Comparison of sporadic and familial behavioral variant frontotemporal dementia (FTD) in a North American cohort.

INTRODUCTION: Behavioral variant frontotemporal dementia (bvFTD) may present sporadically or due to an autosomal dominant mutation. Characterization of both forms will improve understanding of the generalizability of assessments and treatments. METHODS: A total of 135 sporadic (s-bvFTD; mean age 63.3 years; 34% female) and 99 familial (f-bvFTD; mean age 59.9; 48% female) bvFTD participants were identified. f-bvFTD cases included 43 with known or presumed chromosome 9 open reading frame 72 (C9orf72) gene expansions, 28 with known or presumed microtubule-associated protein tau (MAPT) mutations, 14 with known progranulin (GRN) mutations, and 14 with a strong family history of FTD but no identified mutation. RESULTS: Participants with f-bvFTD were younger and had earlier age at onset. s-bvFTD had higher total Neuropsychiatric Inventory Questionnaire (NPI-Q) scores due to more frequent endorsement of depression and irritability. DISCUSSION: f-bvFTD and s-bvFTD cases are clinically similar, suggesting the generalizability of novel biomarkers, therapies, and clinical tools developed in either form to the other.

Efecto de dosis suprafisiológicas de calcitriol sobre la expresión proteica de células de músculo liso vascular / Effect of supra-physiological calcitriol doses on protein expression of vascular smooth muscle cells

Introducción: El calcitriol, fundamental para mantener la homeostasis del calcio y el fósforo en el organismo, puede perjudicar al sistema vascular a dosis elevadas, aumentando el riesgo de calcificación. Objetivo: Evaluar la expresión diferencial de proteínas en células de músculo liso vascular sometidas a una dosis suprafisiológica de calcitriol. Material y métodos: Se cultivaron células de músculo liso vascular de rata (SMAC-R) en presencia de 10-7 M de calcitriol durante 10 días. Se valoró el cambio de fenotipo muscular a óseo mediante actividad fosfatasa alcalina, inmunocitoquímica, reacción en cadena de la polimerasa cuantitativa a tiempo real (qPCR) y Western blot. Mediante electroforesis bidimensional y espectrometría de masas se evaluó el patrón diferencial de proteínas en presencia y ausencia de 10-7 M de calcitriol. Resultados: La exposición a una dosis alta de calcitriol disminuyó significativamente la expresión génica de elastina y la expresión génica y proteica de α-actina, aumentado la expresión génica de osteocalcina y Runx2 y la proteica de osteoprotegerina. A nivel proteómico se identificaron 10 proteínas diferencialmente expresadas, destacando el aumento en superóxido dismutasa mitocondrial, proteínas del citoesqueleto, de formación de vesículas y del inflamasoma. Por el contrario, hubo 4 proteínas que disminuyeron su expresión, destacando alguna de tipo muscular. Conclusiones: En un modelo de células de músculo liso vascular sometidas a una dosis suprafisiológica de calcitriol se observó un aumento de expresión de proteínas del citoesqueleto, que forman vesículas de matriz y que participan en depurar radicales libres y en la respuesta inflamatoria. La pérdida de fenotipo muscular se vio representada por descensos en la expresión de proteínas típicamente musculares (AU)

Introduction: Calcitriol, essential for maintaining calcium and phosphorus homeostasis in the body, may damage the vascular system in high doses, increasing the risk of calcification. Objective: To assess the differential expression of proteins in vascular smooth muscle cells subjected to a supra-physiological dose of calcitriol. Material and methods: Rat vascular smooth muscle cells (VSMC-R) were cultured in the presence of 10-7 M calcitriol for 10 days. The change of muscle to bone phenotype was assessed by alkaline phosphatase activity, immunocytochemistry, quantitative polymerase chain reaction in time (QPCR) and Western blot analysis. By means of two-dimensional electrophoresis and mass spectrometry was evaluated for the differential protein pattern in presence and absence of 10-7 M calcitriol. Results: Exposure to a high dose of calcitriol decreased elastin gene expression and the protein and gene expression of α-actin protein, increased gene expression of osteocalcin and Runx2 and expression of osteoprotegerin protein. At the proteomic level, 10 differentially expressed proteins were identified, highlighting the increase in mitochondrial superoxide dismutase, cytoskeleton proteins, vesicle formation and inflammasome. On the contrary, there were 4 proteins that diminished expression, highlighting some of muscular type. Conclusions: In a model of vascular smooth muscle cells submitted to a supra-physiological dose of calcitriol an increased expression of cytoskeleton proteins was observed. These proteins form matrix vesicles and participate in clearance of free radicals and in the inflammatory response. The loss of muscle phenotype was represented by decreased expression of typically muscle proteins (AU)

