Mutations inducing divergent shifts of constitutive activity reveal different modes of binding among catecholamine analogues to the beta(2)-adrenergic receptor.

1. We compared the changes in binding energy generated by two mutations that shift in divergent directions the constitutive activity of the human beta(2) adrenergic receptor (beta(2)AR). 2. A constitutively activating mutant (CAM) and the double alanine replacement (AA mutant) of catechol-binding serines (S204A, S207A) in helix 5 were stably expressed in CHO cell lines, and used to measure the binding affinities of more than 40 adrenergic ligands. Moreover, the efficacy of the same group of compounds was determined as intrinsic activity for maximal adenylyl cyclase stimulation in wild-type beta(2)AR. 3. Although the two mutations had opposite effects on ligand affinity, the extents of change were in both cases largely correlated with the degree of ligand efficacy. This was particularly evident if the extra loss of binding energy due to hydrogen bond deletion in the AA mutant was taken into account. Thus the data demonstrate that there is an overall linkage between the configuration of the binding pocket and the intrinsic equilibrium between active and inactive receptor forms. 4. We also found that AA mutation-induced affinity changes for catecholamine congeners gradually lacking ethanolamine substituents were linearly correlated to the loss of affinity that such modifications of the ligand cause for wild-type receptor. This indicates that the strength of bonds between catechol ring and helix 5 is critically dependent on the rest of interactions of the beta-ethanolamine tail with other residues of the beta(2)-AR binding pocket.

Development of neuronal markers in aggregating fetal rat telencephalon cells cultured in the presence of triiodothyronine.

The concentrations of the general neuronal markers D2-protein (N-CAM), D3-protein and neuron specific enolase (NSE) in reaggregating cultures of fetal rat telencephalon cells were affected by the presence of 30 nM triiodothyronine in the defined culture medium. The extent of normal developmental changes were enhanced by triiodothyronine, as demonstrated by crossed immunoelectrophoresis. From 13 to 19 days in culture, the concentration of D2-protein decreased, and the concentrations of both D3-protein and NSE increased. Nerve growth factor (NGF) was without effect on the development of these general neuronal markers. However, as shown previously both triiodothyronine and NGF increased the activity of choline acetyltransferase, a marker for cholinergic neurons. The results suggest an enhanced overall differentiation of several types of telencephalon neurons in the presence of triiodothyronine, and a specific stimulation of cholinergic telencephalon neurons by NGF.

Prognostic effect of epithelial cell adhesion molecule overexpression in untreated node-negative breast cancer.

PURPOSE: Epithelial cell adhesion molecule (Ep-CAM) recently received increased attention not only as a prognostic factor in breast cancer but also as a potential target for immunotherapy. We examined Ep-CAM expression in 402 consecutive node-negative breast cancer patients with long-term follow-up not treated in the adjuvant setting. EXPERIMENTAL DESIGN: Ep-CAM expression was evaluated by immunostaining. Its prognostic effect was estimated relative to overexpression/amplification of HER-2, histologic grade, tumor size, age, and hormone receptor expression. RESULTS: Ep-CAM status was positive in 106 (26.4%) patients. In multivariate analysis, Ep-CAM status was associated with disease-free survival independent of age, pT stage, histologic grade, estrogen receptor (ER), progesterone receptor (PR), as well as HER2 status (P = 0.028; hazard ratio, 1.60; 95% confidence interval, 1.05-2.44). Recently, so-called triple-negative (HER-2, ER, and PR) breast cancer has received increased attention. We noticed a similar association of Ep-CAM with disease-free survival in the triple-negative group as for the entire cohort. CONCLUSION: In this study of untreated breast cancer patients, Ep-CAM overexpression was associated with poor survival in the entire cohort and in the subgroup of triple-negative breast cancer. This suggests that Ep-CAM may be a well-suited target for specific therapies particularly in HER-2-, ER-, and PR-negative tumors.

