Population consequences of environmental sex reversal.

When sex determination in a species is predominantly genetic but environmentally reversible, exposure to (anthropogenic) changes in the environment can lead to shifts in a population's sex ratio. Such scenarios may be common in many fishes and amphibians, yet their ramifications remain largely unexplored. We used a simple model to study the (short-term) population consequences of environmental sex reversal (ESR). We examined the effects on sex ratios, sex chromosome frequencies, and population growth and persistence after exposure to environmental forces with feminizing or masculinizing tendencies. When environmental feminization was strong, X chromosomes were driven to extinction. Analogously, extinction of normally male-linked genetic factors (e.g., Y chromosomes) was caused by continuous environmental masculinization. Although moderate feminization was beneficial for population growth in the absence of large viability effects, our results suggest that the consequences of ESR are generally negative in terms of population size and the persistence of sex chromosomes. Extreme sex ratios resulting from high rates of ESR also reduced effective population sizes considerably. This may limit any evolutionary response to the deleterious effects of ESR. Our findings suggest that ESR changes population growth and sex ratios in some counter-intuitive ways and can change the predominant factor in sex determination from genetic to fully environmental, often within only a few tens of generations. Populations that lose genetic sex determination may quickly go extinct if the environmental forces that cause sex reversal cease.

The evolution of punishment through reputation.

Punishment of non-cooperators has been observed to promote cooperation. Such punishment is an evolutionary puzzle because it is costly to the punisher while beneficial to others, for example, through increased social cohesion. Recent studies have concluded that punishing strategies usually pay less than some non-punishing strategies. These findings suggest that punishment could not have directly evolved to promote cooperation. However, while it is well established that reputation plays a key role in human cooperation, the simple threat from a reputation of being a punisher may not have been sufficiently explored yet in order to explain the evolution of costly punishment. Here, we first show analytically that punishment can lead to long-term benefits if it influences one's reputation and thereby makes the punisher more likely to receive help in future interactions. Then, in computer simulations, we incorporate up to 40 more complex strategies that use different kinds of reputations (e.g. from generous actions), or strategies that not only include punitive behaviours directed towards defectors but also towards cooperators for example. Our findings demonstrate that punishment can directly evolve through a simple reputation system. We conclude that reputation is crucial for the evolution of punishment by making a punisher more likely to receive help in future interactions, and that experiments investigating the beneficial effects of punishment in humans should include reputation as an explicit feature.

Nutrient leaching potential following application of papermill lime-sludge to an acidic clay soil

This experiment was carried out under greenhouse conditions with soil pots during 210 days, to evaluate the effect of calcitic papermill lime-sludge application (at the rates 0, 773, 1.547, and 2.320 mg kg-1 or respective equivalents to control, 2, 4, and 6 t ha-1), on chemical composition of soil leachate and its effects on eucalypt growth and yield. Highest soil leachate pH, SO4, and Na concentrations occurred in the 4 and 6 t ha-1 treatments. Soil leachate nitrate concentrations decreased with increasing lime-sludge rate. Soil leachate phosphate remained low (below the detection limit) in all treatments until 120 days, while the concentration increased in the lime-sludge treatments at 210 days (last sampling) in about 600 mg L-1. Lime-sludge decreased leachate Mg concentration, but had no significant effect among rates. Soil leachate Ca, K, B, Cu, Fe, and Zn did not change significantly for any lime-sludge application rates. The maximum NO3, Ca, Mg, K, and Na concentrations in the soil leachate occurred at 60 days after lime-sludge application (leaching equivalent to 1 pore volume), but for pH and SO4, the maximum occurred at 210 days (leaching equivalent to 4 pore volumes). Lime-sludge application decreased the concentration of exchangeable Al in the soil. Plant diameter growth and dry matter yield were increased with increasing lime-sludge rate. Beneficial effects on mineral nutrition (P, K, Ca, B, and Zn) of eucalypts were also obtained by the application of 4 and 6 t ha-1 of lime-sludge.

Fat poetry: a kingdom for PPAR gamma.

