Thyroid hormone activation by type 2 deiodinase mediates exercise-induced peroxisome proliferator-activated receptor-γ coactivator-1α expression in skeletal muscle.

KEY POINTS: In skeletal muscle, physical exercise and thyroid hormone mediate the peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1a) expression that is crucial to skeletal muscle mitochondrial function. The expression of type 2 deiodinase (D2), which activates thyroid hormone in skeletal muscle is upregulated by acute treadmill exercise through a ß-adrenergic receptor-dependent mechanism. Pharmacological block of D2 or disruption of the Dio2 gene in skeletal muscle fibres impaired acute exercise-induced PGC-1a expression. Dio2 disruption also impaired muscle PGC-1a expression and mitochondrial citrate synthase activity in chronically exercised mice. ABSTRACT: Thyroid hormone promotes expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1a), which mediates mitochondrial biogenesis and oxidative capacity in skeletal muscle (SKM). Skeletal myocytes express the type 2 deiodinase (D2), which generates 3,5,3'-triiodothyronine (T3 ), the active thyroid hormone. To test whether D2-generated T3 plays a role in exercise-induced PGC-1a expression, male rats and mice with SKM-specific Dio2 inactivation (SKM-D2KO or MYF5-D2KO) were studied. An acute treadmill exercise session (20 min at 70-75% of maximal aerobic capacity) increased D2 expression/activity (1.5- to 2.7-fold) as well as PGC-1a mRNA levels (1.5- to 5-fold) in rat soleus muscle and white gastrocnemius muscle and in mouse soleus muscle, which was prevented by pretreatment with 1 mg (100 g body weight)(-1) propranolol or 6 mg (100 g body weight)(-1) iopanoic acid (5.9- vs. 2.8-fold; P < 0.05), which blocks D2 activity . In the SKM-D2KO mice, acute treadmill exercise failed to induce PGC-1a fully in soleus muscle (1.9- vs. 2.8-fold; P < 0.05), and in primary SKM-D2KO myocytes there was only a limited PGC-1a response to 1 µm forskolin (2.2- vs. 1.3-fold; P < 0.05). Chronic exercise training (6 weeks) increased soleus muscle PGC-1a mRNA levels (∼25%) and the mitochondrial enzyme citrate synthase (∼20%). In contrast, PGC-1a expression did not change and citrate synthase decreased by ∼30% in SKM-D2KO mice. The soleus muscle PGC-1a response to chronic exercise was also blunted in MYF5-D2KO mice. In conclusion, acute treadmill exercise increases SKM D2 expression through a ß-adrenergic receptor-dependent mechanism. The accelerated conversion of T4 to T3 within myocytes mediates part of the PGC-1a induction by treadmill exercise and its downstream effects on mitochondrial function.

Clinical characteristics and biopsy accuracy in suspected cases of Sjögren's syndrome referred to labial salivary gland biopsy.

BACKGROUND: Labial salivary gland biopsy (LSGB) is the most important diagnostic tool for the diagnosis of Sjögren's syndrome (SS), but its diagnostic value is rarely studied. This study assessed the sensibility and specificity of LSGB, and the clinical profiles of patients who were referred for biopsy. METHODS: Retrospective analysis of the histopathological reports from LSGB and medical report data from patients who underwent LSGB between 2008 and 2011 was conducted. RESULTS: About 290 biopsies were performed and 74 were excluded due to insufficient clinical data. Of the 216 patients, 0.46% was carrier of hepatitis C virus, 30.1% had primary SS (pSS), and 8.8% had secondary SS (sSS). Of the samples, 94.3% presented dryness symptoms, 51.6% experienced dryness only, 42.7% had systemic manifestations, and 66.9% presented low unstimulated salivary flow and/or Schirmer's test. LSGB was necessary in 67.6% to confirm the presence of SS based on the American-European Consensus Group 2002 criteria (AECG). Based on specialist's opinion, sensibility level was 86.57%, and specificity was 97.43%. Positive predictive value (PPV) was 95%, and negative predictive value (NPV) was 92.6%. Determined accuracy was 93.3%. Concordance (kappa coefficient) of LSGB and specialist's opinion was 0.851, and LSGB with AECG criteria was 0.806. Of the 98 patients referred with fibromyalgia and dryness, 36.7% had SS and LSBG focus score of ≥ 1. Patients with SS were older, and showed more severe lachrymal and salivary dysfunctions, greater frequency of fibromyalgia, anti-nuclear antibodies (ANA), anti-SSA-Ro, and anti-SSB-La. CONCLUSIONS: Labial salivary gland biopsy has high sensibility, specificity, positive and negative predictive values for diagnosis of pSS. In the clinical practice, it is useful, especially for those patients with glandular dysfunctions and negative antibodies.

