去甲肾上腺素参与吗啡神经适应性改变的中枢机制

That relapse still exists even after prolonged withdrawal is a difficult issue in the medical cure of drug addiction. Neuro-adaptation induced by prolonged exposure to addictive drugs is the neural mechanisms of both compulsive drug seeking and relapse.Neuro-adaptation caused by addictive drugs increases the individuals’ response to drugs and on the other hand, it reduces the response to natural reward in withdrawn individuals.There must be common neural mechanisms between the co-existing phenomena, and there must also be unique neural mechanisms in the drugs.To reveal the neuro-adaptation arising in the process from random, controllable drug-use to uncontrollable compulsive drug seeking is of great significance both theoretically and practically.Based on the above hypothesis, in order to reveal the function of alpha adrenergic receptor in compulsive drug-seeking motivation during the process of drug addiction, using sensitization of morphine-induced psychomotor activity as behavioral model, through the method of behavioral pharmacology, the neural mechanisms of alpha adrenergic receptor’s involvement in the process of addiction has been studied.The adjustment function caused by alpha receptors in medial prefrontal cortex and nucleus accumbens to morphine-induced psychomotor activity has been compared in the period of first use of drugs and in repetitive-use period. Furthermore, the effect on novelty seeking caused by alpha-receptors in relevant brain areas has also been compared. Major results are as follow: 1 After prolonged morphine exposure, rats’ response to morphine-induced psychomotor activity is strengthened and response to novel object induced reward weakened. 2 Injection of prazosin in medial prefrontal cortex will block morphine-induced psychomotor activity of naïve rats, however, it will not block that of morphine-withdrawn rats, but it will block the novelty seeking behavior of morphine-withdrawn rats. 3 Injection of clonidine in medial prefrontal cortex will block morphine-induced psychomotor effect of both naïve rats and morphine-withdrawn rats, and will block the novelty seeking behavior of morphine-withdrawn rats. 4 Injection of prazosin in nucleus accumbens will not affect the morphine-induced psychomotor effect of either naïve rats or morphine-withdrawn rats, nor will it affect the novelty seeking behavior of morphine-withdrawn rats. 5 Injection of clonidine in nucleus accumbens will block morphine-induced psychomotor effect of naïve rats, however, it will not block that of morphine-withdrawn rats, nor will it affect the novelty seeking behavior of morphine-withdrawn rats. These results show: 1 The weakening of the function of alpha1 receptors in medial prefrontal cortex and alpha2 receptors in nucleus accumbens caused by repetitive exposure to morphine is probably the cause of compulsive drug-seeking activity. 2 Blocking alpha1 receptors in medial prefrontal cortex accelerates the loss of interest in natural reward after morphine withdrawal. 3 Blocking alpha2 receptors in medial prefrontal cortex not only restrains drug-seeking motivation, but also blocks the individual’s seeking motivation for novelty stimulus, which suggests that, while selecting medicine for curing addiction, it should be considered to reduce the influence on natural reward as much as possible and to avoid major side-effect.

5-13岁儿童对惯性运动的认知发展

Research on naïve physics investigates children’s intuitive understanding of physical objects, phenomena and processes. Children, and also many adults, were found to have a misconception of inertia, called impetus theory. In order to investigate the development of this naïve concept and the mechanism underlying it, four age groups (5-year-olds, 2nd graders, 5th graders, and 8th graders) were included in this research. Modified experimental tasks were used to explore the effects of daily experience, perceptual cues and general information-processing ability on children’s understanding of inertia. The results of this research are: 1) Five- to thirteen-year-olds’ understanding of inertia problems which were constituted by two ogjects moving at the same spped undergoes an L-shaped developmental trend; Children’s performance became worse as they got older, and their performance in the experiment did not necessarily ascend with the improvement of their cognitive abilities. 2) The L-shaped developmental curve suggests that children in different ages used different strategies to solve inertia problems: Five- to eight-year-olds only used heuristic strategy, while eleven- to thirteen-year-olds solved problems by analyzing the details of inertia motion. 3) The different performance between familiar and unfamiliar problems showed that older children were not able to spontaneously transfer their knowledge and experience from daily action and observation of inertia to unfamiliar, abstract inertia problems. 4) Five- to eight-year-olds showed straight and fragmented pattern, while more eleven- to thirteen-year-olds showed standard impetus theory and revised impetus theory pattern, which showed that younger children were influenced by perceptual cues and their understanding of inertia was fragmented, while older children had coherent impetus theory. 5) When the perceptual cues were controlled, even 40 percent 5 years olds showed the information-processing ability to analyze the distance, speed and time of two objects traveling in two different directions at the same time, demonstrating that they have achieved a necessary level to theorize their naïve concept of inertia.