Oferta educativa i desenvolupament econòmic a la comarca del Berguedà

Tard o d’hora, en algun moment de la nostra vida, hem de prendre decisions respecte allò que volem estudiar per tal de poder desenvolupar el capital humà que portem a dins. En algun moment deixarem de ser individus inactius, simples estudiants, per passar a ocupar un lloc en el món laboral. Però, és sempre tant senzilla aquesta decisió? Trobem sempre el que busquem allà on volem i en el moment adequat?Qüestions com aquestes no només sorgeixen a persones com vostè, lector, sinó també potser, a la persona que es troba asseguda al seu costat, al seu company de cafè,... en definitiva, a tota una societat amb diferents inquietuds i preocupacions. I és en aquest moment, en el qual la decisió personal es transforma en global, quan els requeriments d’una societat esdevenen unaprioritat.La necessitat d’especialitzar-se en aquells estudis que cadascú desitja i la importància de saber amb certesa que allà on estudiem disposarem de l’oferta laboral adequada, semblen qüestions insignificants per aquells qui viuen en grans ciutats, però, passa el mateix en les zones amb poca densitat de població? Què passa amb aquell capital humà que abandona la seva llar per buscar la formació o el treball que més desitja i manca allà on viu?Amb el treball que presentem a continuació pretenem mostrar la rellevància que pot tenir la manca d’una oferta educativa adequada, sobre el desenvolupament econòmic d’una societat. Tractem d’explicar fins a quin punt la connexió entre el món educatiu i laboral d’una població, poden condicionar al desenvolupament socioeconòmic, tot basant-nos en el cas específic de la comarca del Berguedà.

Postoperative delirium. Part 2: detection, prevention and treatment.

To target pharmacological prevention, instruments giving an approximation of an individual patient's risk of developing postoperative delirium are available. In view of the variable clinical presentation, identifying patients in whom prophylaxis has failed (that is, who develop delirium) remains a challenge. Several bedside instruments are available for the routine ward and ICU setting. Several have been shown to have a high specificity and sensitivity when compared with the standard definitions according to DSM-IV-TR and ICD-10. The Confusion Assessment Method (CAM) and a version specifically developed for the intensive care setting (CAM-ICU) have emerged as a standard. However, alternatives allowing grading of the severity of delirium are also available. In many units, the approach to delirium follows a three-step strategy. Initially, non-pharmacological multicomponent strategies are used for primary prevention. As a second step, pharmacological prophylaxis may be added. Perioperative administration of haloperidol has been shown to reduce the severity, but not the incidence, of delirium. Perioperative administration of atypical antipsychotics has been shown to reduce the incidence of delirium in specific groups of patients. In patients with delirium, both symptomatic and causal treatment of delirium need to be considered. So far symptomatic treatment of delirium is primarily based on antipsychotics. Currently, cholinesterase inhibitors cannot be recommended and the data on dexmedetomidine are inconclusive. With the exception of alcohol-withdrawal delirium, there is no role for benzodiazepines in the treatment of delirium. It is unclear whether treating delirium prevents long-term sequelae.

Financiamento dos Sistemas de Saúde

A promoção e protecção da saúde são essenciais para o bem-estar do homem e para o desenvolvimento económico e social sustentável. Isto foi reconhecido há mais de 30 anos pelos signatários da Declaração de Alma-Ata, que assinalaram que a Saúde para Todos contribuiria tanto para melhor qualidade de vida como também para a paz e segurança globais. Não constitui surpresa que as pessoas na maioria dos países classifi quem a saúde como uma das suas maiores prioridades, ultrapassada apenas pelas preocupações económicas, tais como desemprego, baixos salários ou alto custo de vida (1, 2). Daqui resulta que a saúde se transforma frequentemente num tema político à medida que os governos tentam responder às expectativas da população. Há muitas maneiras de promover e manter a saúde. Algumas fi cam fora dos limites do sector da saúde. As “circunstâncias em que as pessoas crescem, vivem, trabalham e envelhecem” infl uenciam fortemente como as pessoas vivem e morrem (3). A educação, habitação, alimentação e emprego infl uenciam a saúde. Reduzir as desigualdades nestas áreas irá reduzir as desigualdades em saúde. Mas o acesso atempado a cuidados de saúde – uma combinação de promoção, prevenção, tratamento e reabilitação – também é crítico. Isto não será atingido, excepto para uma minoria da população, sem um sistema de fi nanciamento de saúde bem funcionante, que permita às pessoas usar os serviços de saúde quando deles precisam.

