Functional association of NR4A3 downregulation with impaired differentiation in myeloid leukemogenesis.

The coincident downregulation of NR4A1 and NR4A3 has been implicated in myeloid leukemogenesis, but it remains unknown how these two genes function in myeloid cells and how their combined downregulation promotes myeloid leukemogenesis. Since NR4A1 abrogation is thought to confer a survival and proliferation advantage to myeloid cells, we hypothesized that downregulation of NR4A3 may have a complementary effect on myeloid cell differentiation. First, we tested the association between differentiation status of leukemic cells and NR4A3 expression using two large clinical datasets from patients with different acute myeloid leukemia (AML) subtypes. The analysis revealed a close association between differentiation status and different subtypes of AML Then, we probed the effects of differentiation-inducing treatments on NR4A3 expression and NR4A3 knockdown on cell differentiation using two myeloid leukemia cell lines. Differentiation-inducing treatments caused upregulation of NR4A3, while NR4A3 knockdown prevented differentiation in both cell lines. The cell culture findings were validated using samples from chronic myeloid leukemia (CML) patients at chronic, accelerated and blastic phases, and in acute promyelocytic leukemia (APL) patients before and after all trans-retinoic acid (ATRA)-based differentiation therapy. Progressive NR4A3 downregulation was coincident with impairments in differentiation in patients during progression to blastic phase of CML, and NR4A3 expression was increased in APL patients treated with ATRA-based differentiating therapy. Together, our findings demonstrate a tight association between impaired differentiation status and NR4A3 downregulation in myeloid leukemias, providing a plausible mechanistic explanation of how myeloid leukemogenesis might occur upon concurrent downregulation of NR4A1 and NR4A3.

Guía de práctica clínica hipotiroidismo en personas de 15 años y más / Hypothyroidism clinical practice guide in people aged 15 years and over

Generar recomendaciones basadas en la mejor evidencia disponible acerca del tamizaje, diagnóstico y tratamiento de personas con sospecha o diagnóstico de hipotiroidismo, como actualización de la Guía de Práctica Clínica Hipotiroidismo 2013. Las recomendaciones se enfocan en hipotiroidismo primario. El hipotiroidismo secundario y terciario no son abordados en esta actualización

Levothyroxine use and the risk of breast cancer: a nation-wide population-based case-control study.

PURPOSE: To investigate whether the use of levothyroxine was associated with breast cancer risk. METHODS: We conducted a population-based case-control study in Taiwan. Cases consisted of all patients who were aged 20 years and older, and had a first-time diagnosis of breast cancer for the period between 2001 and 2011. The controls were matched to the cases by age, sex, year, and month of diagnosis. Adjusted odd ratios (ORs) and 95% confidence intervals (CIs) were estimated by a conditional logistic regression. RESULTS: We examined 65,491 breast cancer cases and 261,964 controls. We found that use of levothyroxine was associated with a significant increase in breast cancer risk (OR 1.24, 95% CI 1.15-1.33; P < 0.001). Compared with no use levothyroxine, the adjusted odd ratio was 1.22 (95% CI 1.11-1.35; P = 0.01) for the group having been prescribed levothyroxine 2 months to 1 year, and 1.26 (95% CI 1.12-1.41; P < 0.01) for the group with more than 1 year. When stratified by age, the adjusted odd ratio was 1.45 (95% CI 1.23-1.71; P < 0.01) for the patients aged 65 years or more and 1.19 (95% CI 1.09-1.29, P < 0.01) for the patients aged less than 65 years. CONCLUSION: The results of the present study are the first to suggest that levothyroxine use increased the risk of breast cancer. However, a larger long-term prospective randomized-controlled trial specifically designed to assess the effect of levothyroxine use on the risk of developing breast cancer is needed.

Effect of adaptive replanning in patients with locally advanced nasopharyngeal carcinoma treated by intensity-modulated radiotherapy: a propensity score matched analysis