Efecto del sistema RANK/RANKL/OPG sobre la desmineralización ósea y la calcificación vascular en la enfermedad renal crónica / Effect of RANK/RANKL/OPG pathway on bone demineralization and vascular calcification in chronic kidney disease

Introducción: En la enfermedad renal crónica (ERC) se producen alteraciones del metabolismo óseo y mineral que favorecen la calcificación de tejidos blandos. Alteraciones del sistema RANK/RANKL/OPG podrían estar favoreciendo la calcificación vascular, importante causa de morbimortalidad en la ERC. Objetivo: Valorar en un modelo experimental in vivo de insuficiencia renal crónica el efecto de la progresión de la misma sobre la calcificación vascular y sobre la pérdida de hueso correlacionando estos cambios con alteraciones en el sistema RANK/RANKL/OPG, utilizando un sistema in vitro para confirmar los hallazgos encontrados. Material y métodos: Se utilizaron dos modelos de calcificación vascular: un modelo in vivo en ratas con insuficiencia renal crónica alimentadas con dieta con diferente contenido en fósforo, y un modelo in vitro en células de músculo liso vascular (CMLV) sometidas a diferentes estímulos calcificantes. Resultados: A las 20 semanas, un 50% de los animales con dieta alta en fósforo presentó calcificaciones aórticas que se acompañó de aumento en la expresión aórtica de RANKL. Por el contrario, la OPG disminuyó como consecuencia probablemente del componente inflamatorio. A las 20 semanas en la tibia aumentó la expresión de RANKL y OPG, mientras que el aumento de OPG ocurrió en fases más tempranas. En CMLV la adición de suero urémico y medio calcificante indujo un incremento del contenido de calcio y de la expresión de RANKL y OPG. La adición de OPG y el silenciamiento de RANK inhibieron este aumento. Conclusiones: Nuestros resultados confirman la participación del eje RANK/RANKL/OPG en el proceso de calcificación vascular (AU)

Introduction: In cases of chronic kidney disease (CKD), bone and mineral metabolism changes occur which favor soft tissue calcification. Alterations in the RANK/RANKL/OPG system could also favor vascular calcification, a major cause of morbidity and mortality in CKD. Objective: In an in vivo experimental model of chronic renal failure progression, we assess the effect of CKD on vascular calcification and bone loss correlating these changes in the RANK/RANKL/OPG pathway. An in vitro system was used to confirm findings. Material and methods: Two models of vascular calcification were used: an in vivo rat model with chronic renal failure fed on a diet with different phosphorus content, and an in vitro model in vascular smooth muscle cells (VSMC) subjected to different calcifying stimuli. Results: At 20 weeks, 50% of animals with a diet high in phosphorus presented aortic calcification accompanied by increased aortic expression of RANKL. In contrast, OPG decreased probably as a consequence of an inflammatory component. At 20 weeks, expression of RANKL and OPG in the tibia increased, while the increase in OPG occurred at earlier stages. In VSMC, the addition of uremic serum and calcification medium increased calcium content and expression of RANKL and OPG. The addition of OPG and silencing of RANK inhibited this increase. Conclusions: Our results confirm RANK/RANKL/OPG system involvement in the vascular calcification process (AU)

Dealing with the genetic load in bacterial synthetic biology circuits: convergences with the Ohm's law.