Similarities and dissimilarities between the Movement ABC-2 and the Zurich Neuromotor Assessment in children with suspected developmental coordination disorder.

An established tool for the assessment of motor performance in children with developmental coordination disorder (DCD) is the Movement-ABC-2 (M-ABC-2). The Zurich Neuromotor Assessment (ZNA) is also widely used for the evaluation of children's motor performance, but has not been compared with the M-ABC-2. Fifty-one children (39 males) between 5 and 7 years of age with suspected DCD were assessed using the M-ABC-2 and the ZNA. Rank correlations between scores of different test components were calculated. The structure of the tests was explored using canonical-correlation analysis. The correlation between total scores of the two motor tests was reasonable (0.66; p<0.001). However, ZNA scores were generally lower than those of M-ABC-2, due to poor performance in the fine motor adaptive component and increased contralateral associated movements (CAM). The canonical-correlation analysis revealed that ZNA measures components like pure motor skills and CAM that are not represented in the M-ABC-2. Furthermore, there was also no equivalent for the aiming and catching items of the M-ABC-2 in ZNA. The two tests measure different motor characteristics in children with suspected DCD and, thus, can be used complementary for the diagnosis of the disorder.

Problemes de proximitat en xarxes de carreteres

L'objectiu principal d'aquest projecte és analitzar problemes de proximitat en xarxes de carreteres. La distància entre dos punts de la xarxa de carreteres ve definida pel cost del camí mínim entre ells, el qual depèn de la connectivitat i dels pesos de la nostra xarxa. Calcular camins mínims i distàncies en la xarxa és un problema fonamental d'optimització amb importants aplicacions en diferents dominis com Sistemes d’Informació Geogràfica, Serveis de Localització, Sistemes de Navegació, etc

Up-regulation of the levels of expression and function of a constitutively active mutant of the hamster alpha1B-adrenoceptor by ligands that act as inverse agonists.

The alpha1-adrenergic agonist phenylephrine stimulated phospholipase D (PLD) activity in Rat 1 fibroblasts transfected to express either the wild-type hamster alpha1B-adrenoceptor or a constitutively active mutant (CAM) form of this receptor. The EC50 for agonist stimulation of PLD activity was substantially lower at the CAM receptor than at the wild-type receptor as previously noted for phenylephrine stimulation of phosphoinositidase C activity. Sustained treatment of cells expressing the CAM alpha1B-adrenoceptor with phentolamine resulted in a marked up-regulation in levels of this receptor with half-maximal effects produced within 24 h and with an EC50 of approx. 40 nM. Such an up-regulation could be produced with a range of other ligands generally viewed as alpha1-adrenoceptor antagonists but equivalent treatment of cells expressing the wild-type alpha1B-adrenoceptor was unable to mimic these effects. After sustained treatment of the CAM alpha1B-adrenoceptor expressing cells with phentolamine, basal PLD activity was increased and phenylephrine was now able to stimulate PLD activity to greater levels than in vehicle-treated CAM alpha1B-adrenoceptor-expressing cells. The EC50 for phenylephrine stimulation of PLD activity was not altered, however, by phentolamine pretreatment and the associated up-regulation of the receptor. After phentolamine-induced up-regulation of basal PLD activity, a range of alpha1-antagonists were shown to possess the characteristics of inverse agonists of the CAM alpha1B-adrenoceptor as they were able to substantially decrease the elevated basal PLD activity.

Federico II de Prusia : el rey flautista

En un momento histórico en el que las tendencias musicales en Europa estaban a medio camino entre el Barroco y el Clasicismo, confluyeron en la corte de Federico el Grande una serie de músicos que trabajaron para el rey prusiano y que compusieron una gran cantidad de música para flauta, instrumento que él tocaba. La actividad musical del Berlín de esos años se convirtió así en relevante para el mundo flautístico. Profundizaremos en este trabajo en la figura del monarca, en la relación de éste con sus músicos y en las características principales de la música de la segunda mitad del siglo XVIII.