5-9岁儿童对常见食物及其功能的认知发展

Research on naïve biology investigates children spontaneous understanding of biology objects, phenomena and function. Previous researches focus mostly on biology phenomena. Little has done on organism’s function, such as eating food. Many research in this field found that children were unable to categorize food by nutrition criterion, but rely on physical cues. In order to investigate the development of children’s naïve understanding of food and to find if they can classify food by nutrition criterion, three age groups (5-year-olds, 7-year-olds, and 9-year-olds) were included in this study. Varies experimental tasks were also used to explore the children’s understanding of food and its function. The results showed as the followings: 1) A few 5-year- old children can classify food by nutrition criterion when they take the spontaneous classification task. However, more and more children can realize what make a kind of food different from another can be the nutrition it contains. 2) Kindergarteners can find the relation between food and its output. When they become older, more and more children can explain the relation by consistent theory. It can be said that 9-year-old children have already have a profound understanding of nutrition. They gradually developed naive theory of biology on nutrition level. 3) Even kindergarteners can understand the concept of “food balance”. However, with development there was a significant age increase in food balance choice. 4) Children’s knowledge of food balance grows with age, but urban and rural educational background influence cognitive performance.

5-9岁儿童对常见病病因及其致病不确定性的认知发展

Research on children's naive concepts has previously tended to focus on the domains of physics and psychology, but more recently attention has turned to conceptual development in biology as a core domain of knowledge. Because of its familiarity, illness has been a popular topic for researchers in this domain. However, they have only studied the children’s understanding of its causes. Other aspects of illness, such as treatment and prognosis, have received little attention. This research addresses the development of 5- to 9-year-old children’s understanding of the causes of illness and their probabilities via open-ended and forced choice interviews. The results of this research are: 1) Most of the 5- to 7-year-old children used behavioral causes to explain illness, and the 9-year-old children primarily used biological causes to interpret illness. With age, more and more children selected psychological causes to explain illness. 2) Pre-school children did not over-generalize contagions to non-contagious illnesses. They used behavioral and biological causes to explain contagious illnesses. For non-contagious illnesses, they chose only behavioral causes. 3) Most of the children used only one kind of cause to explain illness. 4) Some preschool-aged children viewed outcomes of familiar causes of illness as probabilistic. With age, more and more could make uncertain predictions of illness. 5) The children’s understanding of the causes’ probabilities appeared to be based on naïve biology. 5- to 9-year-old children often made probabilistic predictions by analyzing a single cause of illness. 6) Children coming from higher educational backgrounds outperformed their counterparts coming from lower educational backgrounds with respect to understanding illness. 7) Specific knowledge acquired could generally improved the preschoolers’ understanding of causes of illness and their probabilities.

Dialogue for bass clarinet and bassoon

This work specifically focuses on the lower register of both instruments, an area I've been led to explore as a result of my profound high frequency hearing loss. It was selected for performance following an international competitive call for scores and premiered at the 16th London New Wind Festival, 22nd November 2013. It was performed by Phil Edwards (bass clarinet) and Glyn Williams (bassoon).