Adipose tissue is not an inert cell mass contributing only to the storage of fat, but a sophisticated ensemble of cellular components with highly specialized and complex functions. In addition to managing the most important energy reserve of the body, it secretes a multitude of soluble proteins called adipokines, which have beneficial or, alternatively, deleterious effects on the homeostasis of the whole body. The expression of these adipokines is an integrated response to various signals received from many organs, which depends heavily on the integrity and physiological status of the adipose tissue. One of the main regulators of gene expression in fat is the transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma), which is a fatty acid- and eicosanoid-dependent nuclear receptor that plays key roles in the development and maintenance of the adipose tissue. Furthermore, synthetic PPARgamma agonists are therapeutic agents used in the treatment of type 2 diabetes.This review discusses recent knowledge on the link between fat physiology and metabolic diseases, and the roles of PPARgamma in this interplay via the regulation of lipid and glucose metabolism. Finally, we assess the putative benefits of targeting this nuclear receptor with still-to-be-identified highly selective PPARgamma modulators.

Radio-immunothérapie du lymphome folliculaire: un pas vers la guérison [Radioimmunotherapy of follicular lymphoma: a step towards cure?]

Advanced stage follicular lymphoma is incurable by conventional treatment. Important progress has been observed with the development of new therapies based on monoclonal antibodies and on the use of radioimmunotherapy (RIT) in the treatment of non-Hodgkin lymphomas (NHL). Rituximab in combination with chemotherapy in the upfront setting significantly improved treatment outcome as compared with chemotherapy alone. Different studies also indicate that RIT has an important role in the management of NHL and could be beneficial in combination with chemotherapy. These two new treatment options have clearly distinctive mechanisms of action, rituximab being an exclusively biological treatment and RIT adding targeted systemic radiation therapy. Both RIT and the unlabeled antibody treatments might be further improved by different strategies including repetition of RIT or combination of different antibodies. We present here our experience with RIT using 131I-tositumomab (Bexxar) and discuss different topics regarding RIT, like the use of different antibodies, the best choice of the radioisotope or the place of radio-imaging. From the therapeutic point of view, we argue that the debate should not be as to which one among antibody immunotherapy or RIT should be best added to chemotherapy, but that all three treatments might be optimally combined with the aim to get the highest chance of cure for advanced stage follicular lymphoma.

Characterization of insulators and barrier elements for gene therapy

Gene transfer that relies on integrating vectors often suffers from epigenetic or regulatory effects that influence the expression of the therapeutic gene and=or of cellular genes located near the vector integration site in the chromosome. Insulator elements act to block gene activation by enhancers, while chromatin domain boundary or barrier sequences prevent gene-silencing effects. At present, the modes of action of insulator and barriers are poorly understood, and their use in the context of gene therapies remains to be documented. Using combinations of reporter genes coding for indicator fluorescent proteins, we constructed assay systems that allow the quantification of the insulator or barrier activities of genetic elements in individual cells. This presentation will illustrate how these assay systems were used to identify short DNA elements that insulate nearby genes from activation by viral vector elements, and=or that block the propagation of a silent chromatin structure that leads to gene silencing. We will show that some barrier elements do not merely block repressive effects, but that they can act to stabilize and sustain transgene expression. We will illustrate that this may be beneficial when transgenes are introduced into stem or precursor cells using non-viral vectors, where later differentiation may lead to the silencing of the therapeutic gene. We will show that these elements can be used to maintain efficient transgene expression upon the differentiation of murine precursor cells towards myofibers, in a model of cell therapy for muscle dystrophies.

Posttranscriptional repression of GacS/GacA-controlled genes by the RNA-binding protein RsmE acting together with RsmA in the biocontrol strain Pseudomonas fluorescens CHA0.