A quantitative analysis of antagonism and inverse agonism at wild-type and constitutively active hamster alpha1B-adrenoceptors.

In order to characterize inverse agonism at alpha1B-adrenoceptors, we have compared the concentration-response relationships of several quinazoline and non-quinazoline alpha1-adrenoceptor antagonists at cloned hamster wild-type (WT) alpha1B-adrenoceptors and a constitutively active mutant (CAM) thereof upon stable expression in Rat-1 fibroblasts. Receptor activation or inhibition thereof was assessed as [3H]inositol phosphate (IP) accumulation. Quinazoline (alfuzosin, doxazosin, prazosin, terazosin) and non-quinazoline alpha1-adrenoceptor antagonists (BE 2254, SB 216,469, tamsulosin) concentration-dependently inhibited phenylephrine-stimulated IP formation at both WT and CAM with Ki values similar to those previously found in radioligand binding studies. At CAM in the absence of phenylephrine, the quinazolines produced concentration-dependent inhibition of basal IP formation; the maximum inhibition was approximately 55%, and the corresponding EC50 values were slightly smaller than the Ki values. In contrast, BE 2254 produced much less inhibition of basal IP formation, SB 216,469 was close to being a neutral antagonist, and tamsulosin even weakly stimulated IP formation. The inhibitory effects of the quinazolines and BE 2254 as well as the stimulatory effect of tamsulosin were equally blocked by SB 216,469 at CAM. At WT in the absence of phenylephrine, tamsulosin did not cause significant stimulation and none of the other compounds caused significant inhibition of basal IP formation. We conclude that alpha1-adrenoceptor antagonsits with a quinazoline structure exhibit greater efficacy as inverse agonists than those without.

Femoroacetabular impingement: normal values of the quantitative morphometric parameters in asymptomatic hips.

OBJECTIVE: To determine the means and the reference intervals of the quantitative morphometric parameters of femoroacetabular impingement (FAI) in normal hips with high-resolution computed tomography (CT). METHODS: We prospectively included 94 adult individuals who underwent CT for thoracic, abdominal or urologic pathologies. Patients with a clinical history of hip pathology and/or with osteoarthritis on CT were excluded. We calculated means and 95 % reference intervals for imaging signs of cam-type (alpha angle at 90° and 45° and femoral head-neck offset) and pincer-type impingement (acetabular version angle, lateral centre-edge angle and acetabular index). RESULTS: The 95 % reference interval limits were all far beyond the abnormal thresholds found in the literature for cam-type and to a lesser extent for pincer-type FAI. The upper limits of the reference intervals for the alpha angles (at 90°/45°) were 68°/83° (men) and 69°/84° (women), compared to thresholds from the literature (50°, 55° or 60°). Reference intervals were similar between genders for cam-type parameters, and slightly differed for pincer-type. CONCLUSION: The 95 % reference intervals of morphometric measurements of FAI in asymptomatic hips were beyond the abnormal thresholds, which was especially true for cam-type FAI. Our results suggest the need for redefining the current morphometric parameters used in the diagnosis of FAI. KEY POINTS: ? 95 % reference intervals limits of FAI morphotype were beyond currently defined thresholds. ? Reference intervals of pincer-type morphotype measurements were close to current definitions. ? Reference intervals of cam-type morphotype measurements were far beyond the current definitions. ? Current morphometric definitions of cam-type morphotype should be used with care.

Contributo das TIC na integração de famílias oriundas do Brasil no concelho de Albufeira

