Glucocorticoid pharmacogenetics in pediatric idiopathic nephrotic syndrome

Idiopathic nephrotic syndrome represents the most common type of primary glomerular disease in children: glucocorticoids (GCs) are the first-line therapy, even if considerable interindividual differences in thepir efficacy and side effects have been reported. Immunosuppressive and anti-inflammatory effects of these drugs are mainly due to the GC-mediated transcription regulation of pro- and anti-inflammatory genes. This mechanism of action is the result of a complex multistep pathway that involves the glucocorticoid receptor and several other proteins, encoded by polymorphic genes. Aim of this review is to highlight the current knowledge on genetic variants that could affect GC response, particularly focusing on children with idiopathic nephrotic syndrome

Association of Insulin Resistance with Serum Interleukin-6 and TNF-α Levels During Normal Pregnancy

Overview The purpose of this study was to evaluate the role of Tumor Necrosis Factor-α (TNF-α) in insulin resistance (IR) during normal pregnancy. Approach This cross sectional study was carried out on 86 healthy pregnant women including 26, 23 and 37 individuals in the 1st, 2nd and 3rd trimesters, respectively, and in 21 healthy non pregnant women. Serum TNF-α concentration was measured by Enzyme Linked Immunosorbent Assay (ELISA) method. Results There were significant differences between serum TNF-α and IL-6 levels in pregnant women as compared with maternal healthy controls. There was significant correlation between gestational age and Body Mass Index (BMI) (r = 0.28, P = 0.01). There was no significant correlation between gestational age and insulin resistance (IR). We also did not find correlations between IR and TNF-α and IR and IL-6 in pregnant women. Conclusion In conclusion, our findings suggest that TNF-α and IL-6 are not greatly contributed to pregnancy induced insulin resistance in normal pregnancy

Naturally occurring C-terminal splice variants of nuclear receptors

Alternative mRNA splicing in the region encoding the C-terminus of nuclear receptors results in receptor variants lacking the entire ligand-binding domain (LBD), or a part of it, and instead contain a sequence of splice variant-specific C-terminal amino acids. A total of thirteen such splice variants have been shown to occur in vertebrates, and at least nine occur in humans. None of these receptor variants appear to be able to bind endogenous ligands and to induce transcription on promoters containing the response element for the respective canonical receptor variant. Interestingly, ten of these C-terminal splice variants have been shown to display dominant-negative activity on the transactivational properties of their canonical equivalent. Research on most of these splice variants has been limited, and the dominant-negative effect of these receptor variants has only been demonstrated in reporter assays in vitro, using transiently transfected receptors and reporter constructs. Therefore, the in vivo function and relevance of most C-terminal splice variants remains unclear. By reviewing the literature on the human glucocorticoid receptor β-isoform (hGRβ), we show that the dominant-negative effect of hGRβ is well established using more physiologically relevant readouts. The hGR β-isoform may alter gene transcription independent from the canonical receptor and increased hGRβ levels correlate with glucocorticoid resistance and the occurrence of several immune-related diseases. Thus, available data suggests that C-terminal splice variants of nuclear receptors act as dominant-negative inhibitors of receptor-mediated signaling in vivo, and that aberrant expression of these isoforms may be involved in the pathogenesis of a variety of diseases

A common and functional mineralocorticoid receptor haplotype enhances optimism and protects against depression in females

Mineralocorticoid (MR) and glucocorticoid receptors (GR) are abundantly expressed in the limbic brain and mediate cortisol effects on the stress-response and behavioral adaptation. Dysregulation of the stress response impairs adaptation and is a risk factor for depression, which is twice as abundant in women than in men. Because of the importance of MR for appraisal processes underlying the initial phase of the stress response we investigated whether specific MR haplotypes were associated with personality traits that predict the risk of depression. We discovered a common gene variant (haplotype 2, frequency 0.38) resulting in enhanced MR activity. Haplotype 2 was associated with heightened dispositional optimism in study 1 and with less hopelessness and rumination in study 2. Using data from a large genome-wide association study we then established that haplotype 2 was associated with a lower risk of depression. Interestingly, all effects were restricted to women. We propose that common functional MR haplotypes are important determinants of inter-individual variability in resilience to depression in women by differentially mediating cortisol effects on the stress system. © 2011 Macmillan Publishers Limited All rights reserved

