Maximal sfermion flavour violation in super-GUTs.

We consider supersymmetric grand unified theories with soft supersymmetry-breaking scalar masses [Formula: see text] specified above the GUT scale (super-GUTs) and patterns of Yukawa couplings motivated by upper limits on flavour-changing interactions beyond the Standard Model. If the scalar masses are smaller than the gaugino masses [Formula: see text], as is expected in no-scale models, the dominant effects of renormalisation between the input scale and the GUT scale are generally expected to be those due to the gauge couplings, which are proportional to [Formula: see text] and generation independent. In this case, the input scalar masses [Formula: see text] may violate flavour maximally, a scenario we call MaxSFV, and there is no supersymmetric flavour problem. We illustrate this possibility within various specific super-GUT scenarios that are deformations of no-scale gravity.

Sex differences in adherence to highly active antiretroviral therapy: a meta-analysis.

Observational studies have found that women tend to have lower adherence to highly active antiretroviral therapy (HAART) than men do, though no meta-analysis has yet investigated this trend. The aims of the current meta-analysis are to determine if and to what degree the percentage of men versus women maintaining ≥90% adherence to prescribed HAART differs, and if the external variables moderating adherence differs by gender. Eight electronic databases were searched to locate all relevant studies available by May 2011. Fifty-six observational studies were eligible for inclusion in the meta-analysis. A random effect model was assumed for the global percentage estimation and to explain the heterogeneity. Across these studies, the difference between men and women in the proportion of individuals with ≥90% adherence to HAART was marginally significant (p<0.1; 67% and 62%, respectively). A greater proportion of men maintaining ≥90% adherence to HAART was more likely in studies with higher proportions of men who have sex with men (MSM), lower proportions of male alcohol users or lower proportions of men in a methadone program. In women, higher rates of adherence were found in studies conducted in Africa, Asia, and South America, when the sample included more widows or when the sample had a lower basal CD4 count. That both the percentage of adherent individuals and the variables associated with such adherence differ between men and women are suggestive of the need for improving gender-tailored interventions for adherence to HAART.

Evaluación de la Gestión Clínica y sus resultados. Modelo consensuado y diseñado en el Hospital Clínico de Zaragoza / Clinical Management assessment and its results. Consensual model designed at the Clincial Hospital of Zaragoza

Es razonable incentivar el uso adecuado de los recursos, la mejora de la práctica clínica y de la salud de las personas, a un coste que la sociedad pueda asumir. Para ello deben diseñarse sistemas de incentivos que estén basados en el consenso y la participación suficientes por parte de los profesionales. En el año 2000 la Comisión Mixta del Hospital Clínico Universitario de Zaragoza (HCU) tomó la decisión de diseñar un modelo de evaluación de la gestión clínica de los Servicios que permitiese con su aplicación repartir la productividad en función de los resultados alcanzados a fin de año. Ese modelo de evaluación está basado fundamentalmente en indicadores de actividad, calidad y costes. Y ha sido utilizado desde entonces, en el HCU de Zaragoza para el reparto anual de la productividad de forma variable (AU)

In this work, the authors present the results of the Mixed Commission of the University Clinical Hospital of Zaragoza which, in 2000, designed an assessment model for the clinical management of the Services which, with its application, makes it possible to distribute productivity according to the results obtained (AU)

Experiencia en la asignación de la productividad de forma variable en el Hospital Clínico Universitario de Zaragoza / Experience in the alocation of variable productivity in the University Hospital Clinic of Zaragoza

Desde el año 2000 el Hospital Clínico Universitario de Zaragoza (HCU) viene utilizado un modelo de evaluación de la gestión clínica, diseñado por el propio centro, para el reparto de la productividad anual de forma variable en función de los resultados alcanzados por cada servicio a fin de año. Este método de evaluación e incentivación ha representado importantes cambios en la cultura de gestión de los profesionales, incrementando el interés por el seguimiento de los indicadores y por los resultados obtenidos así como un mayor compromiso con los acuerdos de gestión. A pesar de haber existido diferencias importantes entre la cuantías percibidas entre Servicios, el modelo ha sido bien aceptado y no ha generado ningún tipo de conflicto ya que se ha basado en a transparencia y el consenso de la metodología utilizada (AU)