Type 2 iodothyronine deiodinase is upregulated in rat slow- and fast-twitch skeletal muscle during cold exposure.

During cold acclimation, shivering is progressively replaced by nonshivering thermogenesis. Brown adipose tissue (BAT) and skeletal muscle are relevant for nonshivering thermogenesis, which depends largely on thyroid hormone. Since the skeletal muscle fibers progressively adapt to cold exposure through poorly defined mechanisms, our intent was to determine whether skeletal muscle type 2 deiodinase (D2) induction could be implicated in the long-term skeletal muscle cold acclimation. We demonstrate that in the red oxidative soleus muscle, D2 activity increased 2.3-fold after 3 days at 4°C together with the brown adipose tissue D2 activity, which increased 10-fold. Soleus muscle and BAT D2 activities returned to the control levels after 10 days of cold exposure, when an increase of 2.8-fold in D2 activity was detected in white glycolytic gastrocnemius but not in red oxidative gastrocnemius fibers. Propranolol did not prevent muscle D2 induction, but it impaired the decrease of D2 in BAT and soleus after 10 days at 4°C. Cold exposure is accompanied by increased oxygen consumption, UCP3, and PGC-1α genes expression in skeletal muscles, which were partialy prevented by propranolol in soleus and gastrocnemius. Serum total and free T3 is increased during cold exposure in rats, even after 10 days, when BAT D2 is already normalized, suggesting that skeletal muscle D2 activity contributes significantly to circulating T3 under this adaptive condition. In conclusion, cold exposure is accompanied by concerted changes in the metabolism of BAT and oxidative and glycolytic skeletal muscles that are paralleled by type 2 deiodinase activation.

PAD-UFES-20: A skin lesion dataset composed of patient data and clinical images collected from smartphones.

Over the past few years, different Computer-Aided Diagnosis (CAD) systems have been proposed to tackle skin lesion analysis. Most of these systems work only for dermoscopy images since there is a strong lack of public clinical images archive available to evaluate the aforementioned CAD systems. To fill this gap, we release a skin lesion benchmark composed of clinical images collected from smartphone devices and a set of patient clinical data containing up to 21 features. The dataset consists of 1373 patients, 1641 skin lesions, and 2298 images for six different diagnostics: three skin diseases and three skin cancers. In total, 58.4% of the skin lesions are biopsy-proven, including 100% of the skin cancers. By releasing this benchmark, we aim to support future research and the development of new tools to assist clinicians to detect skin cancer.

Effect of thimerosal on thyroid hormones metabolism in rats.

Mercury seems to exert an inhibitory effect on deiodinases, but there are few studies using Thimerosal (TM) as the mercury source. We aimed to elucidate the effect of TM on thyroid hormones peripheral metabolism. Adult Wistar female rats received 0.25 µg or 250 µg TM/100 g BW, IM, twice a week, for a month. We evaluated serum total T3 and T4, D1 activity using 125I-rT3 as tracer, and D2 activity using 125I-T4 NADPH oxidase activity was measured by Amplex-red/HRP method and mRNA levels by real time PCR. Serum T4 was increased and T3 decreased by the greatest dose of TM. Even though D1 activity in pituitary and kidney was reduced by the highest dose of TM, hepatic D1 activity and D1 mRNA levels remained unchanged. D2 activity was also significantly decreased by the highest dose of TM in all CNS samples tested, except cerebellum, but D2 mRNA was unaltered. mRNA levels of the tested NADPH oxidases were not affected by TM and NADPH oxidase activity was either unaltered or decreased. Our results indicate that TM might directly interact with deiodinases, inhibiting their activity probably by binding to their selenium catalytic site, without changes in enzyme expression.