Synthetic biology seeks to envision living cells as a matter of engineering. However, increasing evidence suggests that the genetic load imposed by the incorporation of synthetic devices in a living organism introduces a sort of unpredictability in the design process. As a result, individual part characterization is not enough to predict the behavior of designed circuits and thus, a costly trial-error process is eventually required. In this work, we provide a new theoretical framework for the predictive treatment of the genetic load. We mathematically and experimentally demonstrate that dependences among genes follow a quantitatively predictable behavior. Our theory predicts the observed reduction of the expression of a given synthetic gene when an extra genetic load is introduced in the circuit. The theory also explains that such dependence qualitatively differs when the extra load is added either by transcriptional or translational modifications. We finally show that the limitation of the cellular resources for gene expression leads to a mathematical formulation that converges to an expression analogous to the Ohm's law for electric circuits. Similitudes and divergences with this law are outlined. Our work provides a suitable framework with predictive character for the design process of complex genetic devices in synthetic biology.

In silico analysis of arginine catabolism as a source of nitric oxide or polyamines in endothelial cells.

We use a modeling and simulation approach to carry out an in silico analysis of the metabolic pathways involving arginine as a precursor of nitric oxide or polyamines in aorta endothelial cells. Our model predicts conditions of physiological steady state, as well as the response of the system to changes in the control parameter, external arginine concentration. Metabolic flux control analysis allowed us to predict the values of flux control coefficients for all the transporters and enzymes included in the model. This analysis fulfills the flux control coefficient summation theorem and shows that both the low affinity transporter and arginase share the control of the fluxes through these metabolic pathways.

The usefulness of post-genomics tools for characterization of the amine cross-talk in mammalian cells.

Evidence is growing in favour of a relationship between cancer and chronic inflammation, and particularly of the role of a polyamine and histamine metabolic interplay involved in these physiopathological problems, which are indeed highly complex biological systems. Decodification of the complex inter- and intra-cellular signalling mechanisms that control these effects is not an easy task, which must be helped by systems biology technologies, including new tools for location and integration of database-stored information and predictive mathematical models, as well as functional genomics and other experimental molecular approaches necessary for hypothesis validation. We review the state of the art and present our latest efforts in this area, focused on the amine metabolism field.

[Effectiveness of venlafaxine in the treatment of alcohol dependence with comorbid depression]. / Efectividad de la venlafaxina en el tratamiento de la dependencia de alcohol con depresión comórbida.

INTRODUCTION: There are no conclusive data on the effectiveness of antidepressant drugs in the treatment of comorbid cases of alcohol dependence and depression. OBJECTIVES: To determine the effectiveness of venlafaxine on depression and on severity (need of treatment) of alcohol dependence and related problems. METHODS: Observational, open-label, multicenter, 24-week follow-up study. PATIENTS: 90 outpatients with diagnosis of alcohol dependence and associated major depression disorder (DSMIV criteria). OUTCOMES MEASURES: the Hamilton Rating Scale for Depression (HAM-D17), European Addiction Severity Index (EuropASI) and Clinical Global Impression, severity and improvement subscales, (CGI-S and CGI-I). Evaluations were performed at baseline and at weeks 2, 4, 8 and 24. RESULTS: Mean age 44.94+/-9.74 years; 73.3 % man. HAM-D17 mean scores significantly decreased from baseline (24.85+/-5.94) to week 24 (5.976+/-4.68) and at each of the follow-up visits vs previous visit (p < 0.0005). Significant decreases from baseline to week 24 were obtained in four areas of EuropASI: medical status (2.12+/-2.45 to 1.07+/-1.68), alcohol use (5.29+/-2.24 to 3.04+/-2.35), family/ social relationships (3.68+/-2.36 to 1.71+/-2.06) and psychiatric status (5.61+/-1.81 to 2.67+/-2.03). Tolerance was excellent or good in 76.7% of the patients. CONCLUSIONS: Venlafaxine demonstrated to be effective in the treatment of depressive alcoholic patients. Furthermore, it seems to be useful to decrease the severity of problems related with the alcohol use.