This article presents a clinical management assessment model, designed by the University Hospital Clinic of Zaragoza, to obtain a distribution of the annual variable productivity according to the results achieved by each service at the end of the year (AU)

DNA deposition through laser induced forward transfer.

Laser induced forward transfer (LIFT) is a laser direct write technique that appears to be specially adequate for the production of biosensors, since it permits to deposit patterns of biomolecules with high spatial resolution. In the LIFT technique, a laser pulse is focused on a thin film of the material to be transferred through a transparent support, and under the action of the laser pulse, a small fraction of the film is transferred to a receptor substrate that is placed parallel to the film-support system. In the case of biomolecules transfer, the thin film consists in a liquid solution containing the biomolecules. In this work, microarrays of two different cDNAs have been both spotted by LIFT and pin microspotting onto a poly-L-lysine treated glass slide. Once transferred, all the microarrays have been submitted to hybridization with the complementary strands of the spotted cDNAs, each one tagged with a different fluorochrome. Comparative fluorescence scanner analyses have revealed that the microarrays transferred through LIFT are equivalent to those transferred through pin microspotting in terms of signal intensity and gene discrimination capacity, and that the action of the laser pulse does not result in significant damage of the transferred DNA.

Validación de un instrumento para evaluar el funcionamiento y repartir incentivos entre los servicios de un hospital / Validation of an instrument to assess functioning and distribute incentives among the services of a hospital

Objetivo: Diseñar y examinar la fiabilidad de una herramienta para evaluar los resultados y distribuir incentivos entre los servicios del hospital. Material y Métodos: Se definieron de forma explícita las características de la herramienta de evaluación (representatividad, transparencia, claridad, pertinencia, accesibilidad, veracidad, carácter reproducible, sensibilidad, especificidad, estabilidad, eficiencia y aceptación) y se utilizaron dichos criterios para seleccionar indicadores y desarrollar los modelos de evaluación específicos de cada servicio. Para validar el método se midió su precisión (coherencia intra e interobservador, coeficiente de variación y bondad de ajuste a la normal) y su validez de contenido, de construcción y de criterio con respecto a una encuesta de opinión previa entre el equipo directivo (correlación de Pearson e índice Kappa). Resultados: La herramienta desarrollada constaba de 15 modelos de evaluación elaborados a partir de 49 indicadores (31 de actividad, cuatro de costes y 14 de calidad asistencial). Se evaluaron 56 unidades aistenciales, cuya calificación media fue de 73,5 ñ 18,1 puntos, con un mínimo de 29 y un máximo de 100. En Actividad la puntuación media fue de 52,1 ñ 14,7 sobre 70, en Costes de 13,7 ñ 7,4 sobre 20 y en Calidad de 7,6 ñ 2,1 sobre 10. El modelo se ajustaba a una distribución normal, con un CV de 0,25, un error intraobsevador de 0,25 por ciento e interobservador del 0,48 por ciento. La correlación con la opinión del equipo directivo era positiva (r = 0,43 p = 0,004), pero los índices de concordancia kappa eran bajos (0,21). Conclusiones: El método de evaluación probado es preciso, está bien construido y tiene una aparente validez de criterio. Queda ahora por demostrar si sirve para mejorar los resultados y la calidad de la asistencia prestada (AU)

The endosomal compartment is an insulin-sensitive recruitment site for GLUT4 and GLUT1 glucose transporters in cardiac myocytes.

