presence of ophthalmopathy or pretibial myxoedema; TSH-receptor antibody assays may be useful for the diagnosis of Graves' disease in the absence of other signs of autoimmunity. TBIAb seems to be a good predictor of relapse in Graves' patients treated with anti-thyroid drugs; a fraction of toxic multinodular goitre could be a nodular variant of Graves' disease.     

Histopathological and ultrastructural study of a case of infantile metachromatic leukodystrophy

The histopathological and ultrastructural findings on a nerve biopsy specimen and on a CNS necropsy specimen in a case of IML with a typical clinical course are reported. Nerve biopsy once again proved to be a sure diagnostic guide even at an early stage of the disease. Some differences in the fine structure of the cytosomes between the nerve biopsy and CNS necropsy material studied four years later may be due to the different rates of catabolism of the constituent lipids as well as to post mortem artefacts.This work was supported by CNR Research Grant 81 00336 04     

Increased level of thyroglobulin mRNA in a human familial goiter

Thyroglobulin (Tg) and its specific mRNA were analyzed in the thyroid gland of two cases of familial goiter. A three-fold increase in the level of stable protein and functional Tg mRNA was found in the goiter of one of the two patients in whom a desiodase defect was demonstrated. Normal concentrations of both Tg and its mRNA were found in the other goiter in which no enzymatic defect could be shown. Our results suggest that the increase of Tg mRNA levels found in the goiter with a desiodase defect was due to a chronic stimulation of the gland by TSH.     

Brain metastases from post-radiation malignant peripheral nerve sheath tumour

A 45-year-old female patient developed a malignant peripheral nerve sheath tumour (MPNST) arising from the left brachial plexus, ten years after regional radiation treatment for Hodgkin's disease. The clinical course was characterized by local recurrence, pulmonary and cerebral metastases with endocranic hypertension syndrome, and the death of the patient 18 months after the onset of symptoms. The tumour presented a histopathological picture of schwannoma with a high grade of malignancy. A particular feature of this case was the exceptional occurrence of the early and massive invasion of the brain.This work was partly supported by CTN CNR 92.02771.CT04.     

Enhanced expression of E-selectin on the vascular endothelium of peripheral nerve in critically ill patients with neuromuscular disorders

Neuropathic complication often occurs in critically ill patients, and changes in the microcirculation of the peripheral nerve have been suggested to play a role in the pathogenesis of the nerve lesion. We report the results of a pathological and immunohistochemical study of superficial peroneal nerve biopsy specimens in a series of 22 critically ill patients with sepsis and neuromuscular disorders. Eight patients had histopathological features of axonal neuropathy compatible with critical illness polyneuropathy (CIP). The nerve lesions ranged in severity from mildly reduced myelin-fiber density with sporadic axonal degeneration to marked fiber loss with abundant degenerative changes. In no patient did we detect evidence of primary demyelinization or inflammatory infiltrates. We analyzed the immunohistochemical expression of E-selectin, vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and tumor necrosis factor alpha (TNF-alpha) in nerve microvessels. Expression of E-selectin was significantly increased in endothelium of epineurial and endoneurial vessels, suggesting endothelial cell activation. These findings again confirm axonal degeneration as the major pathological feature of CIP. Our immunohistochemical data provide first evidence that activation of the endothelial cells of the microvessels in the endoneurium of human peripheral nerve does occur during sepsis. This specific activation might have implications with the mechanisms responsible for the axonopathy in critically ill patients.     

