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.

Effects of sodium iodide symporter co-expression on proliferation and cytotoxic activity of chimeric antigen receptor T cells in vitro / 南方医科大学学报

OBJECTIVE@#To investigate the effects of co-expression of sodium iodide symporter (NIS) reporter gene on the proliferation and cytotoxic activity of chimeric antigen receptor (CAR)-T cells in vitro.@*METHODS@#T cells expressing CD19 CAR (CAR-T cells), NIS reporter gene (NIS-T cells), and both (NIS-CAR-T cells) were prepared by lentiviral infection. The transfection rates of NIS and CAR were determined by flow cytometry, and the cell proliferation rate was assessed using CCK-8 assay at 24, 48 and 72 h of routine cell culture. The T cells were co-cultured with Nalm6 tumor cells at the effector-target ratios of 1∶2, 1∶1, 2∶1 and 4∶1 for 24, 48 and 72 h, and the cytotoxicity of CAR-T cells to the tumor cells was evaluated using lactate dehydrogenase (LDH) assay. ELISA was used to detect the release of IFN-γ and TNF-β in the co-culture supernatant, and the function of NIS was detected with iodine uptake test.@*RESULTS@#The CAR transfection rate was 91.91% in CAR-T cells and 99.41% in NIS-CAR-T cells; the NIS transfection rate was 47.83% in NIS-T cells and 50.24% in NIS- CAR-T cells. No significant difference in the proliferation rate was observed between CAR-T and NIS-CAR-T cells cultured for 24, 48 or 72 h (P> 0.05). In the co-cultures with different effector-target ratios, the tumor cell killing rate was significantly higher in CAR-T group than in NIS-CAR-T group at 24 h (P < 0.05), but no significant difference was observed between the two groups at 48 h or 72 h (P>0.05). Higher IFN-γ and TNF-β release levels were detected in both CAR-T and NIS-CAR-T groups than in the control group (P < 0.05). NIS-T cells and NIS-CAR-T cells showed similar capacity of specific iodine uptake (P>0.05), which was significantly higher than that in the control T cells (P < 0.05).@*CONCLUSION@#The co-expression of the NIS reporter gene does not affect CAR expression, proliferation or tumor cell-killing ability of CAR-T cells.

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

Na-K-2Cl symporter contributes to γ-aminobutyric acid-evoked excitation in rat enteric neurons / 生理学报

Gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter in the adult central nervous system (CNS), however, it causes excitation in the immature CNS neurons. The shift from GABA-induced depolarization to hyperpolarization in postnatal brain is primarily due to progressive decrease in the expression of the Na-K-2Cl symporter 1 (NKCC1) and increased expression of the K-Cl cotransporter 2 (KCC2). Unlike CNS neurons, both immature and mature neurons in the enteric nervous system (ENS) are depolarized by GABA. Molecular mechanisms by which GABA excites ENS neurons are unclear. It is understood, however, that the excitatory action depends on elevated intraneuronal Cl. We aimed to test a hypothesis that high intracellular Cl in ENS neurons is maintained by activity of the NKCCs. We found that NKCC2 immunoreactivity (IR) was expressed in the ENS of the rat colon on postnatal day 1 (P1). The expression level of NKCC2 continuously increased and reached a steady high level on P14 and maintained at that level in adulthood. NKCC1 IR appeared in ENS on P14 and maintained through adulthood. KCC2 IR was not detectable in the ENS in any of the developmental stages. Both NKCC1 IR and NKCC2 IR were co-expressed with GABA receptors in ENS neurons. Exogenous GABA (1 mmol/L) caused membrane depolarization in the ENS neurons. The reversal potential of GABA-induced depolarization was about -16 mV. Blockade of NKCC by bumetanide (50 μmol/L) or furosemide (300 μmol/L) suppressed the depolarizing responses to GABA. Bumetanide (50 μmol/L) shifted the reversal potential of GABA-induced depolarization in the hyperpolarizing direction. Neither the KCC blocker DIOA (20 μmol/L) nor the Cl/HCO exchanger inhibitor DIDS (200 μmol/L) suppressed GABA-evoked depolarization. The results suggest that ENS neurons continuously express NKCC2 since P1 and NKCC1 since P14, which contribute to the accumulation of Cl in ENS neurons and GABA-evoked depolarization in neonate and adult ENS neurons. These results provide the first direct evidence for the contribution of both NKCC2 and NKCC1 to the GABA-mediated depolarization.