In nonstimulated cardiomyocytes, the glucose transporter GLUT4 is confined to intracellular vesicles forming at least two populations: a storage pool enriched in GLUT4 (pool 1) and an endosomal pool containing both GLUT4 and GLUT1 (pool 2). We have now studied the dynamics of these pools in response to insulin or the mitochondrial inhibitor rotenone in rat cardiomyocytes. Rotenone recruited GLUT4 and GLUT1 to the cell surface from endosomal pool 2 without affecting pool 1. Kinetic experiments were consistent with rotenone acting on an intracellular compartment that is in close connection with the plasma membrane. In contrast, insulin caused rapid, complete depletion of GLUT4 from pool 1 and reduced the GLUT1 content of pool 2 by approximately 50%, whereas, surprisingly, no net decrease in GLUT4 occurred in this pool. Subsequent insulin withdrawal resulted in slow replenishment of pool 2 with GLUT1 and of pool 1 with GLUT4. When pool 1 was still largely depleted of GLUT4, a second insulin challenge did reduce GLUT4 in pool 2 and stimulated glucose transport to the same extent as the first insulin treatment. In conclusion, the storage pool is the primary source of GLUT4 in response to insulin, but not to rotenone. In addition, the endosomal compartment is an important recruitment site of both GLUT1 and GLUT4 when the storage pool is either unaffected (rotenone) or depleted (by a previous insulin challenge). GLUT4 mobilized by insulin from the storage pool may pass through an intermediary (possibly endosomal) compartment on its way to the cell surface.

Adenosine reverses a preestablished CCl4-induced micronodular cirrhosis through enhancing collagenolytic activity and stimulating hepatocyte cell proliferation in rats.

Cirrhosis is one of the most common causes of mortality worldwide, because hepatic dysfunction constitutes a potentially lethal condition. Having demonstrated the hepatoprotective effect of adenosine against CCl(4)-induced cirrhosis, the present study was aimed at assessing adenosine's effect on an already-established micronodular cirrhosis. Chronic administration of CCl(4) (10 weeks) induced a cirrhotic state, characterized by increased liver fibronectin and collagen types I and III content, enhanced expression of alpha-1 (I) collagen mRNA, portal hypertension, and liver dysfunction. After CCl(4) discontinuation (5 weeks), increased persitance of alpha-1 (I) collagen mRNA expression and deposition, enhanced proline incorporation into collagen and prolyl hydroxylase activity evidenced active fibrogenesis. Several weeks after CCl(4) withdrawal, deposited collagen showed an enhanced type I/III ratio, which was associated with deficient collagenolytic activity in cirrhotic livers. Liver expression of some metalloproteinases (MMPs) and of tissue inhibitors of MMPs (TIMPs) also indicated decreased collagen breakdown in cirrhotic livers. Parameters indicative of oxidative stress (mainly protein oxidation) were persistently augmented. These events were coincident with diminished regenerative capacity of the cirrhotic liver. Intraperitoneal adenosine administration to CCl(4)-induced cirrhotic rats blocked active fibrogenesis and increased the collagen degradation (most probably by decreasing liver TIMPs levels), normalizing collagen-type ratios. In addition, the nucleoside promoted an effective hepatocyte's proliferation in the cirrhotic liver and accelerated normalization of parameters indicative of liver function and oxidative stress. Thus, adenosine readily reversed an experimental cirrhosis through stimulating liver collagenolytic and proliferative capacities, as well as by accelerating functional recovery.

Intracellular transport of MHC class II and associated invariant chain in antigen presenting cells from AP-3-deficient mocha mice.

