Distinct dysregulation of lipid metabolism by unliganded thyroid hormone receptor isoforms.

Thyroid hormone receptors (TRs) play critical roles in energy homeostasis. To understand the role of TRs in lipid homeostasis in vivo, we adopted the loss-of-function approach by creating knock-in mutant mice with targeted mutation in the TRalpha gene (TRalpha1PV mouse) or TRbeta gene (TRbetaPV mouse). The PV mutation, identified in a patient with resistance to thyroid hormone, exhibits potent dominant-negative activity. Here we show that in contrast to TRalpha1PV mouse, TRbetaPV mice exhibited no significant reduction in WAT but had significant increases in serum free fatty acids and total triglycerides. Moreover, the liver of TRbetaPV mice was markedly increased (33%) with excess lipid accumulation, but the liver mass of TRalpha1PV mouse was decreased (23%) with paucity of lipids. These results indicate that apo-TRbeta and apo-TRalpha1 exerted distinct abnormalities in lipid metabolism. Further biochemical analyses indicate that increased lipogenic enzyme expression, activated peroxisome proliferator-activated receptor gamma (Ppargamma) signaling, and decreased fatty acid beta-oxidation activity contributed to the adipogenic steatosis and lipid accumulation in the liver of TRbetaPV mice. In contrast, the expression of lipogenic enzymes and Ppargamma was decreased in the liver of TRalpha1PV mice. These results suggest that the regulation of genes critical for lipid metabolism by TRs in the liver is isoform dependent. These results indicate that apo-TRbeta and apo-TRalpha1 had different effects on lipid metabolism and that both TR isoforms contribute to the pathogenesis of lipid metabolism in hypothyroidism.

[Bronchoplasty and pulmonary arterioplasty for treatment of lung cancer].

OBJECTIVE: We evaluated the outcomes of bronchoplasty (BP) and pulmonary arterioplasty (PAP) for treatment of patients with lung cancer. SUBJECTS: We studied 33 patients who underwent BP and/or PAP over the previous 7 years at our institution. METHODS: A telescope procedure was utilized for anastomosis of a tubular excision performed in the bronchus. One patient received induction chemoradiotherapy, in whom the anastomosis section was covered with an intercostal muscle flap to assure anastomosis completion, then PAP was performed under heparinization. RESULTS: BP including a sleeve resection was performed in 15 patients, while that with a wedge resection and partial side wall resection was performed in 7 and 1 patient, respectively. PAP was performed in 18 patients, and a combination of BP and PAP was used in 8. The seam was incomplete in 2 patients and stenosis was recognized in the anastomosis section in 1. No local recurrence at the anastomosis site was seen in any of the 33 cases. The survival rate for patients who underwent BP was similar to that of those who underwent a standard resection for primary lung cancer. CONCLUSION: Our results indicate that BP and PAP are safe and useful surgical procedures for patients with lung cancer.

PPARgamma insufficiency promotes follicular thyroid carcinogenesis via activation of the nuclear factor-kappaB signaling pathway.

The molecular genetic events underlying thyroid carcinogenesis are poorly understood. Mice harboring a knock-in dominantly negative mutant thyroid hormone receptor beta (TRbetaPV/PV mouse) spontaneously develop follicular thyroid carcinoma similar to human thyroid cancer. Using this mutant mouse, we tested the hypothesis that the peroxisome proliferator-activated receptor gamma (PPARgamma) could function as a tumor suppressor in thyroid cancer in vivo. Using the offspring from the cross of TRbetaPV/+ and PPARgamma+/- mice, we found that thyroid carcinogenesis progressed significantly faster in TRbetaPV/PV mice with PPARgamma insufficiency from increased cell proliferation and reduced apoptosis. Reduced PPARgamma protein abundance led to the activation of the nuclear factor-kappaB signaling pathway, resulting in the activation of cyclin D1 and repression of critical genes involved in apoptosis. Treatment of TRbetaPV/PV mice with a PPARgamma agonist, rosiglitazone, delayed the progression of thyroid carcinogenesis by decreasing cell proliferation and activation of apoptosis. These results suggest that PPARgamma is a critical modifier in thyroid carcinogenesis and could be tested as a therapeutic target in thyroid follicular carcinoma.