In the plant-beneficial soil bacterium Pseudomonas fluorescens CHA0, the production of biocontrol factors (antifungal secondary metabolites and exoenzymes) is controlled at a posttranscriptional level by the GacS/GacA signal transduction pathway involving RNA-binding protein RsmA as a key regulatory element. This protein is assumed to bind to the ribosome-binding site of target mRNAs and to block their translation. RsmA-mediated repression is relieved at the end of exponential growth by two GacS/GacA-controlled regulatory RNAs RsmY and RsmZ, which bind and sequester the RsmA protein. A gene (rsmE) encoding a 64-amino-acid RsmA homolog was identified and characterized in strain CHA0. Overexpression of rsmE strongly reduced the expression of target genes (hcnA, for a hydrogen cyanide synthase subunit; aprA, for the main exoprotease; and phlA, for a component of 2,4-diacetylphloroglucinol biosynthesis). Single null mutations in either rsmA or rsmE resulted in a slight increase in the expression of hcnA, aprA, and phlA. By contrast, an rsmA rsmE double mutation led to strongly increased and advanced expression of these target genes and completely suppressed a gacS mutation. Both the RsmE and RsmA levels increased with increasing cell population densities in strain CHA0; however, the amount of RsmA showed less variability during growth. Expression of rsmE was controlled positively by GacA and negatively by RsmA and RsmE. Mobility shift assays demonstrated specific binding of RsmE to RsmY and RsmZ RNAs. The transcription and stability of both regulatory RNAs were strongly reduced in the rsmA rsmE double mutant. In conclusion, RsmA and RsmE together account for maximal repression in the GacS/GacA cascade of strain CHA0.

Construction of Pseudomonas strains with improved biocontrol activity

Selected strains of fluorescent pseudomonads suppress various plant diseases caused by soil-borne pathogenic fungi, by a blend of several mechanisms including aggressive root colonization, antibiosis, competition for nutrients, induction of resistance in the plant, and enzymatic attack of the pathogen. These traits are amenable to genetic analysis and, therefore, to modification by genetic engineering. Biocontrol activities of Pseudomonas spp. have been enhanced in two ways: (i) by overexpression of traits known to involved in diseaese suppression, and (ii) by introduction of additional beneficial traits into strains having basal biocontrol activities. Under experimental conditions in microcosms, a number of genetically modified Pseudomonas strains have given promising results. It remains to be seen whether such strains will be superior to the best naturally occurring strains, applied singly or in combination, under greenhouse and field conditions.

Preretinal partial pressure of oxygen gradients before and after experimental pars plana vitrectomy.

PURPOSE: To evaluate preretinal partial pressure of oxygen (PO2) gradients before and after experimental pars plana vitrectomy. METHODS: Arteriolar, venous, and intervascular preretinal PO2 gradients were recorded in 7 minipigs during slow withdrawal of oxygen-sensitive microelectrodes (10-μm tip diameter) from the vitreoretinal interface to 2 mm into the vitreous cavity. Recordings were repeated after pars plana vitrectomy and balanced salt solution (BSS) intraocular perfusion. RESULTS: Arteriolar, venous, and intervascular preretinal PO2 at the vitreoretinal interface were 62.3 ± 13.8, 22.5 ± 3.3, and 17.0 ± 7.5 mmHg, respectively, before vitrectomy; 97.7 ± 19.9, 40.0 ± 21.9, and 56.3 ± 28.4 mmHg, respectively, immediately after vitrectomy; and 59.0 ± 27.4, 25.2 ± 3.0, and 21.5 ± 4.5 mmHg, respectively, 2½ hours after interruption of BSS perfusion. PO2 2 mm from the vitreoretinal interface was 28.4 ± 3.6 mmHg before vitrectomy; 151.8 ± 4.5 mmHg immediately after vitrectomy; and 34.8 ± 4.1 mmHg 2½ hours after interruption of BSS perfusion. PO2 gradients were still present after vitrectomy, with the same patterns as before vitrectomy. CONCLUSION: Preretinal PO2 gradients are not eliminated after pars plana vitrectomy. During BSS perfusion, vitreous cavity PO2 is very high. Interruption of BSS perfusion evokes progressive equilibration of vitreous cavity PO2 with concomitant progressive return of preretinal PO2 gradients to their previtrectomy patterns. This indicates that preretinal diffusion of oxygen is not altered after vitrectomy. The beneficial effect of vitrectomy in ischemic retinal diseases or macular edema may be related to other mechanisms, such as increased oxygen convection currents or removal of growth factors and cytokines secreted in the vitreous.

Ventricular but not atrial electro-mechanical delay of the embryonic heart is altered by anoxia-reoxygenation and improved by nitric oxide.