MHC class II-restricted antigen presentation requires trafficking of newly synthesized class II-invariant chain complexes from the trans-Golgi network to endosomal, peptide-loading compartments. This transport is mediated by dileucine-like motifs within the cytosolic tail of the invariant chain. Although these signals have been well characterized, the cytosolic proteins that interact with these dileucine signals and mediate Golgi sorting and endosomal transport have not been identified. Recently, an adaptor complex, AP-3, has been identified that interacts with dileucine motifs and mediates endosomal/lysosomal transport in yeast, Drosophila, and mammals. In this report, we have assessed class II-invariant chain trafficking in a strain of mice (mocha) which lacks expression of AP-3. Our studies demonstrate that the lack of AP-3 does not affect the kinetics of invariant chain degradation, the route of class II-invariant chain transport, or the rate and extent of class II-peptide binding as assessed by the generation of SDS-stable dimers. The possible role of other known or unknown adaptor complexes in class II-invariant chain transport is discussed.

The insulin-sensitive GLUT4 storage compartment is a postendocytic and heterogeneous population recruited by acute exercise.

Insulin and acute exercise stimulate glucose transport in skeletal muscle by translocating GLUT4 glucose transporters to the cell surface. GLUT4 is distributed in skeletal muscle in two intracellular membrane populations, an endosomal pool that remains unaltered after insulin treatment and an storage population that is markedly GLUT4 depleted in response to insulin. Here we have further characterized the storage GLUT4 compartment in regard to protein composition and sensitivity to acute exercise. This GLUT4 compartment contained IRAP (insulin-regulated aminopeptidase), transferrin receptors or mannose-6-phosphate/IGF-II receptors, indicating a postendocytic origin. Insulin administration caused a depletion of GLUT4 and IRAP but no changes in transferrin receptors, which suggests that this pool is heterogeneous. In addition, acute exercise caused a marked GLUT4 depletion in the storage compartment, whereas no changes were detected in the endosomal population. In all, our data indicate that the GLUT4 storage population represents a postendocytic and heterogeneous compartment; the storage compartment represents the recruitment site that triggers GLUT4 translocation to the cell surface in response to both insulin and acute exercise.

Transcriptional regulation of the bcl-x gene encoding the anti-apoptotic Bcl-xL protein by Ets, Rel/NFkappaB, STAT and AP1 transcription factor families.

Transcription factors play an essential role in determining the fate of a cell by affecting the expression of target genes involved in proliferation, in differentiation and in programmed cell death. Under certain conditions, some of these factors are capable of deregulating expression of genes involved in the cell cycle and/or in programmed cell death resulting in uncontrolled proliferation of the cell. The focus of this review is on the transcriptional regulation of the bcl-x gene encoding the anti-apoptotic Bcl-xL protein. Since 1999, several papers have implicated members of the Ets, Rel/NFkappaB, STAT and AP-1 families as transcription factors regulating bcl-x expression. A specific emphasis of these different transcription factor families on bcl-x regulation in hematopoietic cells is discussed.

Bcl-XL expression correlates with primary macrophage differentiation, activation of functional competence, and survival and results from synergistic transcriptional activation by Ets2 and PU.1.

Depriving primary bone marrow-derived macrophages of colony-stimulating factor-1 (CSF-1) induces programmed cell death by apoptosis. We show that cell death is accompanied by decreases in the expression of anti-apoptotic Bcl-x(L) protein and the Ets2 and PU.1 proteins of the Ets transcription factor family. Macrophages require both priming and triggering signals independent of CSF-1 to kill neoplastic cells or microorganisms, and this activation of macrophage competence is accompanied by increased expression of bcl-x(L), ets2, and PU.1. Furthermore, we show that only Ets2 and PU.1, but not Ets1, function in a synergistic manner to transactivate the bcl-x promoter. The synergy observed between PU.1 and Ets2 is dependent on the transactivation domains of both proteins. Although other transcription factors like Fos, c-Jun, Myc, STAT3, and STAT5a are implicated in the activation of macrophage competence or in CSF-1 signaling, no synergy was observed between Ets2 and these transcription factors on the bcl-x promoter. We demonstrate that the exogenous expression of both Ets2 and PU.1 in macrophages increases the number of viable cells upon CSF-1 depletion and that Ets2 and PU.1 can functionally replace Bcl-x(L) in inhibiting Bax-induced apoptosis. Together, these results demonstrate that PU.1 and Ets2 dramatically increase bcl-x activation, which is necessary for the cytocidal function and survival of macrophages.

