Screening of nineteen unrelated families with generalized resistance to thyroid hormone for known point mutations in the thyroid hormone receptor beta gene and the detection of a new mutation.

Generalized resistance to thyroid hormone (GRTH) is a syndrome characterized by impaired tissue responsiveness to thyroid hormone. Two distinct point mutations in the hormone binding domain of the thyroid hormone receptor (TR) beta have recently been identified in two unrelated families with GRTH. One, Mf, involves a replacement of the normal glycine-345 for arginine in exon 7 and another, Mh, replaces the normal proline-453 for histidine in exon 8. To probe for the presence of the Mf and Mh defect in 19 unrelated families with GRTH, we applied separate polymerase chain reactions using allele-specific oligonucleotide primers containing the normal and each of the two mutant nucleotides at the 3'-position. A total of 24 affected subjects and 13 normal family members were studied. The mode of inheritance was dominant in 13 families, was unknown in 5 families, and was clearly recessive in 1 family in which only the consanguineous subjects were affected. Primers containing the substitutions specific for Mf and Mh amplified exons 7 and 8, respectively, only in affected members of each of the two index families. Primers containing the normal sequences amplified exons 7 and 8 of the TR beta gene in all subjects except affected members of one family. In this family with recessively inherited GRTH, neither exon could be amplified using any combinations of primers and DNA blot revealed absence of all coding exons. These results indicate a major deletion of the TR beta gene, including both DNA and hormone binding domains. Since heterozygous members of this family are not affected, the presence of a single normal allele is sufficient for normal function of the TR beta. These data also support the hypothesis that in the dominant mode of GRTH inheritance the presence of an abnormal TR beta interferes with the function of the normal TR beta. Distinct mutations are probably responsible for GRTH in unrelated families.

Effect of total sleep deprivation on 5'-deiodinase activity of rat brown adipose tissue.

Prolonged sleep deprivation of the rat produces a progressive increase in energy expenditure and an eventual decrease in body temperature, which suggests a profound derangement in thermoregulation. Because increased thermogenic activity in brown adipose tissue (BAT) is a likely mechanism mediating the observed increase in energy expenditure, we focused our attention on the effect of total sleep deprivation on BAT type II 5'-deiodinase (5'D-II), since its activation indicates BAT stimulation and is essential for full BAT thermogenic response. Five euthyroid rats were subjected to total (92%) sleep deprivation (euD-rats). Sharing the sleep deprivation apparatus, yoked control rats (euC-rats) received the same degree of physical stimulation as the D-rats, but were only partially (25%) sleep deprived. Additional cage controls (euCC-rats) were housed in the same room. Since during sleep deprivation the animals undergo a reduction in plasma T4 concentration and inability to maintain body temperature heralds death, an identical study was performed in five trios of hyperthyroid rats (hyperD-, hyperC-, and hyper CC-rats) given daily ip injections of 15 micrograms T4/100 g BW, 10 days before and throughout the deprivation period. Experiments were carried out at an ambient temperature of 29 C, close to thermoneutrality for rats. Sleep deprivation in hyperD-rats was maintained until death seemed imminent (9-14 days), and in euD-rats for 12-15 days. Sleep deprivation induced a significant increase in BAT 5'D-II activity in both hyperD- and euD-rats compared with that in euCC-rats (P less than 0.01). BAT 5'D-II in euC-rats was also significantly higher than that in euCC-rats (P less than 0.05), probably because they were partially sleep deprived. BAT 5'D-II activity in hyperD-rats was increased compared to that in both hyperC- and hyperCC-rats (P less than 0.05), in which the activity was slightly but not significantly lower than that in euCC-rats. No significant differences were observed in liver and kidney type I 5'-D (5'D-I) and in pituitary 5'D-II among euD-rats, euC-rats, and euCC-rats. As expected, the hyperthyroid groups (hyperD-rats, hyperC-rats, and hyperCC-rats) had significantly higher kidney 5'D-I and lower pituitary 5'D-II than the euCC-rats. Liver 5'D-I was also significantly increased in the hyperC-rats and hyperCC-rats, but not in the hyperD-rats. These observations indicate that total sleep deprivation is associated with a marked increase in BAT 5'D-II activity in both euthyroid and hyperthyroid rats.(ABSTRACT TRUNCATED AT 400 WORDS)

Parity as a thyroid size-determining factor in areas with moderate iodine deficiency.