Perfil competencial de los estudiantes de últimos cursos de grado en las universidades de la Comunidad de Madrid: diferencias en función del género y la edad

El cambio de modelo de enseñanza que han sufrido las Universidades con la implementación del Espacio Europeo de Educación Superior, puso el foco en el desarrollo competencial, buscando que los estudiantes adquieran las habilidades y capacidades. Con el fin de comprobar si el desarrollo de las competencia académicas se ve afectado por el género y la edad de los estudiantes, a una muestra de 364 estudiantes de diferentes Universidades de la Comunidad de Madrid se les aplicó COMPEUEM, un test que evalúa en qué medida los estudiantes poseen 8 competencias académicas: Comunicación, Liderazgo, Trabajo en Equipo, Adaptación a los Cambios, Iniciativa, Solución de Problemas, Toma de Decisiones, Organización y Planificación. Los resultados encontrados ponen de manifiesto que los sujetos de más edad presentan mayores niveles en la adquisición de competencias que los de menor edad. Por otro lado, encontramos diferencias significativas en función del género de los estudiantes.

Goizuetako hizkera: adinduen eta L.H.-ko 3. zikloko ikasleen arteko desberdintasunak

[EUS] Bizitza ohiturak aldatzen ari direla begi bistakoa da, eta horrek hizkuntza baten garapenean eragina izaten du. Proiektu honen bitartez, Goizuetako euskalkiak azken berrogeita hamar urte hauetan, gutxi gorabehera, izan duen garapena frogatzen saiatuko naiz. Horretarako, ikerketa bat egin dut gazte eta adinduen artean, euskalkiaren ezaugarrietan eman diren aldakuntzak zeintzuk izan diren ikusteko. Ikerketa honekin hizkuntzaren “transmisioa” nolakoa izan den ikusi ahalko da. Lan honen bidez, euskalkiak eman duen beherakada, hein batean, oraingo biztanleriak kanpo harreman gehiago dituelako eta bizi ohitura berriak hartzen ari delako eman dela ikusten da. Etorkizuneko irakasle bezala, proiektu honen bidez eskualde bakoitzeko hizkuntza garapenaren jakitun izatea ezinbestekoa dela ikusten da.

Diseños en cerámica para Fedar (Popayán - Cauca).

41 hojas.

Investigation of p75 neurotrophin receptor and the role of its post-translational modifications in tumour cell motility and invasiveness

The p75 neurotrophin receptor (p75NTR) is a member of the tumour necrosis factor superfamily, which relies on the recruitment of cytosolic protein partners - including the TNF receptor associated factor 6 (TRAF6) E3 ubiquitin ligase - to produce cellular responses such as apoptosis, survival, and inhibition of neurite outgrowth. Recently,p75NTR was also shown to undergo γ-secretase-mediated regulated intramembrane proteolysis, and the receptor ICD was found to migrate to the nucleus where it regulates gene transcription. Moreover, γ-secretase-mediated proteolysis was shown to be involved in glioblastoma cell migration and invasion. In this study we report that TRAF6-mediated K63-linked polyubiquitination at multiple or alternative lysine residues influences p75NTR-ICD stability in vitro. In addition, we found that TRAF6-mediated ubiquitination of p75NTR is not influenced by inhibition of dynamin. Moreover, we report beta-transducin repeats-containing protein (β-TrCP) as a novel E3- ligase that ubiquitinates p75NTR, which is independent of serine phosphorylation of the p75NTR destruction motif. In contrast to its influence on other substrates, co-expression of β-TrCP did not reduce p75NTR stability. We created U87-MG glioblastoma cell lines stably expressing wild type, γ-secretaseresistant and constitutively cleaved receptor, as well as the ICD-stabilized mutant K301R. Interestingly, only wild-type p75NTR induces increased glioblastoma cell migration, which could be reversed by application of γ-secretase inhibitor. Microarray and qRT-PCR analysis of mRNA transcripts in these cell lines yielded several promising genes that might be involved in glioblastoma cell migration and invasion, such as cadherin 11 and matrix metalloproteinase 12. Analysis of potential transcription factor binding sites revealed that transcription of these genes might be regulated by well known p75NTR signalling cascades such as NF-κB or JNK signalling, which are independent of γ-secretase-mediated cleavage of the receptor. In contrast, while p75NTR overexpression was confirmed in melanoma cell lines and a patient sample of melanoma metastasis to the brain, inhibition of γ-secretase did not influence melanoma cell migration. Collectively, this study provides several avenues to better understand the physiological importance of posttranslational modifications of p75NTR and the significance of the receptor in glioblastoma cell migration and invasion.