Efectividad de la venlafaxina en el tratamiento de la dependencia de alcohol con depresión comórbida / Effectiveness of venlafaxine in the treatment of alcohol dependence with comorbid depression

Introducción. Faltan datos concluyentes sobre la efectividad de los antidepresivos en el tratamiento de los casos comórbidos de dependencia de alcohol y depresión. Objetivos. Determinar la efectividad de la venlafaxina sobre la depresión y sobre la gravedad (necesidad de tratamiento) de la dependencia de alcohol y problemas relacionados. Métodos. Estudio observacional, abierto, multicéntrico de 24 semanas de seguimiento. Pacientes. Noventa pacientes ambulatorios con diagnóstico de dependencia de alcohol y trastorno depresivo mayor (criterios DSM-IV). Medidas de resultados: escala de Hamilton de depresión (HAM-D17), Índice Europeo de Severidad de la Adicción (EuropASI) e Impresión Clínica Global (subescalas de gravedad y mejoría) (ICG-S e ICG-M). Evaluaciones basal y en las semanas 2, 4, 8 y 24. Resultados. Edad media: 44,94+-9,74 años; 73,3 % varones. Disminución significativa de las puntuaciones en la HAM-D17 desde la visita basal (24,85+-5,94) a la semana 24 (5,97+-4,68) y en cada una de las visitas de seguimiento frente a la visita previa (p<0,0005). Reducciones significativas en el EuropASI desde la basal a la semana 24 en las áreas: situación médica (2,12 ± 2,45 a 1,07+-1,68), uso de alcohol (5,29+-2,24 a 3,04+-2,35), relaciones familiares/sociales (3,68+-2,36 a 1,71+-2,06) y estado psiquiátrico (5,61+-1,81 a 2,67+-2,03). La tolerancia fue excelente o buena en el 76,7% de los casos. Conclusiones. La venlafaxina demostró ser efectiva en el tratamiento de la depresión en pacientes dependientes de alcohol. Además parece ser útil para reducir la gravedad

Introduction. There are no conclusive data on the effectiveness of antidepressant drugs in the treatment of comorbid cases of alcohol dependence and depression. Objectives. To determine the effectiveness of venlafaxine on depression and on severity (need of treatment) of alcohol dependence and related problems. Methods. Observational, open-label, multicenter, 24-week follow-up study. Patients. 90 outpatients with diagnosis of alcohol dependence and associated major depression disorder (DSMIV criteria). Outcomes measures: the Hamilton Rating Scale for Depression (HAM-D17), European Addiction Severity Index (EuropASI) and Clinical Global Impression, severity and improvement subscales, (CGI-S and CGI-I). Evaluations were performed at baseline and at weeks 2, 4, 8 and 24. Results. Mean age 44.94+-9.74 years; 73.3 % man. HAM-D17 mean scores significantly decreased from baseline (24.85+-5.94) to week 24 (5.976+-4.68) and at each of the follow-up visits vs previous visit (p < 0.0005). Significant decreases from baseline to week 24 were obtained in four areas of EuropASI: medical status (2.12+-2.45 to 1.07+-1.68), alcohol use (5.29+-2.24 to 3.04+-2.35), family/ social relationships (3.68+-2.36 to 1.71+-2.06) and psychiatric status (5.61+-1.81 to 2.67+-2.03). Tolerance was excellent or good in 76.7% of the patients. Conclusions. Venlafaxine demonstrated to be effective in the treatment of depressive alcoholic patients. Furthermore, it seems to be useful to decrease the severity of problems related with the alcohol use

Green tea epigallocatechin-3-gallate is an inhibitor of mammalian histidine decarboxylase.

(-)-epigallocatechin-3-gallate, an antiproliferative and antiangiogenic component of green tea, has been reported to inhibit dopa decarboxylase. In this report,we show that this compound also inhibits histidine decarboxylase, the enzymic activity responsible for histamine biosynthesis. This inhibition was proved by a double approach, activity measurements and UV-Vis spectra of enzyme-bound pyridoxal-5'-phosphate. At 0.1 mM (-)-epi-gallocatechin-3-gallate, histidine decarboxylase activity was inhibited by more than 60% and the typical spectrum of the internal aldimine form shifted to a stable major maximum at 345 nm, suggesting that the compound causes a stable change in the structure of the holoenzyme. Since histamine release is one of the primary events in many inflammatory responses, a new potential application of (-)-epigallocatechin-3-gallate in prevention or treatment of inflammatory processes is suggested by these data.

