Tratamiento con TRIAC en pacientes pediátricos con deficiencia de MCT8 / Treatment with TRIAC in pediatric patients with MCT8

Los transportadores de monocarboxilatos (MCT) permiten el ingreso celular de hormonas tiroideas, especialmente en el sistema nervioso central (SNC), donde son indispensables para el neurodesarrollo. La deficiencia de MCT8 produce la combinación de hipotiroidismo en SNC e hipertiroidismo periférico, caracterizada por T3 elevada. El único tratamiento actualmente disponible es el ácido 3,3',5-triyodotiroacético (TRIAC), un análogo de hormonas tiroideas que tiene como objetivo mejorar la tirotoxicosis periférica y prevenir la progresión del deterioro neurológico. En el presente artículo, se evalúan las características clínicas, imagenológicas, bioquímicas y genéticas de 4 pacientes con deficiencia de MCT8 tratados con TRIAC hasta la fecha, las dosis utilizadas y la respuesta al tratamiento.

Monocarboxylate transporters (MCTs) allow the cellular entry of thyroid hormones, especially into the central nervous system (CNS), where they are crucial for neurodevelopment. MCT8 deficiency results in the combination of hypothyroidism in the CNS and peripheral hyperthyroidism, characterized by elevated T3 levels. The only treatment currently available is 3,3',5-triiodothyroacetic acid (TRIAC), a thyroid hormone analogue aimed at improving peripheral thyrotoxicosis and preventing the progression of neurological impairment. Here we assess the clinical, imaging, biochemical, and genetic characteristics of 4 patients with MCT8 deficiency who have received TRIAC to date, the doses used, and the response to treatment.

Genetic variants in the SLC16A11 gene are associated with increased BMI and insulin levels in nondiabetic Chilean population

ABSTRACT Objective: To study the association of SLC16A11 gene variants with obesity and metabolic markers in nondiabetic Chilean adults. Materials and methods: This cross-sectional study included 263 non-diabetic adults. The genotype of the rs75493593 polymorphism of SLC16A11 gene was performed by real-time PCR. It's association with adiposity markers (body weight, BMI, waist circumference and fat mass percentage), metabolic markers (glucose, insulin, HOMAIR, leptin, total cholesterol, LDLc, HDLc, triglycerides, ALT, GGT and hsCRP) and blood pressure was analyzed by linear regression. Results: The minor allele (T) of the SLC16A11 gene (rs75493593) has a frequency of 29.7% among Chileans. Risk genotypes (GT and TT) were associated with a significant 1.49 mU/l increase in plasmatic insulin for each copy of the minor allele (95% CI: 0.12, 2.87, p < 0.05). This association remained significant after adjusting for socio-demographic variables, physical activity and smoking (1.36 mU/l, 95% CI: 0.16, 2.58 p < 0.05), but was lost when BMI was included as a confounding factor. Higher BMI was also significantly associated with polymorphic genotypes in SLC16A11, independent of socio-demographic variables. Conclusion: The minor allele of the SLC16A11 gene (T) is highly prevalent among Chileans and is associated with increased insulin and BMI in nondiabetic individuals. These findings suggest that the genetic variant in SLC16A11 is not only associated with type 2 diabetes as previously shown in Mexicans, but is also related to early metabolic alterations in healthy subjects that may lead to type 2 diabetes.

Loss of monocarboxylate transporter 1 aggravates white matter injury after experimental subarachnoid hemorrhage in rats / 医学前沿

Monocarboxylic acid transporter 1 (MCT1) maintains axonal function by transferring lactic acid from oligodendrocytes to axons. Subarachnoid hemorrhage (SAH) induces white matter injury, but the involvement of MCT1 is unclear. In this study, the SAH model of adult male Sprague-Dawley rats was used to explore the role of MCT1 in white matter injury after SAH. At 48 h after SAH, oligodendrocyte MCT1 was significantly reduced, and the exogenous overexpression of MCT1 significantly improved white matter integrity and long-term cognitive function. Motor training after SAH significantly increased the number of ITPR2