Purpose. Limited data have been published regarding the effect of adaptive radiotherapy (ART) on clinical outcome in patients with nasopharyngeal carcinoma (NPC). We compared the long-term outcomes in patients with locally advanced NPC treated by adaptive intensity-modulated radiotherapy (IMRT) replanning versus IMRT. Methods. 200 NPC patients with stage T3/T4 were included between October 2004 and November 2010. Patients in both treatment groups were matched using propensity score matching method at the ratio of 1:1. Clinical outcomes were analyzed with Kaplan-Meier method, log-rank test and Cox regression. Results. After matching, 132 patients (66 patients in each group) were included for analysis. The median follow-up for the IMRT replanning group was 70 months, while the IMRT group was 69 months. The 5-year local-regional recurrence-free survival (LRFS) rate was higher in IMRT replanning group (96.7 vs. 88.1 %, P = 0.022). No significant differences in distant metastasis-free survival (DMFS), progression-free survival (PFS) and overall survival (OS) were observed between the two groups. 21.2 % patients in IMRT replanning group and 28.8 % patients in IMRT group had distant metastasis. In multivariable analysis, IMRT replanning was identified as an independent prognostic factor for LRFS (hazard ratio 0.229; 95 % CI 0.062-0.854; P = 0.028), but not for DMFS, PFS and OS. Conclusions. IMRT replanning provides an improved LRFS for stage T3/T4 NPC patients compared with IMRT. Distant metastasis remains the main pattern of treatment failure. No significant advantage was observed in DMFS, PFS and OS when adaptive replanning was used (AU)

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Thyroid function in the nutritionally obese child and adolescent.

PURPOSE OF REVIEW: In recent years, there has been an increasing focus on thyroid function in obese children. There is controversy concerning whether the changes in the levels of thyroid hormones and thyroid-stimulating hormone (thyrotropin - TSH) in obesity are causes or consequences of weight status and whether these subtle differences merit treatment with thyroxine. This review aimed to study the prevalence of disturbed thyroid hormone and TSH values in childhood obesity and the underlying pathophysiologic mechanisms linking obesity to thyroid function. RECENT FINDINGS: In the past 18 months, four studies demonstrated moderate elevation of TSH concentrations in 10-23% of obese children, which was associated with normal or slightly elevated thyroxine and triiodothyronine values. Two studies reported ultrasonographic hypoechogenicity of the thyroid in obese children with hyperthyrotropinemia, which was not caused by autoimmune thyroiditis; therefore, the authors hypothesized a link to chronic inflammation in obesity. Weight loss led to a normalization of elevated TSH levels in two studies. The adipokine leptin is the most promising link between obesity and hyperthyrotropinemia since leptin stimulates the hypothalamic-pituitary-thyroid. SUMMARY: The elevated TSH levels in obesity seem a consequence rather than a cause of obesity. Therefore, treatment of hyperthyrotropinemia with thyroxine seems unnecessary in obese children.

Thyroid hormone receptor and lipid regulation.

The concept of thyroid hormone (TH) analogs that retain the beneficial effects of TH excess on lipid lowering and fat metabolism, while avoiding any harmful effects on the heart, muscle, bone and other tissues, has interested scientists and physicians for several decades. While there have been many attempts to develop selective TH receptor (TR) modulators (STRMs) for safe lipid lowering, these approaches have failed consistently. This review details recent advances in the development of TRß subtype- and liver-selective STRM analogs, and presents the results of preliminary clinical trials with one of these compounds, eprotirome (KB-2115; Karo Bio AB).

Multiple autoimmune syndrome: Hashimoto's thyroiditis, coeliac disease and systemic lupus erythematosus (SLE).

Various autoimmune diseases have association with each other but it is very rare to see multiple autoimmune diseases in one patient. Presence of more than two autoimmune diseases in one patient is known as multiple autoimmune syndrome (MAS). We report the case of an 11 years old girl who presented with history of swelling in front of the neck along with constipation, anorexia, weight gain and increasing pallor over a period of six months. Additionally she had an episodic history of joint pains and abdominal pain with no specific relation to diet, time, other gastrointestinal or genitourinary symptom. Hypothyroid goiter (Autoimmune thyroiditis, Hashimoto's thyroidits) was diagnosed by raised thyroid stimulating hormone (TSH), low T4 and presence of thyroid specific antibodies in blood. Patient was discharged on tablet Levothyroxine to which she responded well with reduction in size of the swelling and relief of the symptoms except for the joint pains and abdominal pain. To evaluate the persistent symptoms she was investigated further for other autoimmune diseases and was diagnosed to be having systemic lupus erythematosus (SLE) and Coeliac disease also. The final diagnosis was multiple autoimmune syndrome (Hashimoto's thyroiditis, Coeliac disease and SLE).

Prospective study of the impact of thyroid hormone replacement on objective voice parameters.