Among the factors that may influence thyroid size, pregnancy and its goitrogenic effect have been widely investigated, but thyroid volume and pregnancy have never been compared retrospectively, and there are no data on the possible relationship between thyroid size and parity. The purpose of this work was to evaluate the effects of pregnancy on thyroid volume in a moderate iodine deficiency area, to assess the possibility of a relationship between thyroid size and parity status in healthy females. A group of 208 nongoitrous healthy women underwent thyroid volume estimation by ultrasound examination. All subjects were euthyroid and negative for thyroid autoantibodies. They were assigned to different groups, according to the number of completed pregnancies. Five groups were formed (0, 1, 2, 3, 4 or more term pregnancies). Mean thyroid volume increased progressively among the groups: group 0 (14.8 +/- 0.7 mL); group I (16.0 +/- 0.9 mL); group II (17.1 +/- 0.6 mL); group III (18.2 +/- 0.6 mL); group IV (20.3 +/- 0.9 mL). The increment in thyroid volume was statistically significant between group 0 and groups III (P: < 0.01) and IV (P: < 0.001), and also between group I and group IV (P: < 0. 05). No independent effect of body weight and age on thyroid volume was seen. Our results indicate that, in an area with moderate iodine deficiency, the goitrogenic effect of pregnancy is not fully reversible. Moreover, the statistically significant increase in thyroid volume, observed in relation to parity, is the first clinical demonstration of a cumulative goitrogenic effect of successive pregnancies, providing a strong argument to increase the iodine supply during pregnancy, even in conditions with moderate iodine deficiency.

Evaluation of the nocturnal serum thyrotropin (TSH) surge, as assessed by TSH ultrasensitive assay, in patients receiving long term L-thyroxine suppression therapy and in patients with various thyroid disorders.

Circadian variations of serum TSH concentrations have been reported, with higher values occurring in the late evening or early morning. In patients receiving long term L-T4 suppression therapy, it may be important to achieve suppression of TSH secretion throughout the day. To investigate whether undetectable serum TSH values in the morning are associated with undetectable serum TSH levels at night, serum TSH concentrations were measured by an ultrasensitive immunoradiometric assay in 16 normal subjects, 20 hyperthyroid patients, 10 patients with primary hypothyroidism (either untreated or inadequately treated with L-T4), 1 patient with central hypothyroidism, 10 patients with nontoxic nodular goiter, 5 patients with functioning thyroid adenoma, 20 patients receiving L-T4 replacement therapy, and 30 patients receiving L-T4 suppression. In 6 subjects blood was drawn at hourly intervals for 24 h; in 2 normal subjects a major TSH surge occurred between 2300-0100 h, with other minor peaks, and the same pattern was found in two patients receiving L-T4 replacement, whereas in 2 patients receiving L-T4 suppression, serum TSH was constantly below the limit of detection of the assay (i.e. less than 0.07 mU/L). In the remaining patients blood was drawn at hourly intervals between 2300-0200 h and on the next morning before (0830-0900 h) and 30 min after iv TRH administration. In normal subjects, in patients receiving L-T4 replacement therapy, and in hypothyroid patients, serum TSH values at night were higher than in the morning, with normal responses to TRH in the first 2 groups and exaggerated responses in the latter. The patient with central hypothyroidism had no nocturnal TSH surge and no TSH response to TRH. In all hyperthyroid patients, serum TSH was undetectable both at night and during the day, and none had a serum TSH response to TRH. Among patients with nontoxic goiter, 7 had detectable serum TSH in the morning, with higher values at night, and a normal response to TRH; the remainder had undetectable serum TSH both at night and in the morning, and subnormal or absent TSH responses to TRH. All 5 patients with a functioning thyroid adenoma had undetectable serum TSH levels in the morning and during the night, and subnormal or absent TSH responses to TRH. Of the 30 patients receiving long term (greater than 6 months) L-T4 suppression therapy, 28 had undetectable serum TSH both during the night and in the morning and unresponsiveness to TRH.(ABSTRACT TRUNCATED AT 400 WORDS)

Sleep deprivation in the rat: XIX. Effects of thyroxine administration.