Clinical and genetic analysis of a pediatric patient with sodium taurocholate cotransporting polypeptide deficiency / 中国当代儿科杂志

Sodium taurocholate cotransporting polypeptide (NTCP) deficiency is an inborn error of bile acid metabolism caused by mutations of SLC10A1 gene. This paper reports the clinical and genetic features of a patient with this disease. A 3.3-month-old male infant was referred to the hospital with the complaint of jaundiced skin and sclera over 3 months. Physical examination revealed moderate jaundice of the skin and sclera. The liver was palpable 3.5 cm below the right subcostal margin with a medium texture. Serum biochemistry analysis revealed markedly elevated bilirubin (predominantly direct bilirubin) and total bile acids (TBA), as well as decreased 25-OH-VitD level. On pathological analysis of the biopsied liver tissue, hepatocyte ballooning and cholestatic multinucleate giant cells were noted. The lobular architecture was distorted. Infiltration of inflammatory cells, predominantly lymphocytes, was seen in the portal tracts. In response to the anti-inflammatory and liver protective drugs as well as fat-soluble vitamins over 2 months, the bilirubin and transaminases levels were improved markedly while the TBA kept elevated. Because of persisting hypercholanemia on the follow-up, SLC10A1 gene analysis was performed at his age of 17.2 months. The child proved to be a homozygote of the reportedly pathogenic variant c.800C>T (p. Ser267Phe), while the parents were both carriers. NTCP deficiency was thus diagnosed. The infant was followed up until 34.3 months old. He developed well in terms of the anthropometric indices and neurobehavioral milestones. The jaundice disappeared completely. The liver size, texture and function indices all recovered. However, the hypercholanemia persisted, and the long-term outcome needs to be observed.

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.

Sodium taurocholate cotransporting polypeptide deficiency manifesting as cholestatic jaundice in early infancy: a complicated case study / 中国当代儿科杂志

Sodium taurocholate cotransporting polypeptide (NTCP) deficiency is caused by SLC10A1 mutations impairing the NTCP function to uptake plasma bile salts into the hepatocyte. Thus far, patients with NTCP deficiency were rarely reported. The patient in this paper was a 5-month-19-day male infant with the complaint of jaundiced skin and sclera for 5.5 months as well as abnormal liver function revealed over 4 months. His jaundice was noticed on the second day after birth, and remained visible till his age of 1 month and 13 days, when a liver function test unveiled markedly elevated total, direct and indirect bilirubin as well as total bile acids (TBA). Cholestatic liver disease was thus diagnosed. Due to unsatisfactory response to medical treatment, the patient underwent exploratory laparotomy, cholecystostomy and cholangiography when aged 2 months. This revealed inspissated bile but unobstructed bile ducts. Thereafter, his jaundice subsided, but the aminotransferases and TBA levels gradually rose. Of note, his mother also had mildly elevated plasma TBA. Since the etiology was unclear, no specific medication was introduced. The infant has been followed up over 2 years. The aminotransferases recovered gradually, but TBA levels fluctuated within 23.3-277.7 μmol/L (reference range: 0-10 μmol/L). On SLC10A1 genetic analysis at 2 years and 9 months, both the infant and his mother proved to be homozygous for a pathogenic variant c.800C>T(p.S267F), and NTCP deficiency was thus definitely diagnosed. The findings suggest that, although only mildly increased plasma TBA is presented in adults with NTCP deficiency, pediatric patients with this disorder exhibit persistent and remarkable hypercholanemia, and some patients might manifest as cholestatic jaundice in early infancy.

Screening and verifying potential NTCP inhibitors from herbal medicinal ingredients using the LLC-PK1 cell model stably expressing human NTCP / 中国天然药物

