Multi-institutional validation of the prognostic value of Ki-67 labeling index in patients treated with radical prostatectomy.

OBJECTIVE: Several smaller single-center studies have reported a prognostic role for Ki-67 labeling index in prostate cancer. Our aim was to test whether Ki-67 is an independent prognostic marker of biochemical recurrence (BCR) in a large international cohort of patients treated with radical prostatectomy (RP). METHODS: Ki-67 immunohistochemical staining on prostatectomy specimens from 3,123 patients who underwent RP for prostate cancer was retrospectively performed. Univariable and multivariable Cox regression models were used to assess the association of Ki-67 status with BCR. RESULTS: Ki-67 positive status was observed in 762 (24.4 %) patients and was associated with lymph node involvement (LNI) (p = 0.039). Six hundred and twenty-one (19.9 %) patients experienced BCR. The estimated 3-year biochemical-free survivals were 85 % for patients with negative Ki-67 status and 82.1 % for patients with positive Ki-67 status (log-rank test, p = 0.014). In multivariable analysis that adjusted for the effects of age, preoperative PSA, RP Gleason sum, seminal vesicle invasion, extracapsular extension, positive surgical margins, lymphovascular invasion, and LNI, Ki-67 was significantly associated with BCR (HR = 1.19; p = 0.019). Subgroup analysis revealed that Ki-67 is associated with BCR in patients without LNI (p = 0.004), those with RP Gleason sum 7 (p = 0.015), and those with negative surgical margins (p = 0.047). CONCLUSION: We confirmed Ki-67 as an independent predictor of BCR after RP. Ki-67 could be particularly informative in patients with favorable pathologic characteristics to help in the clinical decision-making regarding adjuvant therapy and optimized follow-up scheduling.

Transcriptional regulator PRDM12 is essential for human pain perception.

Pain perception has evolved as a warning mechanism to alert organisms to tissue damage and dangerous environments. In humans, however, undesirable, excessive or chronic pain is a common and major societal burden for which available medical treatments are currently suboptimal. New therapeutic options have recently been derived from studies of individuals with congenital insensitivity to pain (CIP). Here we identified 10 different homozygous mutations in PRDM12 (encoding PRDI-BF1 and RIZ homology domain-containing protein 12) in subjects with CIP from 11 families. Prdm proteins are a family of epigenetic regulators that control neural specification and neurogenesis. We determined that Prdm12 is expressed in nociceptors and their progenitors and participates in the development of sensory neurons in Xenopus embryos. Moreover, CIP-associated mutants abrogate the histone-modifying potential associated with wild-type Prdm12. Prdm12 emerges as a key factor in the orchestration of sensory neurogenesis and may hold promise as a target for new pain therapeutics.

(Des)obediències de la reducció vocàlica en el català de Mallorca

En el català de Mallorca, el procés de reducció vocàlica de les vocals mitjanes de la sèrie anterior a e neutra en posició àtona no opera (o subaplica) en determinades circumstàncies: (a) en formes derivades productives amb una vocal àtona situada a la síl·laba esquerra o inicial del radical i alternant amb e tancada o e oberta en el radical de la forma primitiva; (b) en formes verbals amb una vocal àtona situada a la síl·laba esquerra o inicial del radical i alternant amb e tancada en una altra forma verbal del mateix paradigma flexiu; (c) en manlleus i paraules apreses amb una vocal àtona e situada, també, a la síl·laba esquerra o inicial del radical i generalment precedida d"una consonant labial. En aquest treball, argumentem que hi ha dos factors que conspiren perquè això sigui d"aquesta manera: (a) tal com ja s"ha fet notar en treballs anteriors, la voluntat d"aquestes vocals d"assemblar-se a les vocals corresponents que apareixen en mots del mateix paradigma derivatiu o flexiu, i, en el cas de la derivació, sobretot quan la relació derivativa és productiva; (b) l"estatus privilegiat de la síl·laba situada a l"esquerra o a l"inici del radical. Per donar compte del primer factor, proposem una nova interpretació dels fets emmarcada en la Teoria de la Correspondència Transderivacional i el model dels Paradigmes Òptims. Per donar compte del segon factor, que ha passat desapercebut en aproximacions anteriors a les mateixes dades, partim de la Teoria de la Fidelitat Posicional i de la Teoria del Marcatge Posicional.

Effect of Smoking on Blood Pressure and Resting Heart Rate: A Mendelian Randomization Meta-Analysis in the CARTA Consortium.