A randomised phase II study of two different schedules of pegylated liposomal doxorubicin in metastatic breast cancer (EORTC-10993).

One hundred and sixteen women with measurable metastatic breast cancer participated in a randomised phase II study of single agent liposomal pegylated doxorubicin (Caelyx) given either as a 60 mg/m2 every 6 weeks (ARM A) or 50 mg/m2 every 4 weeks (ARM B) schedule. Patients were over 65 years of age or, if younger, had refused or been unsuitable for standard anthracyclines. The aims of the study were to evaluate toxicity and dose delivery with the two schedules and obtain further information on the response rate of liposomal pegylated doxorubicin as a single agent in anthracycline nai ve advanced breast cancer. Twenty-six patients had received prior adjuvant chemotherapy (including an anthracycline in 10). Sixteen had received non-anthracycline-based first-line chemotherapy for advanced disease. One hundred and eleven patients were evaluable for toxicity and 106 for response. The delivered dose intensity (DI) was 9.8 mg/m2 (95% CI, 7.2-10.4) with 37 (69%) achieving a DI of >90% on ARM A and 11.9 mg/m2 (95% CI, 7.5-12.8) with 37 (65%) achieving a DI of >90% on ARM B. The adverse event profiles of the two schedules were distinctly different. Mucositis was more common with the every 6 weeks regimen (35% CTC grade 3/4 in ARM A, 14% in ARM B) but palmar plantar erythrodysesthesia (PPE) was more frequent with the every 4 weeks regimen (2% CTC grade 3/4 in ARM A, 16% in ARM B). Confirmed objective partial responses by RECIST criteria were seen with both schedules; 15/51 (29%) on ARM A and 17/56 (31%) on ARM B. Liposomal pegylated doxorubicin showed significant activity in advanced breast cancer with a generally favourable side-effect profile. The high frequency of stomatitis seen with 6 weekly treatment makes this the less preferred of the two schedules tested.

GABRIEL URBAIN FAURÉ, THE UNSUNG MODERNIST: A PERFORMANCE SURVEY OF SELECTED LATE WORKS WRITTEN AFTER 1892 FOR PIANO SOLO, AND PIANO IN COLLABORATION WITH VIOLIN, VIOLONCELLO, AND VOICE

Gabriel Urbain Fauré lived during one of the most exciting times in music history. Spanning a life of 79 years (1845-1924), he lived through the height of Romanticism and the experimental avant-garde techniques of the early 20th century. In Fauré's music, one can find traces of Chopin, Liszt, Mendelssohn, Debussy and Poulenc. One can even argue that Fauré presages Skryabin and Shostakovich. The late works of Gabriel Fauré, chiefly those composed after 1892, testify to the argument that Fauré holds an important position in the shift from tonal to atonal composition and should be counted among such transitional composers as Gustav Mahler, Claude Debussy, Erik Satie, Richard Strauss, and Ferruccio Busoni. Fauré's unique way of fashioning harmonic impetus of almost purely linear means, resulting in a synthesis of harmonic and melodic devices, led me to craft the term mélodoharmonique. This term refers to a contrapuntally motivated technique of composition, particularly in a secondary layer of musical texture, in which a component of harmonic progression (i.e. arpeggiation, broken chord, etc.) is fused with linear motivic or thematic development. This dissertation seeks to bring to public attention through exploration in lecture and recital format, certain works of Gabriel Fauré, written after 1892. The repertoire will be selected from works for solo piano and piano in collaboration with violin, violoncello, and voice, which support the notion of Fauré as a modernist deserving larger recognition for his influence in the transition to atonal music. The recital repertoire includes the following--Song Cycles: La bonne chanson, opus 61; La chanson d'Ève, opus 95; Le jardin clos, opus 106; Mirages, opus 113; L'horizon chimérique, opus 118; Piano Works: Prelude in G minor opus 103, No. 3; Prelude in E minor opus 103, No. 9; Eleventh Nocturne, opus 104, No.1; Thirteenth Nocturne, opus 119; Chamber Works: Second Violin Sonata, opus 108; First Violoncello Sonata, opus 109; Second Violoncello Sonata, opus 117.

