4-Methylthioamphetamine increases dopamine in the rat striatum and has rewarding effects in vivo.

4-Methylthioamphetamine (MTA) is a phenylisopropylamine derivative whose use has been associated with severe intoxications. MTA is usually regarded as a selective serotonin-releasing agent. Nevertheless, previous data have suggested that its mechanism of action probably involves a catecholaminergic component. As little is known about dopaminergic effects of this drug, in this work the actions of MTA upon the dopamine (DA) transporter (DAT) were studied in vitro, in vivo and in silico. Also, the possible abuse liability of MTA was behaviourally assessed. MTA exhibited an in vitro affinity for the rat DAT in the low micromolar range (6.01 µM) and induced a significant, dose-dependent increase in striatal DA. MTA significantly increased c-Fos-positive cells in striatum and nucleus accumbens, induced conditioned place preference and increased locomotor activity. Docking experiments were performed in a homology model of the DAT. In conclusion, our results show that MTA is able to increase extracellular striatal DA levels and that its administration has rewarding properties. These effects were observed at concentrations or doses that can be relevant to its use in human beings.

The REGICOR-calibrated function provides a better classification of high-risk patients on statin treatment in the Spanish population than the Framingham or SCORE classifications.

INTRODUCTION AND OBJECTIVES: To determine which cardiovascular risk function is best for classifying high-risk individuals on statins. METHODS: Descriptive cross-sectional study of 804 randomly selected patients aged 35-74 years. Variables studied included statin treatment, high cardiovascular risk according to Framingham-REGICOR (10-year risk >or=10%), Framingham-Wilson (10-year risk >or=20%) and SCORE (10-year risk >or=5%) functions, age, sex, cardiovascular risk factors, and total and high-density lipoprotein (HDL) cholesterol. RESULTS: Overall, 83 patients (10.3%) were taking statins. The prevalence of hypercholesterolemia was 25.6%. When high-risk patients were compared with low- and medium-risk patients, the SCORE function only found a significant difference in HDL-cholesterol level (difference, 5.1 mg/dl; P< .001), whereas the Framingham-REGICOR and Framingham-Wilson functions showed that hypercholesterolemia was more prevalent (at 41% and 37.8%, respectively), the total cholesterol level was higher (difference, 15 mg/dl and 12.5 mg/dl, respectively), and the HDL-cholesterol level was lower (difference, 11.9 mg/ dl and 12 mg/dl, respectively; all P< .001). The percentage of patients on statins classified as high-risk by each function was 16% for Framingham-REGICOR (odds ratio [OR]=1.81; 95% confidence interval [CI], 1.01-3.27), 13.4% for Framingham-Wilson (OR=1.47; 95% CI, 0.87-2.47) and 10.6% for SCORE (OR=1.09; 95% CI, 0.50-2.37). Statin use was also significantly associated with hypertension (OR=1.89; 95% CI, 1.20-2.99) and hypercholesterolemia (OR=11.01; 95% CI, 6.55-18.53), and inversely associated with age in patients <65 years (OR=0.51; 95% CI, 0.32-0.81). CONCLUSIONS: The Framingham-REGICOR function was better at classifying high-risk patients on statins than the Framingham-Wilson or SCORE functions. Statin use was associated with hypercholesterolemia and hypertension and inversely with age in patients <65 years.

La función calibrada REGICOR mejora la clasificación de los pacientes de alto riesgo tratados con estatinas respecto a Framingham y SCORE en la población española / The REGICOR-calibrated function provides a better classification of high-risk patients on statin treatment in the Spanish population than the Framingham or SCORE classifications