BACKGROUND: Smoking is an important cardiovascular disease risk factor, but the mechanisms linking smoking to blood pressure are poorly understood. METHODS AND RESULTS: Data on 141 317 participants (62 666 never, 40 669 former, 37 982 current smokers) from 23 population-based studies were included in observational and Mendelian randomization meta-analyses of the associations of smoking status and smoking heaviness with systolic and diastolic blood pressure, hypertension, and resting heart rate. For the Mendelian randomization analyses, a genetic variant rs16969968/rs1051730 was used as a proxy for smoking heaviness in current smokers. In observational analyses, current as compared with never smoking was associated with lower systolic blood pressure and diastolic blood pressure and lower hypertension risk, but with higher resting heart rate. In observational analyses among current smokers, 1 cigarette/day higher level of smoking heaviness was associated with higher (0.21 bpm; 95% confidence interval 0.19; 0.24) resting heart rate and slightly higher diastolic blood pressure (0.05 mm Hg; 95% confidence interval 0.02; 0.08) and systolic blood pressure (0.08 mm Hg; 95% confidence interval 0.03; 0.13). However, in Mendelian randomization analyses among current smokers, although each smoking increasing allele of rs16969968/rs1051730 was associated with higher resting heart rate (0.36 bpm/allele; 95% confidence interval 0.18; 0.54), there was no strong association with diastolic blood pressure, systolic blood pressure, or hypertension. This would suggest a 7 bpm higher heart rate in those who smoke 20 cigarettes/day. CONCLUSIONS: This Mendelian randomization meta-analysis supports a causal association of smoking heaviness with higher level of resting heart rate, but not with blood pressure. These findings suggest that part of the cardiovascular risk of smoking may operate through increasing resting heart rate.

La persistente influencia del origen social sobre la desigualdad de resultados. Una aproximación multinivel a partir de PISA 2009

La persistencia del factor del origen social como determinante de los rendimientos académicos ha sido monitorizada a partir de los años sesenta. Los datos de la encuesta PISA que evalúa han corroborado que el factor determinante del contexto socioeconómico de origen a la hora de explicar la desigualdad de resultados y rendimientos (Duru-Bellat, 2004; Gorard, 2004; Ferrer, 2006). Dupriez y Dumay (2004) concluyen que la desigualdad de resultados está más determinada por la composición social de las escuelas que no por sus mecanismos organizativos y pedagógicos. El artículo examina las diferencias de resultados de aprendizaje en matemáticas entre centros y dentro de los centros en los países de la OCDE y se centra sobre algunos factores que son clave a la hora de explicar estas diferencias. El aprendizaje en matemáticas es analizado a través de un modelo de regresión multinivel.

Long-term treatment with insulin induces apoptosis in brown adipocytes: role of oxidative stress

Trying to define the precise role played by insulin regulating the survival of brown adipocytes, we have used rat fetal brown adipocytes maintained in primary culture. The effect of insulin on apoptosis and the mechanisms involved were assessed. Different from the known effects of insulin as a survival factor, we have found that long-term treatment (72 h) with insulin induces apoptosis in rat fetal brown adipocytes. This process is dependent on the phosphatidylinositol 3-kinase/mammalian target of rapamycin/p70 S6 kinase pathway. Short-term treatment with the conditioned medium from brown adipocytes treated with insulin for 72 h mimicked the apoptotic effect of insulin. During the process, caspase 8 activation, Bid cleavage, cytochrome c release, and activation of caspases 9 and 3 are sequentially produced. Treatment with the caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp (Z-VAD), prevents activation of this apoptotic cascade. The antioxidants, ascorbic acid and superoxide dismutase, also impair this process of apoptosis. Moreover, generation of reactive oxygen species (ROS), probably through reduced nicotinamide adenine dinucleotide phosphate oxidases, and a late decrease in reduced glutathione content are produced. According to this, antioxidants prevent caspase 8 activation and Bid cleavage, suggesting that ROS production is an important event mediating this process of apoptosis. However, the participation of uncoupling protein-1, -2, and -3 regulating ROS is unclear because their levels remain unchanged upon insulin treatment for 72 h. Our data suggest that the prolonged hyperinsulinemia might cause insulin resistance through the loss of brown adipose tissue.

Auto Poisoning of the Respiratory Chain by a Quorum-Sensing-Regulated Molecule Favors Biofilm Formation and Antibiotic Tolerance.