NTCP is specifically expressed on the basolateral membrane of hepatocytes, participating in the enterohepatic circulation of bile salts, especially conjugated bile salts, to maintain bile salts homeostasis. In addition, recent studies have found that NTCP is a functional receptor of HBV and HDV. Therefore, it is important to study the interaction between drugs and NTCP and identify the inhibitors/substrates of NTCP. In the present study, a LLC-PK1 cell model stably expressing human NTCP was established, which was simple and suitable for high throughput screening, and utilized to screen and verify the potential inhibitors of NTCP from 102 herbal medicinal ingredients. The results showed that ginkgolic acid (GA) (13 : 0), GA (15 : 1), GA (17 : 1), erythrosine B, silibinin, and emodin have inhibitory effects on NTCP uptake of TCNa in a concentration-dependent manner. Among them, GA (13 : 0) and GA (15 : 1) exhibited the stronger inhibitory effects, with IC50 values being less than 8.3 and 13.5 μmol·L(-1), respectively, than the classical inhibitor, cyclosporin A (CsA) (IC50 = 20.33 μmol·L(-1)). Further research demonstrated that GA (13 : 0), GA (15 : 1), GA (17 : 1), silibinin, and emodin were not substrates of NTCP. These findings might contribute to a better understanding of the disposition of the herbal ingredients in vivo, especially in biliary excretion.

New perspectives of biomarkers for the management of chronic hepatitis B

With recent advances in molecular and genomic investigations, the impact of hepatitis B viral and host factors on the progression of chronic HBV infection has been explored. For viral factors, hepatitis B viral load is a strong predictor for liver disease progression. Hepatitis B viral kinetics appear to be important for successful anti-viral therapy. Serum HBsAg level serves as a complementary marker to viral load for the prediction of HBV-related adverse outcomes in patients with low viral load. In those with low viral load, high serum HBsAg level is associated with higher risks of cirrhosis and HCC. Hepatitis B core-related antigen (HBcrAg) induces host immune responses, and the reduction of the HBcrAg level as well as the increment of total anti-HBc level are significantly associated with favorable outcomes. HBV genotypes (genotype C/D) and mutants (basal core promoter and deletion mutation in pre-S genes) are well known viral genetic markers to predict disease progression. For host factors, serum inflammatory biomarkers have been developed to evaluate the HBV-associated hepatic necroinflammation and fibrosis. Host single nucleotide polymorphism on sodium taurocholate cotransporting polypeptide (NTCP, an HBV entry receptor) may be associated with a decreased risk for cirrhosis and HCC. In conclusion, patients with chronic hepatitis B should be evaluated with relevant viral and host markers to identify those who are at a higher risk of liver disease progression and then receive timely antiviral therapy.

Effects of BRAF(V600E) mutation on Na(+)/I(-) symporter expression in papillary thyroid carcinoma / 华中科技大学学报（医学）（英德文版）

Radioiodine ablation (RIA) therapy is one of the most important treatments for papillary thyroid carcinoma (PTC), but some patients who received (131)I have radioiodine-refractory disease caused by the decreased expression of the Na(+)/I(-) symporter (NIS). BRAF(V600E) mutation is one possible risk factor that can disturb the NIS expression, but the roles are unclear in clinical practice. This research discussed the association of BRAF(V600E) mutation and NIS expression in PTC tissue and the clinical implications in RIA therapy. 134 PTC samples were collected between June 2013 and June 2014 from Tongji Hospital affiliated to Tongji Medical College, and their clinical characteristics were analyzed. RT-PCR was used to detect the BRAF(V600E) mutation from formalin-fixed paraffin-embedded samples, and immunohistochemistry was applied to detect the NIS expression. IPP software was used to calculate the relative expression quantity of NIS. We found that there was no significant correlation between the absorbance (A) values of NIS and clinicopathologic features in these cases, even thyroid stimulating hormone. BRAF(V600E) mutation showed inhibitory effect on the NIS expression without statistically significant difference in all PTC cases (β=-0.0195, P=0.085), but in the subgroup without hashimoto's thyroiditis (HT), BRAF(V600E) mutation could significantly inhibit the NIS expression (β=-0.0257, P=0.046). The results indicate that BRAF(V600E) mutation is correlated with a lower expression of NIS in PTCs without HT, suggesting the radioiodine-refractory effects during RIA therapy in these patients.