BACKGROUND/AIM: Excitation-contraction coupling is modulated by nitric oxide (NO) which otherwise has either beneficial or detrimental effects on myocardial function during hypoxia-reoxygenation. This work aimed at characterizing the variations of electromechanical delay (EMD) induced by anoxia-reoxygenation within the developing heart and determining whether atrial and ventricular EMD are modulated by NO to the same extent. METHODS: Hearts of 4 or 4.5-day-old chick embryos were excised and submitted in vitro to normoxia (45 min), anoxia (30 min) and reoxygenation (60 min). Electrocardiogram and atrial and ventricular contractions were simultaneously recorded throughout experiment. Anoxia-reoxygenation-induced chrono-, dromo-and inotropic disturbances and changes in EMD in atrium (EMDa) and ventricle (EMDv) were investigated in control hearts and in hearts exposed to 0.1, 1, 10, 50 and 100 microM of DETA-NONOate (a NO donating agent) or to 50 microM of L-NAME (a NOS inhibitor). RESULTS: Under normoxia, heart rate, PR interval, ventricular shortening velocity, EMDa and EMDv were similar in control, L-NAME-treated and DETA-NONOate-treated hearts. Under anoxia, cardiac activity became markedly erratic within less than 10 min in all groups. At the onset of reoxygenation, EMDv was increased by about 300% with respect to the preanoxic value while EMDa did not vary significatively. Compared to control conditions, L-NAME or DETA-NONOate had no influence on the negative chrono-, dromo- and inotropic effects induced by anoxia-reoxygenation. However, L-NAME prolonged EMDv during anoxia and delayed EMDv recovery during reoxygenation while 100 microM DETA-NONOate had the opposite effects. EMDa was neither affected by NOS inhibitor nor NO donor. At the end of reoxygenation, all the investigated parameters returned to their basal values. CONCLUSION: This work provides evidence that a NO-dependent pathway is involved in regulation of the ventricular excitation-contraction coupling in the anoxic-reoxygenated developing heart.

New insights into the role of microRNAs in pancreatic ß-cell maturation and plasticity