Pretranslational regulation of rhythmic type II iodothyronine deiodinase expression by beta-adrenergic mechanism in the rat pineal gland.

It has been demonstrated that type II iodothyronine deiodinase is present in rat pineal gland, and the deiodinase activity markedly increases during the hours of darkness, primarily through beta-adrenergic mechanism. We have studied the relationship between pineal type II iodothyronine deiodinase messenger RNA (mRNA) and the deiodinase activity to elucidate the mechanisms involved in the nocturnal rise in pineal deiodinase activity. Northern analysis has demonstrated that type II iodothyronine deiodinase mRNA is expressed in rat pineal gland, and the mRNA markedly increases during the hours of darkness. The nocturnal increase in pineal type II iodothyronine deiodinase activity is preceded by the increase in its mRNA. Daytime isoproterenol administration resulted in a rapid increase in pineal type II iodothyronine deiodinase mRNA followed by the increase in deiodinase activity. Propranolol treatment, bilateral superior cervical ganglionectomy, or constant light exposure significantly suppressed the nocturnal rise in type II iodothyronine deiodinase mRNA as well as the deiodinase activity. Moreover, isoproterenol or (Bu)2AMP stimulated type II iodothyronine deiodinase mRNA and the deiodinase activity in cultured rat pineal glands. These results suggest that the rhythmic change in pineal type II iodothyronine deiodinase activity is regulated at least in part at the pretranslational level by a beta-adrenergic mechanism transmitted through superior cervical ganglia.

Thyrotropin receptors in brown adipose tissue: thyrotropin stimulates type II iodothyronine deiodinase and uncoupling protein-1 in brown adipocytes.

It has been demonstrated that TSH receptors are expressed not only in thyroid gland but also in extrathyroidal tissues. Brown adipose tissue of guinea pig has been reported to express TSH receptor messenger RNA (mRNA), but the physiological roles of TSH receptors in brown adipose tissue have not been understood. We studied the expression and function of TSH receptors in rat brown adipose tissue and cultured rat brown adipocytes. Northern analysis demonstrated the expression of TSH receptor mRNA in rat brown adipose tissue and cultured rat brown adipocytes. TSH receptor mRNA in rat brown adipose tissue was decreased by cold exposure of the rat, and its mRNA in cultured rat brown adipocytes was also decreased by incubation with TSH or (Bu)(2)cAMP. TSH increased the intracellular cAMP concentration in cultured rat brown adipocytes in a dose dependent manner. Type II iodothyronine deiodinase mRNA, its activity, and uncoupling protein-1 mRNA in cultured rat brown adipocytes were significantly increased by incubation with TSH in a dose-dependent manner. These results suggest the expression of functional TSH receptors in brown adipose tissue, which may be involved in regulation of the expression of type II iodothyronine deiodinase and uncoupling protein-1.

Expression and regulation of type II iodothyronine deiodinase in human thyroid gland.

We have studied the expression of type II iodothyronine deiodinase (DII) in human thyroid tumors and cultured human thyroid cells to elucidate the mechanisms involved in the regulation of DII expression in human thyroid gland. Three cases with hyperfunctioning thyroid adenoma, including a case that showed an activating mutation of G(s)alpha with a constitutive activation of cAMP production in cultured cells, and six cases with papillary thyroid carcinoma were analyzed in the present study. Free T(3) was increased, whereas free T(4) was within the normal range in all patients with hyperfunctioning thyroid adenoma. Thyroid tumor tissue and surrounding nontumor tissue were obtained at the time of surgery, and DII expression was compared between tumor tissue and nontumor tissue in each case. Northern analysis demonstrated the presence of DII messenger RNA (mRNA) approximately 7.5 kb in size in all of the tumor and nontumor tissues. DII mRNA and DII activity in hyperfunctioning thyroid adenoma were significantly increased compared with those in nontumor tissue in each case. In contrast, DII mRNA and DII activity in papillary thyroid carcinoma were decreased compared with those in nontumor tissue in each case. DII mRNA and DII activity in cultured human thyroid cells were significantly stimulated by TSH in a dose-dependent manner. The promoter activity of the human DII gene including the complete cAMP response element, transfected to cultured human thyroid cells, was stimulated by (Bu)(2)cAMP. In summary, these results suggest that DII expression in human thyroid gland is regulated at the transcriptional level through the TSH receptor-G(s)alpha-cAMP regulatory cascade, which may be related to the increase in circulating T(3) level in patients with Graves' disease and hyperfunctioning thyroid adenoma.