Chronic total sleep deprivation (TSD) in the rat produces an initial elevation and then declining body temperatures, increasing metabolic rate and eventual death. Because TSD rats will engage in warming behavior, one hypothesis is that the metabolic increase is an unsuccessful attempt at warming to combat a lethal hypothermia. However, TSD rats also undergo weight loss and progressive deterioration of skin and fur, suggesting TSD-induced pathological catabolic activity, possibly secondary to increased metabolic rate, that could be lethal. To evaluate these alternatives, the metabolic rate of rats was increased by thyroxine (T4) treatment while subjecting them to TSD. Compared to TSD rats not given T4, they had higher metabolic rates, higher body temperatures and reduced warming behavior, but their survival period was 37% shorter. Thus, it is unlikely that hypothermia is the cause of death in TSD rats. Weight and appearance declined more rapidly in T4-treated rats, but at the same proportions of survival time, skin pathology and decline in appearance were less evident in T4-treated rats than in TSD rats not given T4. Thus, there is some doubt whether a general pathological catabolic process is the cause of death. It is also possible that a specific morbid process normally reversed by sleep was accelerated by T4 administration.

Short-term met-hGH infusion inhibits somatotroph response to growth hormone releasing hormone (1-44).

To determine whether the short-term administration of growth hormone inhibits pituitary responsiveness to h-GHRH we measured the somatotroph response to h-GHRH-44 (0.3 micrograms/kg) stimulation in ten normal subjects from the third to the fifth hour of an infusion of met-hGH (2 micrograms/kg/h) or saline. Insulin, insulin-like growth factors (IGF), somatomedins, free fatty acids (FFA), glycerol, and glucose levels also were assessed during the first 3 hours of infusion. Steady-state GH levels of 5 to 20 ng/mL were achieved during met-hGH infusion. No significant changes in IGF, insulin, or glucose levels measured at the beginning and again after three hours of infusion occurred within or between conditions. Infusion of met-hGH was associated with a significantly greater increase in FFA levels (69 +/- 50 mumol/L following saline v 433 +/- 57 mumol/L following three hours of met-hGH infusion (P less than .001)). The somatotroph response to h-GHRH-44 was significantly blunted during met-hGH infusion (incremental area under the GH/time curve decreasing from 1,196 +/- 183 (ng/mL) X min to 380 +/- 139 (ng/mL) X min (P less than .005)). These data demonstrate that this blunting can occur following short-term exogenous GH administration and at serum GH levels comparable to those achieved during naturally occurring bursts of GH secretion. They also suggest that acute mediation of GH release must occur, at least in part, at the pituitary somatotroph level and that IGFs and/or insulin may not be the primary inhibitors. This phenomenon may be directly or indirectly due to GH-dependent metabolic factors such as FFA or glycerol.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of altered thyroid function on serum fructosamine concentrations.

The effect of altered thyroid function on serum fructosamine concentrations was investigated in 31 untreated hyperthyroid patients, 18 short-term hypothyroid patients (i.e., 20 days after withdrawal of thyroid hormone suppressive therapy for thyroid cancer), 7 untreated long-term hypothyroid patients, and 25 age-matched normal controls. No differences in serum fructosamine concentrations were observed between hyperthyroid patients and normal controls; conversely, serum fructosamine concentrations were significantly higher both in short-term and in long-term hypothyroid patients than those found in normal controls. Furthermore, long-term hypothyroid patients showed significantly higher serum fructosamine concentrations than short-term hypothyroid patients. L-Thyroxine (L-T4), replacement therapy in two hypothyroid patients, resulted in a marked decrease in serum fructosamine concentrations. In seven hyperthyroid patients, the restoration of euthyroidism with antithyroid drug therapy was associated with no significant changes in serum fructosamine concentrations. The results of the present study indicate that hypothyroidism is associated with a marked increase in serum fructosamine concentrations. This alteration does not appear to be the consequence of gross abnormalities in plasma protein or glucose metabolism. The duration of hypothyroidism seems to be an important factor, even though the mechanism underlying this alteration remains at present unexplained. These results also suggest that caution must be used in the interpretation of elevated serum fructosamine concentrations as an index of the metabolic control of diabetes mellitus in the presence of hypothyroidism.

[Interventional radiology in thoracic emergencies]. / La radiologia interventistica nelle emergenze toraciche.