Le diabète est une maladie chronique caractérisée par une élévation du taux de sucre dans le sang aussi appelé « glycémie » reflétant un état pathologique. L'élévation de la glycémie au long cours a des répercussions délétères sur nombreux de nos tissus et organes d'où l'apparition de complications sévères chez les sujets diabétiques pouvant atteindre les yeux, les reins, le système nerveux, le système cardiovasculaire et les membres inférieurs. La carence en une hormone essentielle à notre organisme, l'insuline, est au coeur du développement de la maladie. L'insuline induit la captation du glucose circulant dans le sang en excès suite à une prise alimentaire riche en glucides et favorise son utilisation et éventuellement son stockage dans les tissus tels que le foie, le tissu adipeux et les muscles. Ainsi, l'insuline est vitale pour réguler et maintenir stable notre niveau de glycémie. Les cellules bêta du pancréas sont les seules entités de notre corps capables de produire de l'insuline et une perte de fonctionnalité associée à leur destruction ont été mises en cause dans le processus pathologique du diabète de type 2. Cependant la pleine fonctionnalité et la maturation des cellules bêta n'apparaissent qu'après la naissance lorsque le pancréas en développement a atteint sa masse adulte définitive. Enfin, une fois la masse des cellules bêta définitive établie, leur nombre et volume restent relativement constants au cours de la vie adulte chez un sujet sain. Néanmoins, au cours de périodes critiques les besoins en insuline sont augmentés tel qu'observé chez les femmes enceintes et les personnes obèses qui ont une perte de sensibilité à l'insuline qui se traduit par la nécessité de sécréter plus d'insuline afin de maintenir une glycémie normale. Dans l'hypothèse où la compensation n'a pas lieu ou n'est pas aboutie, le diabète se développe. Le processus de maturation postnatale ainsi que les événements compensatoires sont donc des étapes essentielles et de nombreuses questions sont encore non résolues concernant l'identification des mécanismes les régulant. Parmi les acteurs potentiels figurent de petites molécules d'ARN découvertes récemment appelées microARNs et qui ont été rapidement suggérées très prometteuses dans l'identification de nouvelles cibles thérapeutiques dans le cadre du diabète et d'autres pathologies. Les microARNs vont réguler l'expression de notre génome sans en modifier la séquence, phénomène également appelé épigénétique, ce qui résulte en des différences de comportement et de fonction cellulaires. Les microARNs sont donc susceptibles de jouer un rôle clé dans l'ensemble des processus biologiques et notre environnement associé à nos prédispositions génétiques peuvent grandement modifier leur niveau et donc leur action, qui à son tour se répercutera sur notre état physiologique. En effet nous avons identifié des changements de microARNs dans les cellules d'îlots pancréatiques de modèles animaux (rats et souris) associés à un état de résistance à l'insuline (grossesse et obésité). Par le biais d'expériences in vitro sur des cellules bêta extraites de rats et conservées en culture, nous avons pu analyser de plus près l'implication des microARNs dans la capacité des cellules bêta à sécréter de l'insuline mais aussi à se multiplier et à survivre au sein d'un environnement toxique. Ainsi, nous avons identifié des microARNs qui participent positivement à la compensation des cellules bêta, sous la direction d'hormones telles les estrogènes ou d'une hormone libérée par l'intestin au cours de la digestion (l'inerétine GLP1) et qui est largement utilisée comme agent thérapeutique dans la médication contre le diabète. Dans un second temps nous avons utilisé une stratégie similaire afin de déterminer le rôle de microARNs préalablement détectés comme étant changés au cours du développement postnatal des cellules bêta chez le rat. Cette étude a également mené à l'identification de microARNs participant à la maturation et à l'expansion de la masse des cellules bêta sous l'influence de la composition du régime alimentaire et des besoins en insuline adéquats qui en dépendent. Ces études apportent la vision de nouveaux mécanismes moléculaires impliquant les microARNs et démontrant leur importance pour le bon fonctionnement des cellules bêta et leur capacité d'adaptation à l'environnement. -- Les cellules bêta sont une composante des îlots pancréatiques de Langerhans et sont des cellules hautement différenciées qui ont l'unique capacité de sécréter de l'insuline sous l'influence des nutriments suite à une prise alimentaire. L'insuline facilite l'incorporation de glucose dans ses tissus cibles tels le foie, le tissu adipeux et les muscles. Bien que les besoins en insuline soient relativement constants au cours de la vie d'un individu sain, certaines conditions associées à un état de résistance à l'insuline, telles la grossesse ou l'obésité, requièrent une libération d'insuline majorée. En cas de résistance à l'insuline, une dysfonction des cellules bêta plus ou moins associée à leur mort cellulaire, conduisent à une sécrétion d'insuline insuffisante et au développement d'une hyperglycémie chronique, caractéristique du diabète de type 2. Jusqu'à présent, les mécanismes moléculaires sous- jacents à la compensation des cellules bêta ou encore menant à leur dysfonction restent peu connus. Découverts récemment, les petits ARNs non-codant appelés microARNs (miARNs), suscitent un intérêt grandissant de par leur potentiel thérapeutique pour la prise en charge et le traitement du diabète. Les miARNs sont de puissants régulateurs de l'expression génique qui lient directement le 3'UTR de leurs ARN messagers cibles afin