Total clipless cholecystectomy by means of harmonic sealing / Colecistectomia laparoscópica totalmente ultrassônica sem uso de clipe metálico

BACKGROUND: In traditional laparoscopic cholecistectomy, the cystic duct and artery are commonly closed by metallic clips just before their division. Although the placement of these clips for occluding cystic artery and duct can be considered safe, biliary leaks and bleeding may occur especially by its dislodgement. AIM: To report a prospective case-series in total clipless cholecystectomy by means of harmonic shears for closure and division of the artery and cystic duct as well removal of the gallbladder from the liver. METHODS: Was evaluate a series of 125 patients who underwent laparoscopic cholecystectomy where the sealing and division of cystic artery and duct was carried out only by harmonic shears. The intact extracted gallbladder was submitted to a reverse pressure test for assessment of the technique safety by means of CO2 insuflation. RESULTS: The most common indication for surgery was gallstones. The mean operative time was 26 min and all gallbladders were dissected intact from the liver bed. There was no mortality and the overall morbidity rate was 0.8% with no hemorrhage or leaks. The reverse pressure test showed that all specimens support at least 36-mmHg of pressure without leaking. CONCLUSION: The harmonic shears is effective and safe in laparoscopic cholecystectomy as a sole instrument for sealing and division of the artery and cystic duct. The main advantages could be related to the safety and decreased operative time. .

RACIONAL: A colecistectomia laparoscópica na técnica tradicional oclui o ducto cístico e a artéria cística por clipes cirúrgicos, que podem se deslocar ou desprender no pós-operatório, possibilitando a ocorrência de fístula biliar ou hemorragia. OBJETIVO: Relato prospectivo de série de casos de colecistectomias laparoscópicas sem uso de clipe cirúrgico, sendo que a ligadura e secção da artéria cística e do ducto cístico foram realizadas por meio de bisturi ultrassônico. MÉTODO: Foram incluídos 125 pacientes submetidos à colecistectomia laparoscópica sem utilização de clipe cirúrgico metálico, onde a ligadura da artéria e do ducto cístico e também a remoção da vesícula biliar de seu leito hepático foram realizadas por meio de tesoura ultrassônica. Realizou-se teste de pressão reversa na vesícula biliar removida intacta do leito hepático para verificar a segurança da técnica. RESULTADOS: A principal indicação cirúrgica foi a colelitíase. O tempo cirúrgico médio foi de 26 min e todas as vesículas biliares foram retiradas intactas do leito hepático. Não houve mortalidade e a taxa global de morbidade foi de 0,8%, sem hemorragias ou fístulas. O teste de pressão reversa mostrou que o ducto cístico ocluído pelo bisturi harmônico suportou ao pelo menos 36 mmHg de pressão sem que ocorresse nenhum vazamento. CONCLUSÃO: O bisturi harmônico é eficaz e seguro em colecistectomias laparoscópicas eletivas como um instrumento único para ocluir e seccionar tanto a artéria cística quanto o ducto cístico. Vantagens podem ser apontadas ao método com relação a sua segurança e diminuição do tempo cirúrgico. .

From DCPD to NTCP: The long journey towards identifying a functional hepatitis B virus receptor

Hepatitis B virus (HBV) is the prototype of hepatotropic DNA viruses (hepadnaviruses) infecting a wide range of human and non-human hosts. Previous studies with duck hepatitis B virus (DHBV) identified duck carboxypeptidase D (dCPD) as a host specific binding partner for full-length large envelope protein, and p120 as a binding partner for several truncated versions of the large envelope protein. p120 is the P protein of duck glycine decarboxylase (dGLDC) with restricted expression in DHBV infectible tissues. Several lines of evidence suggest the importance of dCPD, and especially p120, in productive DHBV infection, although neither dCPD nor p120 cDNA could confer susceptibility to DHBV infection in any cell line. Recently, sodium taurocholate cotransporting polypeptide (NTCP) has been identified as a binding partner for the N-terminus of HBV large envelope protein. Importantly, knock down and reconstitution experiments unequivocally demonstrated that NTCP is both necessary and sufficient for in vitro infection by HBV and hepatitis delta virus (HDV), an RNA virus using HBV envelope proteins for its transmission. What remains unclear is whether NTCP is the major HBV receptor in vivo. The fact that some HBV patients are homozygous with an NTCP mutation known to abolish its receptor function suggests the existence of NTCP-independent pathways of HBV entry. Also, NTCP very likely mediates just one step of the HBV entry process, with additional co-factors for productive HBV infection still to be discovered. NTCP offers a novel therapeutic target for the control of chronic HBV infection.