Expressions of GPR81, MCT1 and MCT4 in squamous carcinoma and their clinical significance / 中南大学学报(医学版)

To validate the expressions of G protein-coupled receptor 81 (GPR81), monocarboxylate transporter (MCT) 1 and MCT4 in cervical squamous carcinoma and to explore their role in the onset of cervical squamous carcinoma.
 Methods: Immunohistochemical method was used to detect the expressions of GPR81, MCT1 and MCT4 in 16 normal cervical tissue and 44 cervical squamous carcinoma tissue. The associations of these proteins expression with cervical squamous carcinoma or clinicopathological factors were analyzed.
 Results: The expressions of GPR81, MCT1 and MCT4 in cervical squamous carcinoma tissue were higher than those in normal cervical tissue (P0.05). No difference of the expressions of GPR81, MCT1 and MCT4 were found between cases with or without lymphatic metastasis (P>0.05). No correlation was found among GPR81, MCT1 and MCT4 in cervical squamous carcinoma (P>0.05).
 Conclusion: GPR81, MCT1 and MCT4 may be associated with the onset of cervical squamous carcinoma, and GPR81 may be associated with the progression of cervical squamous carcinoma.

Prevalência de depressão em bombeiros / Prevalence of depression among firefighters / Prevalencia de depresión en bomberos

A depressão apresenta alta carga de doença no mundo. Fatores socioeconômicos e exposição a situações extremas no trabalho podem estar associados à doença. O objetivo do trabalho é investigar a prevalência e fatores associados à depressão em bombeiros de Belo Horizonte, Minas Gerais, Brasil. Estudo transversal foi realizado em universo de bombeiros do sexo masculino em Belo Horizonte (n = 711). O Inventário Beck para Depressão (IBD) foi utilizado para avaliar a presença de depressão. Modelos de regressão logística (uni e multivariada) foram utilizados para estudar a associação entre características sociodemográficas, estressores ocupacionais, situação de saúde e depressão. A prevalência de depressão na amostra estudada foi 5,5%. A chance de depressão foi maior entre bombeiros que relataram sintomas de estresse pós-traumático (OR = 12,47; IC95%: 5,64-27,57) e uso abusivo de álcool (OR = 5,30; IC95%: 2,35-11,96). Os resultados são discutidos considerando as inter-relações entre transtornos mentais, o efeito do trabalhador sadio e o reconhecimento social do trabalho dos bombeiros.

Depression burder is high worldwide. Socioeconomic factors and exposure to extreme situations at work may be associated with the illness. This study focused on the prevalence of depression and associated factors among firefighters in Belo Horizonte, Minas Gerais State, Brazil. A cross-sectional study was conducted among male firefighters in Belo Horizonte (n = 711). The Beck Depression Inventory (BDI) was used to assess depression. Univariate and multivariate logistic regression models were used to study the association between socio-demographic characteristics, occupational stressors, health status, and depression. Prevalence of depression in the sample was 5.5%. The likelihood of developing depression was higher among firefighters who reported post-traumatic stress symptoms (OR = 12.47; 95%CI: 5.64-27.57) and alcohol abuse (OR = 5.30; 95%CI: 2.35-11.96). The results are discussed considering the interrelationships between mental disorders, the healthy worker effect, and social recognition of firefighters' work.

La depresión tiene una alta carga como enfermedad mundial. Factores socioeconómicos y la exposición a situaciones extremas en el trabajo pueden estar asociados con la enfermedad. El objetivo de este trabajo es investigar la prevalencia y los factores asociados con la depresión en los bomberos de Belo Horizonte, Minas Gerais, Brasil. Se trata de un estudio transversal, realizado entre los bomberos de sexo masculino de Belo Horizonte (n = 711). Se utilizó el Inventario de Depresión de Beck (IDB) para evaluar la presencia de depresión. Se utilizaron modelos de regresión logística para estudiar la asociación entre características sociodemográficas, estrés ocupacional, estado de salud y depresión. La prevalencia de depresión fue de un 5,5%. La posibilidad de depresión fue mayor entre los bomberos que informaron síntomas de estrés postraumático (OR = 12,47; IC95%: 5,64-27,57) y abuso de alcohol (OR = 5,30, IC95%: 2,35-11,96). Los resultados son discutidos considerando las interrelaciones entre los trastornos mentales, el efecto en trabajadores sanos y el reconocimiento social de la labor de bomberos.