d'inhiber leur traduction ou d'induire leur dégradation, ce qui leur permet de contrôler des fonctions biologiques multiples. Ainsi, nous avons pris pour hypothèse que les miARNs pourraient jouer un rôle essentiel en maintenant la fonction des cellules bêta et des processus compensatoires afin de prévenir le développement du diabète. Lors d'une première étude, une analyse transcriptomique a permis l'identification de miARNs différemment exprimés au sein d'îlots pancréatiques de rattes gestantes. Parmi eux, le miR-338-3p a démontré la capacité de promouvoir la prolifération et la survie des cellules bêta exposées à des acides gras saturés et des cytokines pro-inflammatoires, sans altérer leur propriété sécrétrice d'insuline. Nous avons également identifié deux hormones reconnues pour leurs propriétés bénéfiques pour la physiologie de la cellule bêta, l'estradiol et l'incrétine GLP1, qui régulent les niveaux du miR-338-3p. Ce miARN intègre parfaitement les voies de signalisation de ces deux hormones dépendantes de l'AMP cyclique, afin de contrôler l'expression de nombreux gènes conduisant à son action biologique. Dans un projet ultérieur, notre objectif était de déterminer la contribution de miARNs dans l'acquisition de l'identité fonctionnelle des cellules bêta en période postnatale. En effet, directement après la naissance les cellules bêta sont reconnues pour être encore immatures et incapables de sécréter de l'insuline spécifiquement en réponse à l'élévation de la glycémie. Au contraire, la réponse insulinique induite par les acides aminés ainsi que la biosynthèse d'insuline sont déjà fonctionnelles. Nos recherches ont permis de montrer que les changements de miARNs corrélés avec l'apparition du phénotype sécrétoire en réponse au glucose, sont régis par la composition nutritionnelle du régime alimentaire et des besoins en insuline qui en découlent. En parallèle, le taux de prolifération des cellules bêta est considérablement réduit. Les miARNs que nous avons étudiés coordonnent des changements d'expression de gènes clés impliqués dans l'acquisition de propriétés vitales de la cellule bêta et dans la maintenancé de son identité propre. Enfin, ces études ont permis de clairement démontrer l'importance des miARNs dans la régulation de la fonction des cellules bêta pancréatiques. -- Beta-cells are highly differentiated cells localized in the pancreatic islets and are characterized by the unique property of secreting insulin in response to nutrient stimulation after meal intake. Insulin is then in charge of facilitating glucose uptake by insulin target tissues such as liver, adipose tissue and muscles. Despite insulin needs stay more or less constant throughout life of healthy individuals, there are circumstances such as during pregnancy or obesity which are associated to insulin resistance, where insulin needs are increased. In this context, defects in beta-cell function, sometimes associated with beta-cell loss, may result in the release of inappropriate amounts of insulin leading to chronic hyperglycemia, properly defined as type 2 diabetes mellitus. So far, the mechanisms underlying beta- cell compensation as well as beta-cell failure remain to be established. The recently discovered small non-coding RNAs called microRNAs (miRNAs) are emerging as interesting therapeutic targets and are bringing new hope for the treatment of diabetes. miRNAs display a massive potential in regulating gene expression by directly binding to the 3'UTR of messenger RNAs and by inhibiting their translation and/or stability, enabling them to modify a wide range of biological functions. In view of this, we hypothesized that miRNAs may play an essential role in preserving the functional beta-cell mass and permitting to fight against beta-cell exhaustion and decompensation that can lead to diabetes development. In a first study, global profiling in pancreatic islets of pregnant rats, a model of insulin resistance, led to the identification of a set of differentially expressed miRNAs. Among them, miR-338- 3p was found to promote beta-cell proliferation and survival upon exposure of islet cells to pro- apoptotic stimuli such as saturated fatty acids or pro-inflammatory cytokines, without impairment in their capacity to release insulin. We also discovered that miR-338-3p changes are driven by two hormones, the estradiol and the incretin GLP1, both well known for their beneficial impact on beta- cell physiology. Consistently, we found that miR-338-3p integrates the cAMP-dependent signaling pathways regulated by these two hormones in order to control the expression of numerous genes and execute its biological functions. In a second project, we aimed at determining whether miRNAs contribute to the acquisition of beta-cell identity. Indeed, we confirmed that right after birth beta-cells are still immature and are unable to secrete insulin specifically in response to elevated concentrations of glucose. In contrast, amino acid-stimulated insulin release as well as insulin biosynthesis are already fully functional. In parallel, newborn beta-cells are proliferating intensively within the expanding pancreas. Interestingly, we demonstrated that the miRNA changes and the subsequent acquisition of glucose responsiveness is influenced by the diet composition and the resulting insulin needs. At the same time, beta-cell proliferation declines. The miRNAs that we have identified orchestrate expression changes of essential genes involved in the acquisition of specific beta-cell properties and in the maintenance of a mature beta-cell identity. Altogether, these studies clearly demonstrate that miRNAs play important roles in the regulation of beta-cell function.