Bacterial programmed cell death and quorum sensing are direct examples of prokaryote group behaviors, wherein cells coordinate their actions to function cooperatively like one organism for the benefit of the whole culture. We demonstrate here that 2-n-heptyl-4-hydroxyquinoline-N-oxide (HQNO), a Pseudomonas aeruginosa quorum-sensing-regulated low-molecular-weight excreted molecule, triggers autolysis by self-perturbing the electron transfer reactions of the cytochrome bc1 complex. HQNO induces specific self-poisoning by disrupting the flow of electrons through the respiratory chain at the cytochrome bc1 complex, causing a leak of reducing equivalents to O2 whereby electrons that would normally be passed to cytochrome c are donated directly to O2. The subsequent mass production of reactive oxygen species (ROS) reduces membrane potential and disrupts membrane integrity, causing bacterial cell autolysis and DNA release. DNA subsequently promotes biofilm formation and increases antibiotic tolerance to beta-lactams, suggesting that HQNO-dependent cell autolysis is advantageous to the bacterial populations. These data identify both a new programmed cell death system and a novel role for HQNO as a critical inducer of biofilm formation and antibiotic tolerance. This newly identified pathway suggests intriguing mechanistic similarities with the initial mitochondrial-mediated steps of eukaryotic apoptosis.

Alimentación parenteral total

El intenés médico por alimentar a los humanos por vías distintas a la oral es conocido desde el siglo XVII, pero sólo desde hace unos 20 aftos se puede realizar de una manera segura, prolongada y con posibilidades de éxito. Este progreso se apoya en cuatro puntas principales...

Prostaglandin E2 Prevents Hyperosmolar-Induced Human Mast Cell Activation through Prostanoid Receptors EP2 and EP4.

Background: Mast cells play a critical role in allergic and inflammatory diseases, including exercise-induced bronchoconstriction (EIB) in asthma. The mechanism underlying EIB is probably related to increased airway fluid osmolarity that activates mast cells to the release inflammatory mediators. These mediators then act on bronchial smooth muscle tocause bronchoconstriction. In parallel, protective substances such as prostaglandin E2 (PGE2) are probably also released and could explain the refractory period observed in patients with EIB. Objective: This study aimed to evaluate the protective effect of PGE2 on osmotically activated mast cells, as a model of exercise-induced bronchoconstriction. Methods: We used LAD2, HMC-1, CD34-positive, and human lung mast cell lines. Cells underwent a mannitol challenge, and the effects of PGE2 and prostanoid receptor (EP) antagonists for EP14 were assayed on the activated mast cells. Betahexosaminidase release, protein phosphorylation, and calcium mobilization were assessed. Results: Mannitol both induced mast cell degranulation and activated phosphatidyl inositide 3-kinase and mitogenactivated protein kinase (MAPK) pathways, thereby causing de novo eicosanoid and cytokine synthesis. The addition of PGE2 significantly reduced mannitol-induced degranulation through EP2 and EP4 receptors, as measured by betahexosaminidase release, and consequently calcium influx. Extracellular-signal-regulated kinase 1/2, c-Jun N-terminal kinase,and p38 phosphorylation were diminished when compared with mannitol activation alone. Conclusions: Our data show a protective role for the PGE2 receptors EP2 and EP4 following osmotic changes, through the reduction of human mast cell activity caused by calcium influx impairment and MAP kinase inhibition.

O Quadrante de Ruetsap e a anti-ciência, tecnologia e inovação

The concept of research and the controversy among classical models for C, T & I, outdated by the development of knowledge and Post-modern society needs were revisited through the (3) Quadrants advanced by Donald Stokes in the mid-nineties. The scientific community to fit into these Quadrants was faced with many difficulties and reacted by issuing pseudo-facts, accepted by under-prepared technocrats as viable justifications for conducting research in face of these new paradigms. In a poor country full of contrast and needs such as Brazil, this attitude satisfies the bureaucracy and academic elite, but frustrates government and society, that do not get, in the expected measure, the benefits of their commitment with the Teaching, Research and Extension Sectors mainly embedded in the Public University system. An extension, in fact a contradictory approach, to Pasteur's Quadrant, is proposed to characterize this situation: The Syndrome of Ruetsap's Quadrant.

Does soil moisture overrule temperature dependence of soil respiration in Mediterranean riparian forests?