The changes of monocarboxylate transporter-2 in spinal cord horn in a rat model of chronic inflammatory pain / 中国应用生理学杂志

<p><b>OBJECTIVE</b>To investigate the changes in the levels of monocarboxylate transporter-2 in spinal cord horn in a rat model of chronic inflammatory pain.</p><p><b>METHODS</b>Male SD rats weighting 180 - 220 g were randomly divided into two groups(n = 48): normal saline group (NS group), complete Freund's adjuvant group (CFA group). Rats were given injections of CFA 100 µl in left hind paw in group CFA, and an equal volume of saline was given injection in group NS. Mechanical withdraw threshold(MWT) and thermal withdraw latency(TWL) were measured at before injection(T0 and 3 h, 1 d, 3 d, 7 d, 14 d, and 21 d after injection(T1-7). Four rats were chosen from each group at T0-7 and sacrificed, and L4-5 segments of the spinal cord horn were removed for measurement of the expression of monocarboxylate transporter-2 by Western blot analysis.</p><p><b>RESULTS</b>In CFA group, mechanical hyperalgesia and allodynia appeared on the 3 h after CFA injection, then until the day 14. The expression of monocarboxylate transporter-2 in the spinal dorsal horn of rats in CFA group was significantly higher than that in normal control group at T1-6(P <0.05). The protein level of monocarboxylate transporter-2 was apparently correlated with MWT and TWL(P <0.01 and P <0.05) in CFA group.</p><p><b>CONCLUSION</b>The level of monocarboxylate transporter-2 in spinal dorsal horn is significantly increased in a rat model of chronic inflammatory pain and the change may involve in the formation and maintenance of central sensitization in spinal cord of chronic inflammatory uain.</p>

Iodine deficiency up-regulates monocarboxylate transporter 8 expression of mouse thyroid gland / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Iodine deficiency is a major factor affecting thyroid auto-regulation, the quantity of iodine may greatly influence the synthesis of thyroid hormones (THs). It has long been believed that TH enters the cell through passive diffusion. Recent studies have suggested that several transporters could facilitate transportation of TH. The monocarboxylate transporter 8 (MCT8) was identified as a very active and specific TH transporter. The purpose of this study was to investigate whether iodine insufficient affected the expression of MCT8 in the thyroid gland.</p><p><b>METHODS</b>Sixty BALB/c mice were randomly divided into two groups: control group was fed with standard feed (iodine concentration of 300 µg/kg); while low-iodine (LI) group received iodine-insufficient feed (iodine concentration of 20-40 µg/kg). After 3 months, 10 mice of each group were sacrificed. The remaining 20 mice of each group were kept till 6 months. From the LI group, we randomly selected 15 mice and injected triiodothyronine (T3, 100 µg/kg body weight per day) intraperitoneally for 24, 48 or 72 hours (5 mice for each time-point). Then, all the mice were sacrificed. Mouse serum thyroxine (T4), T3, and thyroid-stimulating hormone (TSH) levels were determined by chemiluminescence immunoassay (CIA). The protein content or messenger RNA (mRNA) level of thyroid MCT8 was measured by Western blotting analysis or real time RT-PCR respectively. MCT8 subcellular location in thyroid tissues was probed with immunohistochemistry (IHC) assay.</p><p><b>RESULTS</b>We found that mouse serum T3 and T4 levels decreased and TSH level increased by the end of the third month. Consistent with these findings, there was significant goiter and hypothyroidism in the LI group. Meanwhile, the MCT8 mRNA increased to 1.36-fold of the level in the control group at the 3(rd) month. At 6(th) month, the serum T4 level in LI mice remained at a lower level, and MCT8 mRNA expression continued rising to nearly 1.60-fold compared with the control group. The protein content was also about 3 times higher than that in the control group. IHC results also revealed MCT8 was of higher expression and localized in the cytoplasm of thyroid follicular cells. After providing exogenous T3 to iodine deficient mice, the serum T3 and T4 gradually increased, whereas MCT8 mRNA and protein both started to decrease and returned to the same level as the control group.</p><p><b>CONCLUSION</b>There is a compensatory increase in thyroid MCT8 expression to enhance its capability to transport TH from thyroid to the blood circulation in iodine deficient mice.</p>