Introducción y objetivos. Estudiar qué función de riesgo cardiovascular clasifica mejor a los pacientes con riesgo cardiovascular alto que toman estatinas. Métodos. Estudio descriptivo transversal que incluye a 804 pacientes de 35-74 años, seleccionados aleatoriamente. Se estudiaron las variables tratamiento con estatinas, riesgo cardiovascular alto con las ecuaciones de Framingham-REGICOR (≥ 10% a 10 años), Framingham-Wilson (≥ 20% a 10 años) y SCORE (≥ 5% a 10 años), edad, sexo, colesterol total, colesterol de las lipoproteínas de alta densidad (cHDL) y factores de riesgo cardiovascular. Resultados. Tomaban estatinas 83 (10,3%) pacientes. La prevalencia de hipercolesterolemia fue del 25,6%. Comparando a los pacientes de bajo y medio riesgo con los de alto riesgo, SCORE sólo halló diferencias significativas en el cHDL más bajo (diferencia: 5,1 mg/dl; p < 0,001), mientras que Framingham-REGICOR y Framingham-Wilson mostraron (p < 0,001) mayor prevalencia de hipercolesterolemia (el 41 y el 37,8% respectivamente), colesterol total más elevado (diferencia, 15 y 12,5 mg/dl respectivamente) y cHDL más bajo (diferencia, 11,9 y 12 mg/dl respectivamente). Tomaba estatinas el 16% de pacientes de alto riesgo con Framingham-REGICOR (odds ratio [OR] = 1,81; intervalo de confianza [IC] del 95%, 1,01-3,27), el 13,4% con Framingham-Wilson (OR = 1,47; IC del 95%, 0,87-2,47) y el 10,6% con SCORE (OR = 1,09; IC del 95%, 0,50-2,37). Se asociaron significativamente al uso de estatinas la hipertensión (OR = 1,89; IC del 95%, 1,20-2,99) y la hipercolesterolemia (OR = 11,01; IC del 95%, 6,55-18,53), con una relación inversa con la edad < 65 años (OR = 0,51; IC del 95%, 0,32-0,81). Conclusiones. La función Framingham-REGICOR clasifica mejor que Framingham-Wilson y SCORE a los pacientes de riesgo alto que reciben tratamiento con estatinas. La prescripción se asoció al diagnóstico de hipercolesterolemia y HTA y fue menor en pacientes < 65 años (AU)

Introduction and objectives. To determine which cardiovascular risk function is best for classifying high-risk individuals on statins. Methods. Descriptive cross-sectional study of 804 randomly selected patients aged 35-74 years. Variables studied included statin treatment, high cardiovascular risk according to Framingham-REGICOR (10-year risk ≥10%), Framingham-Wilson (10-year risk ≥20%) and SCORE (10-year risk ≥5%) functions, age, sex, cardiovascular risk factors, and total and high-density lipoprotein (HDL) cholesterol. Results. Overall, 83 patients (10.3%) were taking statins. The prevalence of hypercholesterolemia was 25.6%. When high-risk patients were compared with low- and medium-risk patients, the SCORE function only found a significant difference in HDL-cholesterol level (difference, 5.1 mg/dl; P < .001), whereas the Framingham-REGICOR and Framingham-Wilson functions showed that hypercholesterolemia was more prevalent (at 41% and 37.8%, respectively), the total cholesterol level was higher (difference, 15 mg/dl and 12.5 mg/dl, respectively), and the HDL-cholesterol level was lower (difference, 11.9 mg/ dl and 12 mg/dl, respectively; all P < .001). The percentage of patients on statins classified as high-risk by each function was 16% for Framingham-REGICOR (odds ratio [OR]=1.81; 95% confidence interval [CI], 1.01-3.27), 13.4% for Framingham-Wilson (OR=1.47; 95% CI, 0.87-2.47) and 10.6% for SCORE (OR=1.09; 95% CI, 0.50-2.37). Statin use was also significantly associated with hypertension (OR=1.89; 95% CI, 1.20-2.99) and hypercholesterolemia (OR=11.01; 95% CI, 6.55-18.53), and inversely associated with age in patients <65 years or 95 ci 0 32-0 81 conclusions the framingham-regicor function was better at classifying high-risk patients on statins than framingham-wilson score functions statin use associated with hypercholesterolemia and hypertension inversely age in <65 years (AU)

Integrin alpha1beta1 controls reactive oxygen species synthesis by negatively regulating epidermal growth factor receptor-mediated Rac activation.

Integrins control many cell functions, including generation of reactive oxygen species (ROS) and regulation of collagen synthesis. Mesangial cells, found in the glomerulus of the kidney, are able to produce large amounts of ROS via the NADPH oxidase. We previously demonstrated that integrin alpha1-null mice develop worse fibrosis than wild-type mice following glomerular injury and this is due, in part, to excessive ROS production by alpha1-null mesangial cells. In the present studies, we describe the mechanism whereby integrin alpha1-null mesangial cells produce excessive ROS. Integrin alpha1-null mesangial cells have constitutively increased basal levels of activated Rac1, which result in its increased translocation to the cell membrane, excessive ROS production, and consequent collagen IV deposition. Basal Rac1 activation is a direct consequence of ligand-independent increased epidermal growth factor receptor (EGFR) phosphorylation in alpha1-null mesangial cells. Thus, our study demonstrates that integrin alpha1beta1-EGFR cross talk is a key step in negatively regulating Rac1 activation, ROS production, and excessive collagen synthesis, which is a hallmark of diseases characterized by irreversible fibrosis.