Soil respiration (SR) is a major component of ecosystems' carbon cycles and represents the second largest CO2 flux in the terrestrial biosphere. Soil temperature is considered to be the primary abiotic control on SR, whereas soil moisture is the secondary control factor. However, soil moisture can become the dominant control on SR in very wet or dry conditions. Determining the trigger that makes soil moisture as the primary control factor of SR will provide a deeper understanding on how SR changes under the projected future increase in droughts. Specific objectives of this study were (1) to investigate the seasonal variations and the relationship between SR and both soil temperature and moisture in a Mediterranean riparian forest along a groundwater level gradient; (2) to determine soil moisture thresholds at which SR is controlled by soil moisture rather than by temperature; (3) to compare SR responses under different tree species present in a Mediterranean riparian forest (Alnus glutinosa, Populus nigra and Fraxinus excelsior). Results showed that the heterotrophic soil respiration rate, groundwater level and 30 cm integral soil moisture (SM30) decreased significantly from the riverside moving uphill and showed a pronounced seasonality. SR rates showed significant differences between tree species, with higher SR for P. nigra and lower SR for A. glutinosa. The lower threshold of soil moisture was 20 and 17% for heterotrophic and total SR, respectively. Daily mean SR rate was positively correlated with soil temperature when soil moisture exceeded the threshold, with Q10 values ranging from 1.19 to 2.14; nevertheless, SR became decoupled from soil temperature when soil moisture dropped below these thresholds.

Identidad de género y cuidados intensivos: influencia de la masculinidad y la feminidad en la percepción de los cuidados enfermeros

Introducción: La enfermería ha sido fundamentalmente un trabajo de mujeres. El incremento en la incorporación de hombres a la enfermería nos hace reflexionar en torno a la cuestión de si existen diferentes formas de expresar y practicar una profesión en relación al género. Objetivo: Describir si existen diferentes maneras de percibir y valorar el trabajo en la UCI desde una perspectiva de género. Metodología: Estudio cualitativo fenomenológico. Muestra: 6 enfermeros y 6 enfermeras de la UCI del HUB Recogida de datos: Entrevista semi-estructurada en profundidad. Análisis de contenido. Resultados: Los enfermeros describen el trabajo en la UCI en términos de autonomía en las decisiones y competencia profesional; reivindican su identidad como enfermeros y destacan el bajo reconocimiento social que se hace de la profesión; priorizan más la responsabilidad en la toma de decisiones que el resultado final y valoran la satisfacción familiar en términos de prestigio y competencia. Son más prácticos. Las enfermeras califican el trabajo en términos de control y seguimiento en la evolución del enfermo; destacan más el resultado final del cuidado y valoran la satisfacción en términos de relación de confianza y calidez asistencial. Son más detallistas. Conclusiones: Existen diferencias en la manera de calificar el trabajo en la UCI, en la valoración de la identidad profesional, el comportamiento en el desarrollo de los cuidados de enfermería y en la percepción de la satisfacción familiar. No se observan diferencias en relación al abordaje en la resolución de problemas con la tecnología.

Natural occurrence, biological activities and synthesis of eight-, nine-, and eleven-membered ring lactones

The natural occurrence, biological activities and synthetic approaches to natural eight-, nine-, and eleven-membered lactones is reviewed. These medium ring lactones are grouped according to ring size, and their syntheses are discussed. The structures of some natural products early identified as medium-ring lactones were revised after total synthesis.

Micro- and nanostructuring of poly(ethylene-2,6-naphthalate) surfaces, for biomedical applications, using polymer replication techniques

Here we investigate the formation of superficial micro- and nanostructures in poly(ethylene-2,6-naphthalate) (PEN), with a view to their use in biomedical device applications, and compare its performance with a polymer commonly used for the fabrication of these devices, poly(methyl methacrylate) (PMMA). The PEN is found to replicate both micro- and nanostructures in its surface, albeit requiring more forceful replication conditions than PMMA, producing a slight increase in surface hydrophilicity. This ability to form micro/nanostructures, allied to biocompatibility and good optical transparency, suggests that PEN could be a useful material for production of, or for incorporation into, transparent devices for biomedical applications. Such devices will be able to be autoclaved, due to the polymer's high temperature stability, and will be useful for applications where forceful experimental conditions are required, due to a superior chemical resistance over PMMA.

Targeting striatal metabotropic glutamate receptor type 5 in Parkinson's disease: bridging molecular studies and clinical trials

Metabotropic glutamate (mGlu) receptors are G protein-coupled receptors expressed primarily on neurons and glial cells modulating the effects of glutamatergic neurotransmission. The pharmacological manipulation of these receptors has been postulated to be valuable in the management of some neurological disorders. Accordingly, the targeting of mGlu5 receptors as a therapeutic approach for Parkinson's disease (PD) has been proposed, especially to manage the adverse symptoms associated to chronic treatment with classical PD drugs. Thus, the specific pharmacological blocking of mGlu5 receptors constitutes one of the most attractive non-dopaminergic-based strategies for PD management in general and for the L-DOPA-induced diskynesia (LID) in particular. Overall, we provide here an update of the current state of the art of these mGlu5 receptor-based approaches that are under clinical study as agents devoted to alleviate PD symptoms.