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Regulation of leptin gene expression and secretion by steroid hormones.

Previous work has shown that 17 beta-estradiol is the primary ovarian signal regulating body weight and adiposity, although its mechanisms of action remain unclear. We hypothesized that 17 beta-estradiol could enhance leptin levels as a mechanism of its anorectic effects. Administration of 5 microg 17 beta-estradiol subcutaneously (s.c.) for 2 days significantly elevated leptin mRNA levels in adipose tissue as compared to vehicle controls (P < 0.003). A time-course administration of estrogen showed increased mRNA levels in adipose tissue between 6 and 12 h after estrogen injection as compared to vehicle controls (P < 0.03). Corresponding to the increased leptin mRNA levels at 6 and 12 h, elevated plasma leptin levels were observed at 12 h after estrogen administration as compared to controls (P < 0.05). Administration of progesterone (1 mg/rat) after estradiol injection did not enhance the elevated leptin mRNA levels in adipose tissue. Serum leptin levels from cycling rats did not differ significantly between metestrous and proestrous animals. In conclusion, the present studies demonstrate that 17 beta-estradiol can regulate leptin gene expression and secretion in the female rat, thus providing a better understanding of the possible anorectic effect of estrogens.

Characterization of ionotropic glutamate receptors in rat hypothalamus, pituitary and immortalized gonadotropin-releasing hormone (GnRH) neurons (GT1-7 cells).

Evidence from various sources suggested that the Gonadotropin-Releasing Hormone (GnRH) neuron does not contain glutamate receptors. Northern analysis of the hypothalamus showed the presence of NMDAR1, GluR1, GluR4 and GluR6 mRNA, while the pituitary showed the presence of NMDAR1, GluR1 and GluR6 mRNA. Western blot analysis also showed the presence of NMDAR1 and GluR1 protein. Since there are relatively few GnRH neurons in the hypothalamus, and GT1-7 cells have been considered to be a GnRH neuronal cell line, GT1-7 cells were studied in detail. GT1-7 cells contained NMDAR1 mRNA levels as shown by Northern analysis but did not contain GluR1, GluR4, or GluR6 mRNA. They did not show the presence of NMDAR1 and GluR1 protein by Western analysis. In addition, GT1-7 cells showed no NMDA receptor binding using the competitive inhibitor CGP-39563 and the noncompetitive inhibitor MK-801. Likewise, no binding was detected for kainate receptors. However, a small amount of binding for AMPA receptors was found in GT1-7 cells. GT1-7 cells did not exhibit glutamate toxicity and NMDA failed to elicit inward currents using patch-clamp techniques, although GABA did induce currents in the cells. As a whole, these studies suggest that GT1-7 cells lack or possess only low levels of ionotropic glutamate receptors.

The Ets2 transcription factor inhibits apoptosis induced by colony-stimulating factor 1 deprivation of macrophages through a Bcl-xL-dependent mechanism.

Bcl-xL, a member of the Bcl-2 family, inhibits apoptosis, and its expression is regulated at the transcriptional level, yet nothing is known about the transcription factors specifically activating this promoter. The bcl-x promoter contains potential Ets binding sites, and we show that the transcription factor, Ets2, first identified by its sequence identity to v-ets of the E26 retrovirus, can transactivate the bcl-x promoter. Transient expression of Ets2 results in the upregulation of Bcl-xL but not of Bcl-xS, an alternatively spliced gene product which induces apoptosis. Ets2 is ubiquitously expressed at low levels in a variety of cell types and tissues but is specifically induced to abundant levels during macrophage differentiation. Since Bcl-xL is also upregulated during macrophage differentiation, we asked whether the bcl-x could be a direct downstream target gene of Ets2 in macrophages. BAC1.2F5 macrophages, which are dependent on macrophage colony-stimulating factor 1 (CSF-1) for their growth and survival, were used in these studies. We show that CSF-1 stimulation of BAC1.2F5 macrophages results in the upregulation of expression of ets2 and bcl-xL with similar kinetics of induction. In the absence of CSF-1, these macrophages undergo cell death by apoptosis, whereas constitutive expression of Ets2 rescues these cells from cell death, and bcl-xL is upregulated. These results strongly suggest a novel role of Ets2 in affecting apoptosis through its regulation of Bcl-xL transcription.