Os fenómenos migratórios tem-se acentuado nas últimas décadas, para este facto muito tem contribuído a era globalizada em que nos encontramos. Com a globalização surgiu o desenvolvimento de redes mundiais, nomeadamente sistemas sociais e económicos, facultando o acesso a meios de transporte mais rápidos e baratos, e as comunicações tornaram-se mais fáceis, promovendo e facilitando as deslocações entre países e continentes, de pessoas e bens. Assim, actualmente com o acesso facilitado nas comunicações e nas deslocações, a migração tornou-se uma constante. Perante a quantidade de indivíduos oriundos das mais diversas partes do globo e com a evolução das tecnologias de informação e comunicação, as barreiras culturais foram reduzidas, permitindo uma rápida difusão de ideias e de meios, possibilitando que indivíduos que se encontram em locais geograficamente longínquos possam comunicar com regularidade. Este estudo teve como objectivo conhecer, por um lado, o impacto da utilização das TIC, por parte dos imigrantes de origem brasileira, como forma de manterem o contacto com o país de origem, por outro, o facto de residirem familiares/amigos em Portugal, aquando da sua vinda, podem contribuir para a sua integração. O estudo foi aplicado no Gabinete da família e no Gabinete do Imigrante, da Divisão de Acção Social Saúde e Juventude, da Câmara Municipal de Albufeira. Teve uma amostragem por conveniência que abrangeu 50 indivíduos oriundos do Brasil, residentes em Albufeira. Foi aplicado um inquérito por questionário que permitiu a caracterização da amostra e recolher informações sobre o impacto da utilização das TIC como forma de manter o contacto com o país de origem e a importância das redes sociais no processo de integração. Constituído por 74 questões fechadas, abertas e semi abertas. Fez-se de seguida uma análise quantitativa e qualitativa dos dados recolhidos. Os resultados obtidos sobre esta problemática permitiram percepcionar que o facto de existir uma rede familiar e de amigos, contribui para a integração da família imigrante na sociedade de acolhimento. Ou seja, todo o suporte familiar e a rede de amigos existente facultam ao imigrante condições para que o mesmo se instale no país de acolhimento e se sinta integrado. O facto de os imigrantes comunicarem, por norma, semanalmente com a família no Brasil, bem como utilizarem as tecnologias de informação e comunicação, contribui em muito para o seu bem estar psicológico e emocional. O contacto regular com a família, ainda que através de uma Web cam, proporciona-lhes tranquilidade e minimiza a distância física, uma vez que os podem ver e ouvir sentindo assim o apoio dos mesmos, ajudando-os a permanecer no nosso país. O uso das novas tecnologias são utilizadas para manter a ligação com a comunidade de origem, fomentando os laços familiares e com amigos. Os imigrantes utilizam a internet para comunicar com os indivíduos da mesma nacionalidade, bem como a família/amigos que se encontram no Brasil. O acesso às TIC e o facto de as utilizarem para comunicar com a família e amigos, no país de origem, pode ser considerada como uma rede social de apoio, proporcionando assim aos imigrantes uma integração no país de acolhimento.

Intra-individual stability of neuromotor tasks from 6 to 18 years: a longitudinal study.

This study investigates the intra-individual stability of the speed of several motor tasks and the intensity of associated movements in 256 children (131 girls, 125 boys) from the Zurich generational study using the Zurich neuromotor assessment battery (ZNA) over a 12-year period from the age of 6 to 18 years. The stability was assessed by correlograms of standard deviation scores calculated from age- and gender-adjusted normative values and compared with standing height and full scale intelligence quotient (IQ). While motor tasks of hand, finger and foot (HFT) and contralateral associated movements (CAM) exhibited a moderate stability (summary measure as correlation coefficients between two measurements made 4 years apart: .61 and .60), other tasks (dynamic balance, static balance and pegboard) were only weakly stable (.46, .47 and .49). IQ and height were more stable than neuromotor components (.72 and .86). We conclude that the moderately stable HFT and CAM may reflect "motor traits", while the stability of the pegboard and balance tasks is weaker because these skills are more experience related and state-dependent.

"Sóc" a la professió infermera

El propòsit de la present investigació és conèixer el model Salutogènic i la sevaaplicació en el treball diari dels professionals d’infermeria. La disciplina infermera escaracteritza pel tracte amb les persones, el seu paradigma està basat en les cures cap aaquestes. Aquest fet causa que formin part de la professió els estímuls estressants tantde l’ambient com de l’interior dels professionals i és important que aquests prenguinconsciència d’aquesta realitat i desenvolupin recursos i mecanismes que possibilitinrealitzar les cures de gran qualitat. Creiem que el model Salutogènic i el seu constructeprincipal, el Sentit de Coherència ens col·loquen en bon camí per poder aprofundir enaquest tema. (Extret de la introducció)