Evaluation of an epithelial plasticity biomarker panel in men with localized prostate cancer.

BACKGROUND: Given the potential importance of epithelial plasticity (EP) to cancer metastasis, we sought to investigate biomarkers related to EP in men with localized prostate cancer (PC) for the association with time to PSA recurrence and other clinical outcomes after surgery. METHODS: Men with localized PC treated with radical prostatectomy at the Durham VA Medical Center and whose prostatectomy tissues were included in a tissue microarray (TMA) linked to long-term outcomes. We performed immunohistochemical studies using validated antibodies against E-cadherin and Ki-67 and mesenchymal biomarkers including N-cadherin, vimentin, SNAIL, ZEB1 and TWIST. Association studies were conducted for each biomarker with baseline clinical/pathologic characteristics an risk of PSA recurrence over time. RESULTS: Two hundred and five men contributed TMA tissue and had long-term follow-up (median 11 years). Forty-three percent had PSA recurrence; three died of PC. The majority had high E-cadherin expression (86%); 14% had low/absent E-cadherin expression. N-cadherin was rarely expressed (<4%) and we were unable to identify an E-to-N-cadherin switch as independently prognostic. No associations with clinical risk group, PSA recurrence or Gleason sum were noted for SNAIL, ZEB1, vimentin or TWIST, despite heterogeneous expression between patients. We observed an association of higher Ki-67 expression with Gleason sum (P=0.043), National Comprehensive Cancer Network risk (P=0.013) and PSA recurrence (hazard ratio 1.07, P=0.016). CONCLUSIONS: The expression of EP biomarkers in this cohort of men with a low risk of PC-specific mortality was not associated with aggressive features or PSA relapse after surgery.

The effects of curcumin (diferuloylmethane) on body composition of patients with advanced pancreatic cancer.

BACKGROUND: Curcumin is a natural product that is often explored by patients with cancer. Weight loss due to fat and muscle depletion is a hallmark of pancreatic cancer and is associated with worse outcomes. Studies of curcumin's effects on muscularity show conflicting results in animal models. METHODS AND RESULTS: Retrospective matched 1:2 case-control study to evaluate the effects of curcumin on body composition (determined by computerized tomography) of 66 patients with advanced pancreatic cancer (22 treated,44 controls). Average age (SEM) was 63(1.8) years, 30/66(45%) women, median number of prior therapies was 2, median (IQR) time from advanced pancreatic cancer diagnosis to baseline image was 7(2-13.5) months (p>0.2, all variables). All patients lost weight (3.3% and 1.3%, treated vs. control, p=0.13). Treated patients lost more muscle (median [IQR] percent change -4.8[-9.1,-0.1] vs. -0.05%[-4.2, 2.6] in controls,p<0.001) and fat (median [IQR] percent change -6.8%[-15,-0.6] vs. -4.0%[-7.6, 1.3] in controls,p=0.04). Subcutaneous fat was more affected in the treated patients. Sarcopenic patients treated with curcumin(n=15) had survival of 169(115-223) days vs. 299(229-369) sarcopenic controls(p=0.024). No survival difference was found amongst non-sarcopenic patients. CONCLUSIONS: Patients with advanced pancreatic cancer treated with curcumin showed significantly greater loss of subcutaneous fat and muscle than matched untreated controls.

Characterization of autonomous thyroid adenoma: metabolism, gene expression, and pathology.