Benfluorex improves muscle insulin responsiveness in middle-aged rats previously subjected to long-term high-fat feeding.

It has been reported that benfluorex ameliorates the insulin resistance induced by high-fat feeding when its administration is initiated at the same time as the change in diet. Here we have examined whether benfluorex reverses insulin resistance when this is established in middle-aged rats chronically maintained on a high-fat diet. Untreated 12-month-old rats that had been subjected to a high-fat diet for the last 6 months showed markedly lower insulin-induced stimulation of 2-deoxyglucose uptake by strips of soleus muscle and a reduced expression of GLUT4 glucose carriers in skeletal muscle. However, animals subjected to the same protocol but treated with benfluorex during the last month of high-fat feeding showed marked improvement in insulin-stimulated glucose transport by soleus muscle. Benfluorex treatment caused a substantial increase in the content of GLUT4 protein in white muscle; however, GLUT4 levels in red muscle remained low. Our results indicate: (i) that benfluorex treatment in middle-aged rats reverses the insulin resistance induced by high-fat feeding in soleus muscle; (ii) benfluorex is active even when it is administered once the insulin-resistant state is already established; (iii) reversion of muscle insulin resistance by benfluorex can occur independently of modifications in GLUT4 protein expression.

Trafficking pathway of GLUT4 glucose transporters in muscle (review).

Skeletal muscle is a major glucose-utilizing tissue in the absorptive state and alterations in muscle insulin-stimulated glucose uptake lead to derangements in whole body glucose disposal. The major glucose transporter expressed in skeletal muscle is the GLUT4 isoform. In the muscle fiber, GLUT4 undergoes insulin-stimulated translocation to T-tubules and to sarcolemma and it represents a pharmacological target for the treatment of diabetes mellitus, insulin-resistant states or in cardiac dysfunction. We review recent studies describing the characterization of the cellular steps followed by GLUT4 in muscle and we propose several working models for an integrated structure of the GLUT4 trafficking pathway.

Synergistic effects of colony-stimulating factor 1 and leukemia inhibitory factor in inducing early myeloid cell differentiation.

Cells of the M1D+ murine myeloid leukemic cell line differentiate into macrophages in response to either leukemia inhibitory factor (LIF) or interleukin 6. Previously, it was shown that LIF treatment of M1D+ cells leads to an increased expression of colony-stimulating factor (CSF) receptor mRNA encoded by c-fms. CSF-1, a macrophage growth factor, induces the survival, growth, and differentiation of mononuclear phagocytes but has not been implicated in the regulation of early myeloid cell differentiation. Here we show that low-dose LIF treatment of M1D+ cells results in CSF-1 secretion and CSF-1 receptor up-regulation. CSF-1, when applied alone, induces some M1D+ adherence and the up-regulation of lysozyme M, a macrophage-specific marker. Finally, we show that when applied together, LIF and CSF-1 act synergistically to induce macrophage morphology, phagocytosis, and the expression of the macrophage-specific markers CD11b/Mac-1 alpha chain, lysozyme M, FcgammaRII, and JE/MCP.1. These results indicate that instead of being part of exclusive pathways, as thought until this work, LIF and CSF-1 can function synergistically to further stimulate the early stages of myeloid differentiation.