Expression of type II iodothyronine deiodinase in brain tumors.

Type II iodothyronine deiodinase (DII) messenger ribonucleic acid (mRNA) and its activity have been demonstrated in human normal brain. Although DII activity has been demonstrated in brain tumors, expression of DII mRNA has not been studied in these tumors. To investigate the mechanisms involved in the expression of DII activity in brain tumors, we studied DII mRNA and DII activity in astrocytoma (two cases), glioblastoma (three cases), and oligodendroglioma (one case). DII mRNA, the size of which was indistinguishable from that in control cerebral cortical tissue, was demonstrated in all of the brain tumors tested, although the intensity of the hybridization signal showed wide variation among the tumors. DII activity was also detected in all tumors. DII mRNA and DII activity were highest in the tissue from oligodendroglioma. A significantly positive correlation was observed between DII mRNA and DII activity in these tumors (r = 0.94; P < 0.01), suggesting that DII expression in brain tumors is regulated at the pretranslational level. The present results demonstrate, for the first time, that DII mRNA as well as DII activity are expressed in brain tumors, and that DII mRNA is significantly correlated with DII activity in those tissues.

Northern analysis of type II iodothyronine deiodinase mRNA in rat Harderian gland.

It has been known that type II iodothyronine deiodinase activity is present in rat Harderian gland and the activity is significantly increased by isoproterenol administration. We have performed Northern analyses to study whether the transcript for type II iodothyronine deiodinase is expressed in rat Harderian gland and whether the isoproterenol stimulation of type II iodothyronine deiodinase activity in rat Harderian gland is due to the change in its mRNA level. Northern analyses have demonstrated that type II iodothyronine deiodinase mRNA, approximately 7.5 kb in size, is expressed in rat Harderian gland, and the mRNA levels as well as the deiodinase activities are greater in hypothyroid rats than those in euthyroid rats. Type II iodothyronine deiodinase mRNA levels and the deiodinase activities in Harderian gland were increased by isoproterenol administration, and the increase in the mRNA levels preceded that in the deiodinase activities. These results indicate that 7.5 kb transcript for type II iodothyronine deiodinase is expressed in rat Harderian gland and beta-adrenergic stimulation of type II iodothyronine deiodinase activity is due at least in part to the increase in its mRNA level.

Expression of thyrotropin receptors in rat thymus.

Thymic hyperplasia is associated with Graves' disease. It has been demonstrated that thyrotropin receptors are expressed in human thymus, and thymic thyrotropin receptors are suggested to be involved in the pathophysiology of Graves' disease. We have studied whether thyrotropin receptors are expressed in rat thymic tissue. Thyrotropin receptor mRNA was demonstrated in 5-day-old, 10-day-old, 20-day-old and adult rat thymus by reverse transcription polymerase chain reaction. Thyrotropin receptor mRNA was also demonstrated in cultured rat thymic epithelial cells. Thyrotropin stimulated cyclic AMP production in cultured rat thymic epithelial cells, suggesting the expression of functional thyrotropin receptors. The present results indicate that thyrotropin receptors are expressed in rat thymus.

[Two cases of spina bifida cystica with congenital dermal sinus].