Mutation screening of the sodium iodide symporter gene in a cohort of 105 China patients with congenital hypothyroidism / Análise de mutações no gene simportador sódio/iodeto em coorte de 105 pacientes chineses com hipotireoidismo congênito

Objective Dyshormonogenetic congenital hypothyroidism (CH) was reported to be associated with a mutation in the sodium iodide symporter (NIS) gene. The present study was undertaken in the Guangxi Zhuang Autonomous Region of China, to determine the nature and frequency of NIS gene mutations among patients with CH due to dyshormonogenesis. Subjects and methods: Blood samples were collected from 105 dyshormonogenetic CH patients in Guangxi Zhuang Autonomous Region, China, and genomic DNA was extracted from peripheral blood leukocytes. All exons of the NIS gene together with their exon-intron boundaries were screened by next-generation sequencing. Results Two silent variations (T221T and T557T) and one missense variation (M435L), as well as two polymorphisms (rs200587561 and rs117626343) were found. Conclusions Our results indicate that the NIS mutation rate is very low in the Guangxi Zhuang Autonomous Region, China, and it is necessary to study mutations of other genes that have major effects on thyroid dyshormonogenesis and have not as yet been studied in this population. .

Objetivo O hipotireoidismo congênito disormonogenético (CH) foi relatado como associado a uma mutação no gene simportador sódio/iodeto (NIS). O presente estudo foi feito na região autônoma de Guangxi Zhuang na China para se determinar a natureza e a frequência das mutações no gene NIS entre pacientes com CH causado por disormonogênese. Sujeitos e métodos: Amostras de sangue foram coletadas de 105 pacientes com CH disormonogenéticos e o DNA genômico foi extraído de leucócitos do sangue periférico. Todos os éxons do gene NIS, junto com seus limites éxon-íntron, foram analisados por sequenciamento de nova geração. Resultados Foram encontradas duas variações silenciosas (T221T e T557T) e uma variação missense (M435L), assim como dois polimorfismos (rs200587561 e rs117626343). Conclusões Nossos resultados indicam que a taxa de mutação em NIS é muito baixa na região de Guangxi Zhuang. É necessário estudar mutações de outros genes que tenham efeitos maiores na disormonogênese da tiroide e que ainda não tenham sido estudados nesta população. .

B-RafV600E inhibits sodium iodide symporter expression via regulation of DNA methyltransferase 1

B-RafV600E mutant is found in 40-70% of papillary thyroid carcinoma (PTC) and has an important role in the pathogenesis of PTC. The sodium iodide symporter (NIS) is an integral plasma membrane glycoprotein that mediates active iodide transport into the thyroid follicular cells, and B-RafV600E has been known to be associated with the loss of NIS expression. In this study, we found that B-RafV600E inhibited NIS expression by the upregulation of its promoter methylation, and that specific regions of CpG islands of NIS promoter in B-RafV600E harboring PTC were highly methylated compared with surrounding normal tissue. Although DNA methyltransferase 3a and 3b (DNMT3a,3b) were not increased by B-RafV600E, DNMT1 expression was markedly upregulated in PTC and B-RafV600E expressing thyrocytes. Furthermore, DNMT1 expression was upregulated by B-RafV600E induced NF-kappaB activation. These results led us to conclude that NIS promoter methylation, which was induced by B-RafV600E, is one of the possible mechanisms involved in NIS downregulation in PTC.

Lesionalized Therapy beyond Personalized Therapy in Cancer Management

No abstract available.

RAI Treatment of Distant Metastasis of Thyroid Cancer / 대한갑상선학회지

For the distant metastasis of differentiated thyroid cancers, such as papillary thyroid carcinoma, follicular thyroid carcinoma, and Hurthle cell carcinoma, radioiodine therapy is one of the standard treatment methods after total thyroidectomy. Radioiodine is accumulated in thyroid cells and thyroid cancer cells through sodium iodide symporter which is located in the membrane of cells. This molecular target specific therapy renders a better prognosis and less adverse effects. Radioiodine 131I emits gamma ray for imaging and beta ray for treatment at the same time, we can monitor patients' specific distribution of radioiodine, which let us know unexpected metastasis lesions or differentiated status of thyroid cancer cells. In this article, I reviewed practical points of view about radioiodine therapy for distant metastasis of thyroid cancers such as methods for administration of radioiodine, patients' preparation before radioiodine treatment, follow up of patients, adverse effects, and radiation safety issues.