OBJECTIVES: Hypothyroidism has long been considered to have an impact on phonation. In this study, objective evaluation of vocal function in women with hypothyroidism was performed in order to characterize potential dysphonia; their subsequent response to thyroid hormone replacement was prospectively studied. It was hypothesized that thyroid hormone replacement therapy in this cohort would have an objectively measurable impact on vocal function. METHODS: Prospectiv evaluation of objective voice parameters and concurrent determination of serum thyroid status was executed both before and after thyroid hormone replacement in a cohort of patients who had had total thyroidectomy. Objective voice parameters before and after treatment were compared. RESULTS: Twenty-four female subjects were recruited over an 18-month period. After surgery, all subjects were hypothyroid (mean thyroid-stimulating hormone level, 81.38 mIU/L; range, 25.26 to 100.00 mIU/L) before replacement. After hormone therapy, their mean thyroid-stimulating hormone level dropped to 1.20 mIU/L (range, 0.28 to 3.83 mIU/L). The mean fundamental frequency significantly increased from a pretreatment average of 223.48 +/- 36.10 Hz to 237.64 +/- 38.81 Hz. Other measured voice parameters (jitter, shimmer, amplitude perturbation quotient, pitch perturbation quotient, noise-to-harmonics ratio, and maximum phonation time) were not affected. CONCLUSIONS: Thyroid hormone replacement therapy following total thyroidectomy has a measurable impact on mean fundamental frequency in female patients. The mechanism of this effect is not known.

Importancia de mantener una suficiente concentración sérica de T4 materna en el primer trimestre del embarazo / Importance of ensuring sufficient maternal T4 levels in the first trimester of pregnancy

El feto impone al sistema endocrino materno unas condiciones de gran valor para su propio desarrollo óptimo, y quedan temporalmente sobreseídos mecanismos endocrinos habituales. La transferencia maternofetal de T4 representa una contribución importante a la economía tiroidea fetal, necesaria para un buen desarrollo del sistema nervioso central del feto, desde comienzos del embarazo hasta el nacimiento, en especial en la primera mitad, antes de que aparezca una significativa función tiroidea fetal propia. A estos efectos, es imprescindible contar con la integridad de la capacidad funcional tiroidea y sus mecanismos de regulación y disponer de adecuados almacenes de yodo. Estudios epidemiológicos y experimentales han puesto claramente en evidencia que la hipotiroxinemia materna en el primer trimestre de embarazo implica un incremento del riesgo para un pobre desarrollo neuropsicológico de los hijos (AU)

The maternal endocrine system is essential for optimal fetal development, and normal endocrine mechanisms are temporarily supplanted during pregnancy. Transplacental transfer of thyroid hormone plays a crucial role in fetal neurodevelopment throughout ontogeny, especially before mid-gestation when fetal thyroid synthesis becomes significant. Thus, normal maternal thyroid hormone function is essential, ensuring adequate thyroid hormone and iodine levels throughout pregnancy. Epidemiological and experimental studies have robustly shown that maternal hypothyroxinemiain the first trimester of pregnancy increases the risk for adverse neurodevelopment land neuropsychological outcomes in offspring (AU)

Resistencia a hormonas tiroideas / Thyroid hormone resistance

La resistencia a las hormonas tiroideas es un síndrome genético poco frecuente (uno por 50.000 nacidos vivos), causado por mutaciones en el gen del receptor de hormonas tiroideas y de herencia generalmente autosómica dominante. El receptor mutado, mediante un mecanismo de inhibición dominante, impide la unión de la triyodotironina a su receptor y da lugar a una menor respuesta tisular a la acción de las hormonas tiroideas. Aunque clásicamente se ha dividido a los pacientes en resistencia generalizada y resistencia hipofisaria, hoy se sabe que esta clasificación es más académica que real. La clínica es muy variable y, en muchas ocasiones, los pacientes están asintomáticos, pero es frecuente encontrar bocio, taquicardia, síndrome de hiperactividad-falta de atención, retraso de la edad ósea, etc. Analíticamente, se caracteriza por concentraciones elevadas de tiroxina y triyodotironina libres, junto con concentraciones de tirotropina no suprimidas, y se mantiene la respuesta de esta hormona al estímulo con hormona liberadora de tirotropina. Es preciso realizar el diagnóstico diferencial con otros procesos, pero fundamentalmente con el tumor hipofisario productor de tirotropina. El diagnóstico definitivo se basa en el estudio genético, que fundamentalmente demuestra mutaciones en los exones 7 a 10 del gen del receptor de hormonas tiroideas. El tratamiento depende de la clínica predominante y, por ello, la actitud terapéutica puede ir desde la no intervención (pacientes asintomáticos) hasta la necesidad de utilizar hormonas tiroideas a dosis altas (pacientes hipotiroideos) o de fármacos que disminuyen la acción de las hormonas tiroideas (pacientes hipertiroideos) (AU)