Disseny i elaboració d'un gimnàs on-line

L’evolució que ha experimentat la societat, les grans ciutats, la industrialització i molts altres factors han modificat l’estil de vida de les persones accentuant-ne, irremediablement, el sedentarisme i l’abstinència de realitzar exercici físic. La pràctica esportiva i/o d’exercici físic realitzada sota les condicions recomanades pels professionals, és beneficiosa per millorar el nivell de salut o mantenir-lo en tot el possible, ja que provoca modificacions beneficioses sobre el metabolisme, el sistema cardiovascular i l’aparell locomotor. Lamentablement, l’hàbit de realitzar exercici físic no és comú en totes les persones, ja sigui per l’estil de vida que genera incompatibilitats d’horaris amb la feina, fills i familiars o bé per mandra o desgana d’haver d’aprofitar aquelles estones de temps lliure per dedicar-los al culte del cos i de la salut. Els efectes negatius que suposa una modalitat de vida sedentària per a la salut són notablement elevats, amb la qual cosa, cal buscar sistemes per augmentar l’ interès de la població per la pràctica de l’esport i l’activitat física. La creació d’aquest projecte neix de la idea d’unir el fet d’enginyar un mètode per incrementar l’interès de les persones per l’exercici físic amb els avenços tecnològics que s’han realitzat aquesta última dècada relacionats amb el desenvolupament web i multimèdia. A grans trets, la idea general d’aquest projecte es basa en el cas d’un gimnàs real i en actiu, amb necessitat de crear un portal web que serveixi alhora de pàgina web informativa i d’eina de gestió acadèmica del centre proporcionant certes funcionalitats als clients tot presentant-los una nova modalitat de realitzar exercici físic dirigit: realitzar-lo des de casa. Per desenvolupar tot el sistema informàtic que ho durà a terme, després de realitzar una recerca, anàlisi i elecció de les eines mitjançant les quals poder-ho realitzar, s’ha optat per crear l’entorn web mitjançant els llenguatges HTML i PHP en combinació amb els fulls d’estil CSS. Pel que fa a l’entorn de desenvolupament, s’ha utilitzat Notepad++ i com a entorn de proves, WAMP Server. Per últim, pel que fa a la transmissió del contingut multimèdia (vídeos de les sessions d’activitats) s’ha utilitzat Flash Media Interactive Server en combinació de Flash Media Live Encoder per codificar-ne el contingut. L’usuari final, des de qualsevol punt del planeta, podrà realitzar (sempre i quan disposi del temps i el material necessari i una connexió a Internet) en temps real i en directe les classes dirigides que es realitzen al centre. Tanmateix, també s’ha desenvolupat una botiga virtual on qualsevol persona podrà comprar-hi, entre d’altres coses relacionades amb la pràctica de l’exercici físic, tot el material necessari per realitzar qualsevol de les activitats que s’imparteixen al gimnàs i ho rebrà còmodament a casa. Aprofitar unes circumstàncies econòmiques adverses per generar una nova manera de captar clients proporcionant-los una alternativa econòmica, diferent, nova i original d’anar al gimnàs. Temps de crisis, temps d’oportunitats. Aquesta és la moralitat que pretén donar aquest projecte.

Use of recombinant tissue plasminogen activator in children with meningococcal purpura fulminans: a retrospective study.

OBJECTIVE: Meningococcal disease causes septic shock with associated disseminated intravascular coagulation and hemorrhagic skin necrosis. In severe cases, widespread vascular thrombosis leads to gangrene of limbs and digits and contributes to morbidity and mortality. Uncontrolled case reports have suggested that thrombolytic therapy may prevent some complications, and the use of tissue plasminogen activator (t-PA) has been widespread. Our aim was to summarize the clinical outcome and adverse effects where systemic t-PA has been used to treat children with fulminant meningococcemia. DESIGN: International, multiple-center, retrospective, observational case note study between January 1992 and June 2000. SETTING: Twenty-four different hospitals in seven European countries and Australia. PATIENTS: A total of 62 consecutive infants and children with severe meningococcal sepsis in whom t-PA was used for the treatment of predicted amputations and/or refractory shock (40 to treat severe ischemia, 12 to treat shock, and ten to treat both). INTERVENTIONS: t-PA was administered with a median dose of 0.3 mg.kg(-1).hr(-1) (range, 0.008-1.13) and a median duration of 9 hrs (range, 1.2-83). MAIN RESULTS: Twenty-nine of 62 patients died (47%; 95% confidence interval, 28-65). Seventeen of 33 survivors had amputations (11 below knee/elbow or greater loss; six less severe). In 12 of 50 patients to whom t-PA was given for imminent amputation, no amputations were observed. Five developed intracerebral hemorrhages (five of 62, 8%; 95% confidence interval, 0.5-16). Of these five, three died, one developed a persistent hemiparesis, and one recovered completely. CONCLUSIONS: The high incidence of intracerebral hemorrhage in our study raises concerns about the safety of t-PA in children with fulminant meningococcemia. However, due to the absence of a control group in such a severe subset of patients, whether t-PA is beneficial or harmful cannot be answered from the unrestricted use of the drug that is described in this report. Our experience highlights the need to avoid strategies that use experimental drugs in an uncontrolled fashion and to participate in multiple-center trials, which are inevitably required to study rare diseases.