There are numerous clinical situations in which interventional angiography fully reveals its two-fold diagnostic and therapeutic value. The present review focuses attention on the use of such procedures in certain thoracic emergencies. Indications, diagnostic results and therapeutic advantages are examined together with possible complications. Pulmonary embolism is a serious circulatory condition that is often difficult to diagnose because of the lack of specificity of its accompanying symptoms. In these cases the role of the angiographic radiologist is often three-fold: diagnosis, therapy (possibility of carrying out locoregional thrombolysis), and prophylaxis (positioning of caval filters that prevent the migration of thrombi). Haemoptysis may arise from both the pulmonary and bronchial vessels and may be caused by various pathologies (cancer, angiodysplasia, vasculitis, aspergillosis). Angiographic study in such cases is indispensable for identifying the source of bleeding and for arresting, using embolising material, haemorrhage that it is no longer possible to control with other therapeutic modalities. Foreign bodies held in the vascular tree are in the main fragments of catheters detached accidentally or as a result of incorrect manoeuvres or for defects of construction of the material. Their removal is possible today by using, percutaneously, angiographic techniques (snare loop, basket, hook system, balloon catheters) which make it possible to hook up the fragment and remove it.

[Transluminal therapy of stenosing lesions of the supra-aortic vessels. Personal experience]. / Terapia transluminale delle lesioni stenosanti dei tronchi epiaortici. Esperienza personale.

Percutaneous transluminal angioplasty (PTA) is commonly used to treat peripheral vascular diseases, but its use has recently spread to the treatment of stenotic lesions involving the supra-aortic vessels. The authors report their initial experience in 10 patients with left subclavian artery stenoses--8 of them treated with PTA and 2 with PTA and vascular stenting--and two more patients with fibromuscular stenosis of the internal carotid artery (ICA), which was treated by means of PTA. In the authors' opinion, PTA can be considered the procedure of choice to treat the stenotic lesions of the supra-aortic vessels. Intravascular stents can be extremely useful to prevent post-PTA restenosis, but further experience and probably further technological refinements are needed. To conclude, PTA of ICA is an effective method in selected cases--e.g., in the patients with symptomatic hemodynamic lesions and low risk of embolism, in the patients with difficult surgical access or in the event of high anesthesiological and/or surgical morbidity.

Short term effects of flutamide administration on hypothalamic-pituitary-testicular axis in man.

The effect of short term administration of flutamide on the hypothalamic-pituitary-gonadal axis was studied in six patients with advanced prostate cancer (C2 stage). Flutamide significantly increased LH pulse frequency in all patients (p less than 0.05 by Wilcoxon's test). The FSH pulse analysis disclosed a similar pattern of LH. Plasma IC-T clearly increased following flutamide therapy; mean IC-T values were 2.67 +/- 0.47 ng./ml. and 4.67 +/- 0.62 ng./ml. before and after flutamide administration, respectively (p less than 0.05 by paired Student's t test). Our study demonstrates that flutamide acts in humans as a selective and specific antiandrogen compound.

Diagnosis of amiodarone-iodine-induced thyrotoxicosis(AIIT) associated with severe nonthyroidal illness.

A rare case of amiodarone-iodine-induced thyrotoxicosis (AIIT) associated with nonthyroidal illness is reported. Serum total thyroxine (TT4) and free T4 (FT4) concentrations were elevated and serum TSH was undetectable as frequently observed also in euthyroid amiodarone-treated patients. At variance with common forms of AIIT, serum total triiodothyronine (TT3) was reduced due to low-T3 syndrome. The laboratory diagnosis was made on the basis of elevated free T3 (FT3) levels. Thus, in patients with severe nonthyroidal illness submitted to chronic amiodarone treatment, thyroid status can only be determined by free hormone measurement, particularly FT3 in the case of thyrotoxicosis.

Treatment of hepatocellular carcinoma: a single-center experience.

PURPOSE: The comparative efficacy of transcatheter arterial chemoembolization (TACE) and percutaneous ethanol injection (PEI) in the treatment of hepatocellular carcinoma (HCC) was investigated. METHODS: Two hundred and sixty consecutive patients were retrospectively analyzed: 156 had received between one and six chemoembolization sessions at 3-month intervals, 33 had had PEI, and the remaining 71 patients refused any treatment. The follow-up ranged from 3 to 36 months. Survival rates were statistically analyzed by life-table analysis. RESULTS: Patients' survival was affected by the number of nodules and by the Child's and Okuda's classes; no relationship was found between survival rates and the histologic grade or vascular supply of the tumor. In the case of a single lesion of Okuda's class I, TACE was more effective than PEI. In multifocal HCC, TACE was better than no treatment in Okuda's class I and Child's class A. CONCLUSION: We suggest TACE as the treatment of choice in Child A or Okuda I patients with multifocal HCCs; it seems of little help in Child B-C or Okuda II-III patients.