Fifty-one in vivo characterized autonomous single adenomas have been studied for functional parameters in vitro, for gene and protein expression and for pathology, and have been systematically compared to the corresponding extratumoral quiescent tissue. The adenomas were characterized by a high level of iodide trapping that corresponds to a high level of Na+ /iodide symporter gene expression, a high thyroperoxidase mRNA and protein content, and a low H2O2 generation. This explains the iodide metabolism characteristics demonstrated before, ie, the main cause of the "hot" character of the adenomas is their increased iodide transport. The adenomas spontaneously secreted higher amounts of thyroid hormone than the quiescent tissue and in agreement with previous in vivo data, this secretion could be further enhanced by thyrotropin (TSH). Inositol uptake was also increased but there was no spontaneous increase of the generation of inositol phosphates and this metabolism could be further activated by TSH. These positive responses to TSH are in agreement with the properties of TSH-stimulated thyroid cells in vitro and in vivo. They are compatible with the characteristics of mutated TSH receptors whose constitutive activation accounts for the majority of autonomous thyroid adenomas in Europe. The number of cycling cells, as evaluated by MIB-1 immunolabeling was low but increased in comparison with the corresponding quiescent tissue or normal tissue. The cycling cells are observed mainly at the periphery; there was very little apoptosis. Both findings account for the slow growth of these established adenomas. On the other hand, by thyroperoxidase immunohistochemistry, the whole lesion appeared hyperfunctional, which demonstrates a dissociation of mitogenic and functional stimulations. Thyroglobulin, TSH receptor, and E-cadherin mRNA accumulations were not modified in a consistent way, which confirms the near-constitutive expression of the corresponding genes in normal differentiated tissue. On the contrary, early immediate genes expressions (c-myc, NGF1B, egr 1, genes of the fos and jun families) were decreased. This may be explained by the proliferative heterogeneity of the lesion and the previously described short, biphasic expression of these genes when induced by mitogenic agents. All the characteristics of the autonomous adenomas can therefore be explained by the effect of the known activating mutations of genes coding for proteins of the TSH cyclic adenosine monophosphate (cAMP) cascade, all cells being functionally activated while only those at the periphery multiply. The reason of this heterogeneity is unknown.

Efecto de los surfactantes siliconados en el tamaño y evaporación de la gota de aspersión

El tamaño de la gota asperjada influye en la posibilidad de encuentro entre el caldo, que contiene el producto fitosanitario, con el blanco. En la probabilidad de ese encuentro, gota-blanco, interactúan variables como: tamaño de gota, modo de acción del producto fitosanitario, presencia de surfactantes en la formulación del producto fitosanitario y/o la incorporación de aditivos o coadyuvantes de aplicación en el caldo de aspersión; condiciones ambientales y características y tamaño de la superficie receptora del caldo asperjado. La interacción de las variables antes descriptas influyen básicamente en las derivas y la evaporación de la gota sobre la superficie del blanco, jugando un papel categórico en el resultado del tratamiento, muchas veces enmascarado por el uso de altas dosis del producto formulado. Los coadyuvantes y/o aditivos del tipo surfactantes básicamente se emplean para disminuir la tensión superficial de una gota, evitando que ésta ruede y no quede retenida en el blanco. En el presente trabajo, se evaluó el efecto que tiene el uso de una mezcla de surfactante siliconado, en comparación con una gota de agua, sobre las variables 'tamaño de la gota' (formada con micropipeta volumétrica) y 'tiempo de evaporación`de dicha gota. Se utilizó una micropipeta volumétrica a fin de analizar el efecto de la dilución del surfactante de manera independiente a la influencia, en el tamaño de la gota asperjada, aportada por la boquilla pulverizadora y la formulación del producto fitosanitario. Los resultados obtenidos confirman que el tamaño de gota se ve reducido, en volumen y en peso, al igual que el tiempo en que tarda en evaporarse una gota que contiene una mezcla de agua más surfactante siliconado vs. una gota de agua. También permite concluir que, el uso de tarjetas hidrosensibles para predecir el comportamiento de los surfactantes sobre el tamaño de gota, es inadecuado.