Monitoring natural hazards

Few subjects have caught the attention of the entire world as much as those dealing with natural hazards. The first decade of this new millennium provides a litany of tragic examples of various hazards that turned into disasters affecting millions of individuals around the globe. The human losses (some 225,000 people) associated with the 2004 Indian Ocean earthquake and tsunami, the economic costs (approximately 200 billion USD) of the 2011 Tohoku Japan earthquake, tsunami and reactor event, and the collective social impacts of human tragedies experienced during Hurricane Katrina in 2005 all provide repetitive reminders that we humans are temporary guests occupying a very active and angry planet. Any examples may have been cited here to stress the point that natural events on Earth may, and often do, lead to disasters and catastrophes when humans place themselves into situations of high risk. Few subjects share the true interdisciplinary dependency that characterizes the field of natural hazards. From geology and geophysics to engineering and emergency response to social psychology and economics, the study of natural hazards draws input from an impressive suite of unique and previously independent specializations. Natural hazards provide a common platform to reduce disciplinary boundaries and facilitate a beneficial synergy in the provision of timely and useful information and action on this critical subject matter. As social norms change regarding the concept of acceptable risk and human migration leads to an explosion in the number of megacities, coastal over-crowding and unmanaged habitation in precarious environments such as mountainous slopes, the vulnerability of people and their susceptibility to natural hazards increases dramatically. Coupled with the concerns of changing climates, escalating recovery costs, a growing divergence between more developed and less developed countries, the subject of natural hazards remains on the forefront of issues that affect all people, nations, and environments all the time.This treatise provides a compendium of critical, timely and very detailed information and essential facts regarding the basic attributes of natural hazards and concomitant disasters. The Encyclopedia of Natural Hazards effectively captures and integrates contributions from an international portfolio of almost 300 specialists whose range of expertise addresses over 330 topics pertinent to the field of natural hazards. Disciplinary barriers are overcome in this comprehensive treatment of the subject matter. Clear illustrations and numerous color images enhance the primary aim to communicate and educate. The inclusion of a series of unique ?classic case study? events interspersed throughout the volume provides tangible examples linking concepts, issues, outcomes and solutions. These case studies illustrate different but notable recent, historic and prehistoric events that have shaped the world as we now know it. They provide excellent focal points linking the remaining terms in the volume to the primary field of study. This Encyclopedia of Natural Hazards will remain a standard reference of choice for many years.

Expression of an uncleavable N-terminal RasGAP fragment in insulin-secreting cells increases their resistance toward apoptotic stimuli without affecting their glucose-induced insulin secretion.

Apoptosis of pancreatic beta cells is implicated in the onset of type 1 and type 2 diabetes. Consequently, strategies aimed at increasing the resistance of beta cells toward apoptosis could be beneficial in the treatment of diabetes. RasGAP, a regulator of Ras and Rho GTPases, is an atypical caspase substrate, since it inhibits, rather than favors, apoptosis when it is partially cleaved by caspase-3 at position 455. The antiapoptotic signal generated by the partial processing of RasGAP is mediated by the N-terminal fragment (fragment N) in a Ras-phosphatidylinositol 3-kinase-Akt-dependent, but NF-kappaB-independent, manner. Further cleavage of fragment N at position 157 abrogates its antiapoptotic properties. Here we demonstrate that an uncleavable form of fragment N activates Akt, represses NF-kappaB activity, and protects the conditionally immortalized pancreatic insulinoma betaTC-tet cell line against various insults, including exposure to genotoxins, trophic support withdrawal, and incubation with inflammatory cytokines. Fragment N also induced Akt activity and protection against cytokine-induced apoptosis in primary pancreatic islet cells. Fragment N did not alter insulin cell content and insulin secretion in response to glucose. These data indicate that fragment N protects beta cells without affecting their function. The pathways regulated by fragment N are therefore promising targets for antidiabetogenic therapy.