Diabetes mellitus increases reactive oxygen species production in the thyroid of male rats.

Diabetes mellitus (DM) disrupts the pituitary-thyroid axis and leads to a higher prevalence of thyroid disease. However, the role of reactive oxygen species in DM thyroid disease pathogenesis is unknown. Dual oxidases (DUOX) is responsible for H(2)O(2) production, which is a cosubstrate for thyroperoxidase, but the accumulation of H(2)O(2) also causes cellular deleterious effects. Nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) is another member of the nicotinamide adenine dinucleotide phosphate oxidase family expressed in the thyroid. Therefore, we aimed to evaluate the thyroid DUOX activity and expression in DM rats in addition to NOX4 expression. In the thyroids of the DM rats, we found increased H(2)O(2) generation due to higher DUOX protein content and DUOX1, DUOX2, and NOX4 mRNA expressions. In rat thyroid PCCL3 cells, both TSH and insulin decreased DUOX activity and DUOX1 mRNA levels, an effect partially reversed by protein kinase A inhibition. Most antioxidant enzymes remained unchanged or decreased in the thyroid of DM rats, whereas only glutathione peroxidase 3 was increased. DUOX1 and NOX4 expression and H(2)O(2) production were significantly higher in cells cultivated with high glucose, which was reversed by protein kinase C inhibition. We conclude that thyroid reactive oxygen species is elevated in experimental rat DM, which is a consequence of low-serum TSH and insulin but is also related to hyperglycemia per se.

Apudomas pancreáticos: um desafio para clínicos e cirurgiões / Pancreatic apudomas: a challenge for surgeons and physicians

OBJETIVO: O propósito do presente estudo é analisar as dificuldades quanto ao diagnóstico, avaliação prognóstica e conduta em sete pacientes portadores de tumores neuroendócrinos do pâncreas (apudomas), estudados na última década, comparando os resultados com aqueles discutidos na literatura. MÉTODO: A idade dos pacientes variou de 15 a 66 anos, com média de 38,4 anos. Todos foram submetidos a alguma forma de ressecção pancreática por tumores neuroendócrinos. Os exames histológicos foram feitos pelas técnicas tradicionais e por imuno-histoquímica. RESULTADOS: Três pacientes tiveram um diagnóstico inespecífico de tumor neuroendócrino; dois de vipoma e dois de gastrinoma. As síndromes não se manifestaram claramente, ainda que cada caso tenha tido um rótulo diagnóstico. Os exames por imuno-histoquímica demonstraram a presença de múltiplos hormônios, mas por falta de sintomas clínicos, as correlações ficaram prejudicadas na maioria dos casos, havendo correlação somente em caso de gastrinoma. Um paciente faleceu no pós-operatório; um sobreviveu sete anos e cinco estão vivos, com sobrevida variando entre três e cinco anos. CONCLUSÕES: Não houve uma manifestação sindrômica evidente, porém a sobrevida dos pacientes tem sido compatível com os dados de literatura.

BACKGROUND: The purpose of the present study is to analyze the difficulties concerning diagnostic, prognostic and clinical conduct of seven patients with pancreatic neuroendocrine tumors (APUDomas), evaluated over the past decade. METHODS: Patients varied in age from 15 to 66 years old, with a mean age of 38.4 years. All patients underwent some type of pancreatic resection as treatment of the neuroendocrine tumor. The histological sections were submitted to traditional and imunohistochemical examination. RESULTS: Three patients were diagnosed with unspecific neuroendocrine tumor, two with VIPoma and two with Gastrinoma. Syndromes were not clearly manifested, although every case had a differential diagnosis. Imunohistochemistry showed the presence of multiple hormones, but due to the lack of clinical symptoms, correlation was harmed in most cases, however one Gastrinoma showed typical clinical symptoms. One patient died in the post-operative period, one survived for 7 years and five are still alive, with a life expectancy varying from 3 to 5 years. CONCLUSIONS: We observed a lack of typical clinical syndromes for most cases, but life expectancy was compatible with the one described in the literature.