Diagnostic and Therapeutic Approaches to Radioactive Iodine Refractory Differentiated Thyroid Cancer / 대한이비인후과학회지

Unlike most thyroid cancers which have an excellent prognosis with standard treatments such as surgery and additional radioactive iodine therapy followed by long term TSH suppression, 15-20% of differentiated thyroid cancers are unresponsive, showing locally aggressive behavior or distant metastasis. It has been reported that the ability of iodine uptake among residual follicular cells is usually impaired in such unresponsive cases. As the general incidence of thyroid cancer increases, the number of this radioactive iodine refractory disease is also increasing. This becomes clinically challenging because iodine-based diagnostic and therapeutic approaches are not applicable anymore. Moreover, other conventional modalities including radiotherapy or cytotoxic chemotherapy is neither effective in this subset of thyroid cancer. So many researches are currently under way to find effective molecular targeted therapies, which will play a role in the treatment of these unresectable and advanced cases. This review discusses the recent research progress regarding the iodine avidity of follicular cells in thyroid cancer, and outcomes of clinical studies using targeted agents.

Changes in expression levels of PV, GAD67 and KCC2 in the brain tissue of rats with schizophrenia induced by MK-801 / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To study changes in the expression levels of parvalbumin (PV), glutamate decarboxylase 67 (GAD67) and K+-Cl- cotransporter 2 (KCC2) in the brain tissue of rats with schizophrenia (SZ) induced by dizocilpine (MK-801), and to investigate the mechanism involving gamma-aminobutyric acid (GABA) by which NMDA receptor blocker induces SZ in the perinatal period.</p><p><b>METHODS</b>Thirty-six neonatal male Sprague-Dawley rats were randomly assigned to two batches on postnatal day 6. Each batch was divided into normal control (treated by 0.9% normal saline), SZ-development model (treated by subcutaneous injection of 0.1 mg/kg MK-801 on postnatal days 7-10; bid), and SZ-chronic medication model groups (treated by intraperitoneal injection of 0.2 mg/kg MK-801 on postnatal days 47-60; qd). On postnatal day 63, the brain tissue of the first batch of rats was obtained and then fixed with paraform for histological sections; expression levels of PV and GAD67 in the medial prefrontal cortex (mPFC) and hippocampus CA1 were measured by immunohistochemistry. Simultaneously, the second batch of rats was sacrificed and the mPFC and hippocampus were obtained and homogenized; expression levels of KCC2 in the mPFC and hippocampus were measured by Western blot.</p><p><b>RESULTS</b>Expression levels of PV and GAD67 in the mPFC and hippocampus CA1 were significantly lower in the SZ-development and chronic medication model groups than in the normal control group (P<0.05). Expression levels of KCC2 in the mPFC and hippocampus were significantly lower in the SZ-development model group than in the SZ-chronic medication model and normal control groups (P<0.05).</p><p><b>CONCLUSIONS</b>The expression changes of PV and GAD67 in SZ can be simulated using the SZ development model induced by MK-801, which might affect the development of the GABA system in the PFC and hippocampus by downregulating KCC2 expression.</p>

Decreased Immunoreactivities of the Chloride Transporters, KCC2 and NKCC1, in the Lateral Superior Olive Neurons of Kanamycin-treated Rats

OBJECTIVES: From our previous study about the weak expressions of potassium-chloride (KCC2) and sodium-potassium-2 chloride (NKCC1) co-transporters in the lateral superior olive (LSO) in circling mice, we hypothesized that partially damaged cochlea of circling mice might be a cause of the weak expressions of KCC2 or NKCC1. To test this possibility, we reproduced the altered expressions of KCC2 and NKCC1 in the LSO of rats, whose cochleae were partially destroyed with kanamycin. METHODS: Rat pups were treated with kanamycin from postnatal (P)3 to P8 (700 mg/kg, subcutaneous injection, twice a day) and sacrificed for immunohistochemical analysis, scanning electron microscope (SEM) and auditory brain stem response. RESULTS: The SEM study revealed partially missing hair cells in P9 rats treated with kanamycin, and the hearing threshold was elevated to 63.8+/-2.5 dB SPL (4 ears) at P16. Both KCC2 and NKCC1 immunoreactivities were more prominent in control rats on P16. On 9 paired slices, the mean densities of NKCC1 immunoreactivities were 118.0+/-1.0 (control) and 112.2+/-1.2 (kanamycin treated), whereas those of KCC2 were 115.7+/-1.5 (control) and 112.0+/-0.8 (kanamycin treated). CONCLUSION: We concluded that weak expressions of KCC2 and NKCC1 in circling mice were due to partial destruction of cochleae.