Congenital intrahepatic portosystemic shunt.

The authors report a congenital intrahepatic portosystemic shunt detected by angiography in a young patient with acute onset of hyperammoniemia and hepatic encephalopathy.

[Stenosis-occlusion of the carotid bifurcation. Angiography with MR and contrast media versus digital angiography]. / Steno-occlusione della biforcazione carotidea. Confronto tra angiografia con RM e mdc versus angiografia digitale.

PURPOSE: To evaluate the comparative sensitivity, specificity and diagnostic accuracy of contrast enhanced magnetic resonance angiography (CE MRA) and digital subtraction angiography (DSA) in the study of carotid bifurcation stenoses. MATERIAL AND METHODS: Twenty-three patients with suspected cerebrovascular insufficiency by carotid stenosis were examined with CE MRA and DSA within 24 hours of each other. A 1.5 superconductive unit (Signa, General Electric) was used for CE MRA; fast spoiled gradient echo recalled (SPGR) images were acquired on the coronal plane 12 s after contrast medium injection, with the following parameters: TR/TE/FA 8/1/60, MA 256 x 128, NEX 1, FOV 18 x 13, slices/slab 28, slice thickness 1 mm, TA 32 s. The images were postprocessed with the maximum intensity projection (MIP) and the targeted MIP algorithms. A Siemens Politron 1000 VR unit was used for DSA examinations. RESULTS: DSA diagnosed 21 true positives, namely 4 grade II, 4 grade III, 10 grade IV and 3 grade V stenoses. CE MRA scored 100% in stenosis identification and grading, accurately diagnosing all the true negatives and the true positives and was always in agreement with DSA as to stenosis site. CONCLUSION: CE MRA can be considered the technique of choice to study stenosis occlusion in the epiaortic vessels, because it permits a rapid panoramic study of the neck vessels and accurate stenosis grading with similar patterns to those of DSA. Thus, CE MRA appears to be a valid alternative to DSA.

Neonatal detection of generalized resistance to thyroid hormone.

Generalized resistance to thyroid hormone (GRTH) is an inherited disease that is usually suspected when elevated serum thyroid hormone levels are associated with nonsuppressed thyrotropin. Often these test results are obtained because of short stature, decreased intelligence, and/or hyperactivity with learning disability noted in childhood and adolescence, or because of goiter in adulthood. We detected GRTH at birth by analysis of blood obtained during routine neonatal screening. The proposita, born to a mother with GRTH, had a thyrotropin level of 26 mU/L and a corresponding thyroxine concentration of 656 nmol/L (normal, 84 to 232 nmol/L). Administration of thyroid hormone in doses eightfold to 10-fold above replacement levels (liothyronine sodium, 21 micrograms/kg per day, and levothyroxine sodium, 44 micrograms/kg per day) were required to reduce serum thyrotropin to normal levels without induction of hypermetabolism. This case, and the retrospective finding of high thyroxine levels in five newborns subsequently diagnosed as having GRTH, suggest that measurement of thyroxine at birth, in conjunction with thyrotropin, could allow the early detection of GRTH.

[Primary hepatocarcinoma. Diagnostic imaging and chemoembolization]. / Epatocarcinoma primitivo. Diagnostica per immagini e chemioembolizzazione.

The diagnostic and therapeutic approach by means of transcatheter arterial chemoembolization is analyzed in 100 patients affected with hepatocellular carcinoma (HCC): in all patients the HCC had been diagnosed by means of US-guided fine-needle biopsy: 75 of 100 patients were in Child A class, 24 in Child B and 1 in Child C class. The most sensitive imaging technique to identify HCC proved to be angiography (95%); post-Lipiodol CT was also of great value to stage the disease. The authors suggest a diagnostic-therapeutic approach including angiography and simultaneous chemoembolization right after US-guided biopsy, avoiding conventional CT; such a protocol allows high diagnostic accuracy at a lower cost. Chemoembolization proved to be a safe technique, with a low incidence of mortality and complications; the latter were easy to treat by medical therapy. The follow-up data relative to 39 of 100 patients who underwent 2 or more chemoembolization treatments prove the latter to be a valuable technique relative to both the evolution of HCC nodules (in 18/21 patients with single lesions and in 9/18 patients with multiple lesions, lesion size was unchanged or decreased) and to survival rates (70% in 65 patients followed-up 1 year at least); on the whole, 77 of 100 patients are still alive.