Spina bifida cystica and congenital dermal sinus are congenital anomalies which are called dysraphic states. Numerous reports of congenital dermal sinus can be seen in Europe and America, but in this country we have been able to find no more than six reported cases. Also in this country, to the best of our knowledge, only two cases of combined spina bifida cystica and congenital dermal sinus have been seen. The small incidence of reported cases may be due to the fact that congenital dermal sinus tends to go unnoticed except when infection develops. Consequently when dermal sinus is asymptomatic, even in both combined cases, it probably is thought to be only spina bifida. We have seen the combination with congenital dermal sinus in two among twenty cases of spina bifida cystica which we have observed during the past seven years. We report on this and discuss it in relation to the other literature.

[Brain abscess: successful treatment of 4 cases including one with ventricular perforation].

The authors experienced with four cases of brain abscess, one of which ruptured into the lateral ventricle. Two cases were treated conservatively and the remaining two were treated surgically. All cases recovered satisfactorily. Case 1: A 30-year-old man with congenital cyanotic heart disease was admitted on Oct. 4, 1979, because of convulsion. Physical examination revealed motor aphasia, right hemihypesthesia, cyanosis, clubbed finger and continuous heart murmur. CT scan showed a ring-enhance mass lesion in the left temporal lobe. Although transient deterioration of the clinical course was observed, he improved satisfactorily after medical treatment of 20 days. Case 2: A 54-year-old man with left homonymous upper quadrantanopia and systolic heart murmur was admitted on Sept. 17, 1979. alpha-streptococcus was detected in the culture of his arterial blood. Vegetation near the mitral valve was revealed by ultrasonic cardiogram. CT scan showed an irregular and ill-shaped ring-enhanced mass in the left temporoparietal region. A saccular aneurysm in the insular portion of the posterior parietal artery was seen on the left carotid angiogram. He was also treated medically and the abscess was gradually reduced and the aneurysm disappeared. Case 3: A 28-year-old man complaining of headache, nausea and vomiting was admitted on Dec. 1, 1979. Physical examination revealed nuchal stiffness, right homonymous hemianopia and bilateral choked disc.(ABSTRACT TRUNCATED AT 250 WORDS)

[Regional continuous intraarterial infusion of urokinase in the acute stage of cervical and intracranial major artery occlusion--particularly on a case of successful improvement after therapeutic recanalization].

We recently applied regional continuous intraarterial infusion of urokinase (UK) for five cases suffering from occlusion of the cervical and intracranial major arteries within nine hours from the onset to the start of infusion. In this paper we reported mainly about a 55-year male patient of occlusion of the left cervical internal carotid artery, which was recanalized by regional continuous intraarterial UK infusion, with discussion about the manipulation of UK infusion, indication of patient and management after recanalization.

Interobserver concordance for endoscopic ultrasonography-guided fine-needle aspiration on-site cytopathology.

INTRODUCTION: Endoscopic ultrasonography-guided fine-needle aspiration (EUS-FNA) is an accurate method of diagnosing and staging gastrointestinal and thoracic malignancy. A key issue in maximizing FNA accuracy is to ensure that an adequate specimen is obtained. On-site cytopathology increases the diagnostic yield of EUS-FNA. However, this increases the time and costs. Physicians trained in EUS and in pathology are capable of interpreting cytologic adequacy from EUS-FNA specimens. Furthermore, on-site interpretation by the endoscopist could reduce cost and procedure duration. The learning curve of endossonographers in on-site cytopathology and how they could contribute in EUS-FNA accuracy increase is unknown. OBJECTIVE: To determine the interobserver concordance of on-site cytopathology interpretation of EUS-FNA specimens by comparing endosonographers trained in cytology with a physician cytopathologist. METHODS: A prospective blinded study comparing one endossonographer with one physician cytopathologist. The study was developed in the Santa Casa Medical School, Brazil from February to November 2012. Fifteen different cases of EUS-FNA were analysed, in a total of 50 slides. Each observer described the slides for the adequate or not of tissue sampling, and classified as benign, suspicious, malign or undefined. The analyses were then matched. RESULTS: We analyzed the concordance of 50 slides description made by the endossonographer and physician cytopathologist, according to enough material, cellular group identification and final diagnosis. Kappa (κ) indexes were: Presence of material κ = 0.480 (P < 0.001); presence of malignance κ = 0.808 (P < 0.001); in subepithelial lesions κ = 0.615 (P = 0.06); in pancreatic lesions κ = 0.675 (P < 0.001); in mediastinal lesions κ = 0.243 (P = 0.128). CONCLUSION: Our study showed that endosonographers and cytopathologists had good concordance in EUS-FNA specimens on-site cytopathology interpretation, except in mediastinal/pulmonary cases.