Clozapine in treatment-resistant patients with schizophrenia,schizoaffective disorder,or psychotic bipolar disorder: a naturalistic 48-month follow-up study

BACKGROUND: The aim of this study was to evaluate the long-term efficacy and safety of clozapine in patients with treatment-resistant schizophrenia, schizoaffective disorder, or bipolar disorder with psychotic features. METHOD: 101 patients with a DSM-III-R diagnosis of schizophrenia (N = 34); schizoaffective disorder, bipolar type (N = 30); or bipolar disorder with psychotic features (N = 37) were naturalistically treated with clozapine at flexible doses over a 48-month period. Data were collected from 1994 to 2000. The Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impressions-Severity of Illness scale total predicted scores over time were estimated with random-effects regression models. Time to response to clozapine, defined as 50% reduction of BPRS score, was analyzed in the 3 diagnostic groups using the Kaplan-Meier method. Survival curves were compared using the log-rank test. RESULTS: The BPRS total predicted score halved its baseline value in 3 months for bipolar disorder patients, in 6 months for schizoaffective disorder patients, and in 24 months for schizophrenia patients. The proportion of subjects who satisfied the criterion for response to clozapine after 48 months of follow-up was significantly (p <.01) higher in the schizoaffective and bipolar disorder groups (90.0% and 83.8%, respectively) than in the schizophrenia group (64.7%). Baseline scores on the Global Assessment of Functioning (GAF) showed low levels of psychosocial and occupational functioning in all 3 groups. After 48 months of treatment, GAF scores showed a functional improvement in all 3 groups, with significantly (p <.01) greater improvement in the bipolar disorder group compared with the other groups. CONCLUSION: The findings of this study confirm the efficacy and safety of clozapine for treatment-resistant patients with a diagnosis of schizophrenia, schizoaffective disorder, or bipolar disorder with psychotic features. Patients with schizoaffective disorder and those with bipolar disorder show greater clinical improvement than those with schizophrenia. Patients with bipolar disorder have the shortest time to response and the highest psychosocial and occupational functioning levels. Patients with schizoaffective disorder have the lowest treatment discontinuation rate.     

Analysis of cancer/testis antigens in sporadic medullary thyroid carcinoma: expression and humoral response to NY-ESO-1

Cancer/testis antigens (CTA) are tumor-associated antigens expressed during ontogenesis, in a number of solid tumors but not in normal tissues except testis. Most of these CTA are highly immunogenic, eliciting a humoral and cellular response in the patients with advanced cancer, and are useful for tumor-specific immunotherapy. Medullary thyroid carcinoma (MTC) is a neoplasm derived from the parafollicular cells of the thyroid and occurs in either a sporadic or a familial form. In the present study, we examined by RT-PCR the expression of a number of genes encoding CTA in 23 surgical samples of sporadic MTC. Among the 11 cDNA antigens examined, RAGE, MAGE-4, and GAGE 1-2, were not expressed in any of the tissues. SSX 2 was present only in one tissue, whereas BAGE, GAGE 1-6, MAGE-1, MAGE-2, MAGE-3, and SSX 1-5 were detected in two to five samples. NY-ESO-1 cDNA was the most frequent, being detected in 15 of 23 examined samples (65.2%). Six (26.1%) tissues did not express any CTA-specific mRNA, whereas 10 tumors expressed only one gene (43.5%), 3 (21.4%) expressed 2 genes, and 4 displayed a broad CTA gene expression. NY-ESO-1 expression in primary MTC tissues significantly correlated with tumor recurrence. The presence of specific anti-NY-ESO-1 antibodies was searched in the sera of MTC-affected patients examined by ELISA using recombinant NY-ESO-1 protein. A humoral response against this CTA was detected in 6 of 11 NY-ESO-1 expressing patients (54.5%), and in 1 of 6 patients with NY-ESO-1-negative tumor. No anti-NY-ESO-1 antibodies were detected in healthy subjects (n = 17). The presence of anti-NY-ESO-1 antibodies was searched also in the sera of MTC affected patients whose tissues were not available for CTA analysis. Anti-NY-ESO-1 antibodies were present in 15 of 42 sera (35.7%), demonstrating that MTC is a neoplasm frequently associated with humoral immune response to NY-ESO-1. Serological survey may be useful as a way to identify patients with humoral immune response to NY-ESO-1 that provide a new attractive target for vaccine-based immunotherapy of MTC.