Expression of Glycolysis-Related Proteins in Solid Papillary Carcinoma of the Breast According to Basement Membrane Status

PURPOSE: The aim of this study was to investigate the differences of expression in glycolysis-related proteins such as Glut-1, carbonic anhydrase (CA) IX, and monocarboxylate transporter (MCT) 4 according to the myoepithelial cell (MEC) and basement membrane (BM) status in solid papillary carcinoma (SPC) of the breast. MATERIALS AND METHODS: Immunohistochemical evaluation of Glut-1, CAIX, and MCT4, as well as p63 and type IV collagen, were performed on 23 SPC cases. RESULTS: Six and nine cases of SPC showed the presence and absence of myoepithelial cells, respectively, and eight cases belonged to the borderline status (p63-positive MEC on some areas of the outer tumor surface but not in others). BM was partially or completely absent in 14 cases and present in nine cases. SPC lacking BM more frequently showed high expression of CAIX than SPC with BM (p=0.037). CONCLUSION: In SPC of the breast, a strong expression of CAIX seems to be associated with an increasing degree of loss of BM, which can be interpreted as BM degradation due to the induction of extracellular acidity with increasing expression of CAIX.

Expression of monocarboxylate transporter 8 mRNA in the brain tissue of rats with cerebral ischemia / 南方医科大学学报

<p><b>OBJECTIVE</b>To investigate the mRNA expression of monocarboxylate transporter 8 (MCT8), a thyroid hormone transport protein, in the lateral ventricle of rats with cerebral ischemia.</p><p><b>METHODS</b>Immunofluorescence staining was used to observe the expression of MCT8 in the lateral ventricle of 5 normal SD rats. Another 20 adult male SD rats were randomized into 4 groups and subject to permanent ligation of both the common carotid arteries (2-vessel occlusion, 2VO) for 3 days, 2 weeks, or 5 weeks, or no ligation (control). At the end of the experiment, the transcriptional level of MCT8 in the brain tissue of the rats were detected using fluorescent quantitative PCR.</p><p><b>RESULTS</b>MCT8 mRNA levels in 3-day and 2-week 2VO groups were comparable with that in the control group (P=0.909; P=0.694), but increased significantly in 5-week 2VO group compared with that in the control and 3-day 2VO groups (P=0.029; P=0.023). No significance was found in MCT8 mRNA between the 2-week and 5-week 2VO groups (P=0.065).</p><p><b>CONCLUSION</b>Prolonged cerebral ischemia causes compensatory increase of MCT8 mRNA expression on the capillary endothelial cell membranes in the lateral ventricle of rats.</p>

Novel mutation in MCT8 gene in a Brazilian boy with thyroid hormone resistance and severe neurologic abnormalities / Mutação nova do gene MCT8 em menino Brasileiro com resistência ao hormônio tireioidiano e neuropatia grave

O MCT8 é um transportador celular de hormônios tireoidianos, importante para sua ação e metabolização. Relatamos o caso de um menino com a nova mutação inativadora 630insG no éxon 1 do MCT8. O paciente caracterizou-se por grave comprometimento neurológico (inicialmente com hipotonia global, evoluindo com hipertonia generalizada), crescimento normal nos dois primeiros anos de vida, reduzido ganho ponderal e ausência dos sinais e sintomas típicos de hipotireoidismo. A sua avaliação sérica revelou elevação do T3, redução do T4 total e livre e TSH levemente aumentado. O tratamento com levotiroxina melhorou o perfil hormonal tireoidiano, mas não modificou o quadro clínico do paciente. Esses dados reforçam o conceito de que o papel do MCT8 é tecido-dependente: enquanto os neurônios são altamente dependentes do MCT8, o osso, o tecido adiposo, o músculo e o fígado são menos dependentes do MCT8 e, portanto, podem sofrer as consequências da exposição a níveis séricos elevados de T3.