A quartz crystal microbalance sensor for the detection of formic acid vapors.

A new quartz crystal microbalance sensor is developed to determine formic acid at low concentrations. Four previously selected polymers with acid-base characteristics were tested as possible coatings. Polyoxyethylene bis [amine] presented the best results. The sensor is rapid, sensitive [0.67 Hz/(mg/m3)], and reversible at low concentrations. The detection limit for formic acid (7.2 mg/m3) is comparable with the short term exposure limit and the threshold limit values. It presents a fast mechanical response to pressure changes, so that it can be quickly used in different environments and situations. The sensor also shows a good stability in a temperature range typical of work atmospheres (16-36 degrees C). It has a wide linear range (7.2-911.2 mg/m3) and a long useful time. It is also applicable to other low molecular mass carboxylic acids such as acetic acid.

Effects of genistein and 2-methoxyestradiol on matrix metalloproteinases and their inhibitors secreted by Ehrlich ascites tumor cells.

BACKGROUND: Ehrlich ascites tumor is an experimental tumor model very suitable for performing comparative studies relating its growth in vitro and in vivo. We used this tumor model to study the potential modulatory effects of genistein and 2-methoxyestradiol, two anti-angiogenic compounds, on the proteolytic balance MMP/TIMP. Ehrlich cells grown in vitro secreted MMP-9, MMP-2 and two TIMPs; the treatment with either of the anti-angiogenic compounds here tested stimulated all these activities, but the increase in TIMPs activities of genistein-treated cells were higher than those of MMPs, thus inducing a decrease in the proteolytic balance. On the other hand, Ehrlich cells growing in vivo did not produce any detectable TIMP activity, but accumulated MMP-9 and MMP-2 during tumor growth. Both compounds induced significant decrease of MMPs activity when tumor cells were actively proliferating. It was concluded that both genistein and 2-methoxyestradiol could shift the proteolytic balance MMP/TIMP towards antiproteolysis in media or ascitic fluid conditioned by actively growing Ehrlich cells.

Quality of apical seal in curved canals using three types of spreaders.

The aim of the present study was to evaluate the influence of spreader shape on the quality of obturation. Forty-five single canal teeth with varying degrees of apical curvature were used throughout. The canals were prepared using the step-back technique and obturated with lateral condensation. The teeth were classified into three groups (A, B, and C) and treated as follows. Group A was treated with markedly conical, flat-ended spreaders (A to D; Dentsply-Maillefer, Ballaigues, Switzerland). Group B was treated with slightly conical (15 to 40) sharp-pointed CC-cord spreaders. Group C was treated with CC-cord, slightly conical but flat-ended spreaders. The obturated teeth were decalcified in 7.5% nitric acid to obtain four cross-sections: the first at 2 mm from the apex and then the following three sections at 1-mm intervals. Section thickness was approximately 1 mm. Each section was photographed under a stereoscopic microscope. The following areas were measured on each of the microphotographs using a planimeter: (a) gutta-percha mass, (b) mass of sealer, (c) foreign bodies, and (d) empty spaces. These four areas were added to determine total cross-sectional canal area and then the percent of that area attributable to a and to b + c + d was calculated. The statistical analysis of the data (parametric Student's t test for independent groups) revealed that only in group B was the area occupied by a, the gutta-percha mass, significantly greater at all levels than the area occupied by b + c + d. Next in obturation effectiveness was group C, followed by group A.

[Relations between atmospheric pollution and the respiratory tract]. / Rapporti fra inquinamento atmosferico ed apparato respiratorio

After mentioning the close relationships between enviornmental pollution and the respiratory system, the various polluting compounds, from solid particles to fumes and gases, are reviewed, special attention being paid to the commonest types (sulphur and nitrogen compounds). Attention is called to two other polluting factors, asbestos and radioactivity, both of which are important in neoplastic pathology. The complexity of the air pollution problem in relation to respiratory pathology is stressed while stating that the most important problem remains that of prevention.