Influence of layer, size and organ of subepithelial lesions of upper gastrointestinal tract in outcomes of endoscopic ultrasound-guided fine-needle aspiration.

INTRODUCTION: The endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) has emerged as a minimally invasive and safe method for material procurement in the differential diagnosis of subepithelial lesions (SEL) of upper gastrointestinal tract (UGT), especially in suspicious lesions of gastrointestinal stromal tumors (GIST). There are few studies discussing the factors that influence the EUS-FNA in the diagnosis of SEL. AIM: To establish possible associations between lesion size, layer and organ of origin with the outcome of EUS-FNA in patients with SELs of UGT. METHODS: A retrospective analysis using data of patients referred to French-Brazilian Center of EUS of endoscopy Department of Santa Casa de São Paulo Hospital, with previous endoscopic diagnosis of SEL, which underwent EUS-FNA from May 2006 to August 2011. RESULTS: A total of 222 patients were submitted to EUS. 15 with extrinsic compressions and 207 with SEL. Of these, 89 underwent to EUS-FNA. Ninety-two SEL were diagnosed on EUS and punctured. The EUS-FNA was positive in 58.7%. In lesions measuring 2-3 cm and >3 cm, the EUS-FNA was positive in 80% and 72%, respectively (P < 0.001). CONCLUSION: The size of SELs was the only variable that influenced the outcome of EUS-FNA. Best results are achieved in lesions larger than 2 cm.

Relevance of endoscopic ultrasound in the management of esophagus cancer therapy.

INTRODUCTION: The objective of this case series study by retrospective analysis was to determine the relevance of endoscopic ultrasound (EUS) in therapeutic decision esophageal cancer. MATERIAL AND METHODS: Using medical records of the Department of Endoscopy of Santa Casa de São Paulo, we have collected data from 16 patients, in 4 years, diagnosed of esophageal cancer, and presented in the form of clinical cases to a specialist surgeon in esophageal cancer and a clinical oncologist, for therapeutic evaluation before and after the outcome of EUS. RESULTS: Both of them choose non-resective and not curative methods (68.8% by surgeon vs. 87.5% oncologist) before EUS. The best treatment by the surgeon was chemotherapy and palliative radiotherapy associated (25%) and palliative endoscopic prostheses (25%), and by the oncologist, neoadjuvant chemotherapy and radiotherapy associated (56.2%). After EUS, the resective surgical treatment was the both choice in only 6.2% of cases, and the rest of 93.8%, non-resective. The surgeon choice was chemotherapy and palliative radiotherapy associated (44%), and oncologist choice was neoadjuvant chemotherapy and radiotherapy associated (44%). Analysis by the Chi-square method, comparing respective versus non-resective treatment, surgeon versus oncologist, with and without the EUS, obtained values of P = 0.39 and P = 0.46, respectively. The comparison between healing and non-healing treatment had the same P value. Regarding the change in behavior (resective vs. non-resective), there was a change of approach by the surgeon in 25% of cases (P = 0.17) and the oncologist moved conduct in 6.25% of cases. Comparing the changing of behavior among experts, the P value was 0.33. Despite evidence of behavior change after the EUS, the statistical point of view, the P value had no significant relevance. The main factor involved is probably due to a reduced number of sample cases. However, this is a pilot study, and is needed other with a larger number of cases. CONCLUSION: The data obtained allow us to conclude that EUS proved to be an important test for the change in staging and therapeutic management of esophageal cancer.