MCT8 is a cellular transporter of thyroid hormones important in their action and metabolization. We report a male patient with the novel inactivating mutation 630insG in the coding region in exon 1 of MCT8. He was characterized clinically by severe neurologic impairment (initially with global hypotonia, later evolving with generalized hypertonia), normal growth during infancy, reduced weight gain, and absence of typical signs and symptoms of hypothyroidism, while the laboratory evaluation disclosed elevated T3, low total and free T4, and mildly elevated TSH serum levels. Treatment with levothyroxine improved thyroid hormone profile but was not able to alter the clinical picture of the patient. These data reinforce the concept that the role of MCT8 is tissue-dependent: while neurons are highly dependent on MCT8, bone tissue, adipose tissue, muscle, and liver are less dependent on MCT8 and, therefore, may suffer the consequences of the exposition to high serum T3 levels.

Effect of brazilein on energy metabolism of cerebral ischemia-reperfusion in mice / 中国中药杂志

<p><b>OBJECTIVE</b>To investigate brazilein's role in energy metabolism of cerebral ischemia-reperfusion in mice.</p><p><b>METHOD</b>Fourty mice were randomly divided into the sham group, ischemia group, brazilein 5 mg x kg(-1) group and brazilein 10 mg x kg(-1) group, each with ten cases. Cerebral ischemia model was the built. Mice were injected with brazilein three days before the operation, then they were killed. Cerebrum homogenate was prepared for the detecting of ATP, ADP, AMP and lactic acid by HPLC, expressions of MCT1 and MCT2 in mRNA level by RT-PCR.</p><p><b>RESULT</b>The lactic acid in cerebrum increased sharply 20 minutes after cerebral ischemia and decreased 1 hour after reperfusion, then returned to the normal level 24 hours after reperfusion. The charge of energy decreased significantly at the beginning of the ischemia-reperfusion, and the charge restored 1 hour after reperfusion though it was still much lower than the normal level at the time point of 24 hours. Moreover, MCT1 and MCT2 upregulated accompanied with the increase of lactate, MCT2 mRNA enhanced in brazilein 5 mg x kg(-1) group (P < 0.05) while both the two factors increased in brazilein 10 mg x kg(-1) group (P < 0.01).</p><p><b>CONCLUSION</b>Brazilein might protect neurons by changing the charge of energy.</p>

Allan-Herndon-Dudley syndrome.

Allan-Herndon-Dudley Syndrome (AHDS) is a rare X-linked disorder caused by mutation in the gene encoding the monocarboxylate transporter-8. Abnormal transport function is reflected by elevated free T3 and decreased free T4 levels along with clinical features characterized by neurological abnormalities including global developmental delay, central hypotonia, rotatory nystagmus, impaired hearing, spasticity and contractures of joints. We report a child with classical clinical features along with confirmatory deranged thyroid levels in blood.

Adenocarcinoma colorretal: aspectos anatomopatológicos e imuno-histoquímicos do crescimento tumoral, do citoesqueleto e de marcadores de regulação do pH intracelular / Colorectal adenocarcinoma: anatomopathological and imunohistochemical aspects of tumor growth, cytoskeleton and of intracellular pH regulator markers

Centrado no carcinoma colorretal, o presente trabalho visou: 1) Estudar a distribuição das principais variáveis anatomopatológicas, pesquisando sua associação com metástase linfonodal ou hepática. 2) Com base nas eventuais associações encontradas, selecionar um conjunto de variáveis que, estudadas no tumor primário, possam predizer a presença de metástase nodal ou hepática. 3) Analisar os perfis de imunoexpressão de alguns marcadores potencialmente relacionados à citoarquitetura (queratina 7 e 20) e ao crescimento tumoral (proliferação através do Ag Ki-67 e apoptose através da queratina 18 clivada) em amostras de mucosa normal, adenocarcinoma primário, metástase linfonodal e metástase hepática, explorando suas eventuais relações com as variáveis histopatológicas e o estadio da lesão. 4) Pesquisar possíveis associações entre a expressão dos transportadores de monocarboxilato 1, 2 e 4, moléculas reguladoras do pH intracelular, e os marcadores acima relacionados e as variáveis anatomopatológicas. A casuística foi constituída por 139 adenocarcinomas colorretais, sendo 96 sem metástase hepática e 39 com metástase hepática. Os casos foram revistos e 13 variáveis anatomopatológicas foram selecionadas para fazer parte do estudo. Foram confecionados manualmente blocos de microarranjos teciduais (TMA) de mucosa normal, tumor primário, metástase linfonodal e metástase hepática, cujos cortes foram submetidos a estudo imuno-histoquímico utilizando anticorpos anti queratina 7 (K7), queratina 20 (K20), Ki-67 e queratina 18 clivada. Em 126 blocos de parafina de tumores, e 86 amostras de mucosa normal correspondentes foram submetidos a estudo imuno-histoquímico utilizando anticopos anti transportadores de monocarboxilato 1, 2 e 4 (MCT1, MCT2 e MCT 4). A presença de metástase linfonodal asociou-se estatisticamente com a presença de infiltração tumoral além da camada muscular própria (T3 ou T4) (p<0,001), presença de desmoplasia tumoral moderada / intensa (p=0,043), presença...

The aims of this study in colorectal carcinoma were: 1) Verify the distribution of the most important anatomopathological variables, and identifying their relationship with lymph node or liver metastasis. 2) Considering the associations obtained in the first aim, a group of variables was selected to verify the prediction of lymph node or liver metastasis. 3) Analyze the immunoprofile of both markers associated with cytoarchitecture (keratins 7 and 20) and with tumor growth (proliferation and apoptosis using Ki-67 and cleaved keratin 18, respectively) in samples of nontumoral mucosa, primary adenocarcinoma, lymph node metastasis and liver metastasis, exploring the eventual relation with anatomopathological variables and tumor stage. 4) Look for possible associations between molecules related to intracellular pH control, as monocarboxylates transporters 1, 2 and 4, and the markers above mentioned and anatomopathological variables. One hundred and thirty nine colorectal carcinomas is the universe of the casuistic, 96 of them without liver metastasis and 39 metastatic to the liver was studied. Thirteen anatomopathological variables were selected and semi-quantified. We mannualy builted tissue microarrays (TMAs) of non tumoral mucosa, primary adenocarcinoma, lymph node metastasis and liver metastasis. The histological sections from the TMAs were submmitted to immunohistochemical study using antibodies against keratin 7 (K7), keratin 20 (K20), Ag Ki-67 and cleaved keratin 18. In 126 tumor paraffin blocks, 86 of which also had non tumoral mucosa were submitted to immunohistochemical stain using antibodies against monocarboxylate transportes 1, 2 and 4 (MCT1, MCT2 e MCT 4). Lymph node metastasis was associated with tumor infiltration across muscularis propria(p<0,001), moderate / intense desmoplasia(p=0,043), lymph vessel infiltration(p<0,001), venous infiltration (p<0,001) and perineural infiltration (p<0,001). Liver metastasis was statistically associated with tumor...

Significant role of poloxamer in drug transport across blood-brain barrier / 药学学报

Poloxamers are found to be an efficient adjuvant with multiple effects and are applied generally in pharmaceutical field. In recent years, it is investigated that poloxamers can increase the permeability of a broad spectrum of drugs through blood-brain barrier (BBB) by means of manifold mechanisms included: (1) inhibiting P-glycoprotein and multidrug-resistance associated protein efflux systems on BBB; (2) adsorbing different apolipoproteins in plasma on the surface of poloxamer-coated nanoparticles, which could interact with BBB through different receptors and mechanisms; (3) connecting to specific ligands and monoclonal antibodies to cross the BBB via specific endogenous transporters localized within the brain capillary endothelium. Significant roles of poloxamer in drug transport across BBB are considered in this review which provides for important guidance to the design of brain-targeted drug delivery system.