Trading Methods and Family Strategies of Genoese People. Almería, XVIII century

Artículo de la sección: EstudiosEnfatizar la importancia de la documentación notarial para el estudio de un grupo social parece una valoración innecesaria. Este estudio pretende, a partir fundamentalmente de los protocolos notariales como núcleo de la investigación y del Catastro de Ensenada, complementados con otras fuentes, libros de Contadurías e Hipotecas de la sección de hacienda del Archivo Histórico Provincial de Almería, documentos de hidalguía y matrícula de extranjeros del Archivo Municipal de Almería, acercarse al flujo de mercaderes genoveses que, durante el siglo XVIII, se avecinda en la ciudad de Almería. La investigación se centra en los mecanismos que cuatro familias genovesas, domiciliadas en la ciudad de Almería durante el Setecientos: Schiafino-Aste, Schiafino- Schiafino, Schiafino-Ansaldo e Iluminatti-Marín, desarrollaron para conseguir la intervención en la administración local y la creación de unas prácticas mercantiles que, desde la ciudad de Almería y su jurisdicción, se extenderían hacia las villas del interior de la provincia y hacia una importante ramificación a lo largo de las costas del levante peninsular y de Andalucía occidental. No olvidaremos las relaciones que el grupo ligur almeriense mantuvo durante el siglo con su Génova natal, que cristalizaron en la creación de una compañía mercantil desarrollada en base a los intereses económicos de familias genovesas de Santa María de Camogli y de la ciudad de Almería. El análisis es un acercamiento, más que hacia aspectos económicos y al mundo del comercio, a la relación que se establece entre la formación de las familias y la creación de estrategias mercantiles que les llevará a la intervención en los mercados.To emphasize the notarial documentation for the study of a social group it seems to be an unnecessary valuation. This research expects basically, from the notarial protocols as the essence of the research work and from the Catastro of Ensenada, completed with other sources, Accountancy books and Mortgages of the section of finance from the Almerías 's Provincial Historical Record Office, nobility documents, and registration of foreigners from the Almería"s Town Record Office, to approach to the flow of Genoese merchants who, during the 18th century, comes near the town of Almería. The investigation is centred in the processes that four Genoese families established in the town of Almería during the Seven hundred, Schiafino-Aste, Shiafino-Shiafino,Shiafino-Ansaldo and Iluminatti-Marin, developped to get the participation in the local administration and the establishment of some trading methods which, from the city of Almería and its jurisdiction, would be spread over the inner small towns of the province and towards an important branch along the levant peninsular coasts and the west of Andalucía. We must not forget the relationship that the almeriense ligur group kept up during the century with its home town Genoa, crystallizing in the establishment of a trading company developped on tha basis of economical interests of Genoese families from Santa Maria of Camogli and the city of Almería. The analysis is a approach, more than to economical aspects and the business world, to the relationship that it is set up between the formation of the families and the establishment of trading strategies that will take them to the participation in the markets.Departamento de Historia Moderna y de América, Universidad de Granad

Changes in cytokine production in healthy subjects practicing Guolin Qigong : a pilot study

BACKGROUND: Guolin Qigong is a combination of meditation, controlled breathing and physical movement designed to control the vital energy (qi) of the body and consequently to improve spiritual, physical and mental health. Practice of Qigong has been reported to alter immunological function, but there have been few studies of its effects on cytokines, the key regulators of immunity. METHODS: Numbers of peripheral blood cytokine-secreting cells were determined by ELISPOT in 19 healthy volunteers aged 27 – 55, before they were taught the practice of Qigong and after 3, 7 and 14 weeks of daily practice. The effect of Qigong on blood cortisol was also examined. RESULTS: Numbers of IL4 and IL12-secreting cells remained stable. IL6 increased at 7 weeks and TNFα increased in unstimulated cultures at 3 and 7 weeks but decreased at these times in LPS and SAC-stimulated cultures. Of particular interest, IFNγ-secreting cells increased and IL10-secreting cells decreased in PHA-stimulated cultures, resulting in significant increases in the IFNγ:IL10 ratio. Cortisol, a known inhibitor of type 1 cytokine production, was reduced by practicing Qigong. CONCLUSION: These preliminary studies in healthy subjects, although not necessarily representative of a randomized healthy population and not including a separate control group, have indicated that blood levels of the stress-related hormone cortisol may be lowered by short-term practice of Qigong and that there are concomitant changes in numbers of cytokine-secreting cells. Further studies of the effect of Qigong in patients with clinical diseases known to be associated with type 2 cytokine predominance are merited

Elevational variation in body-temperature response to immune challenge in a lizard

Immunocompetence benefits animal fitness by combating pathogens, but also entails some costs. One of its main components is fever, which in ectotherms involves two main types of costs: energy expenditure and predation risk. Whenever those costs of fever outweigh its benefits, ectotherms are expected not to develop fever, or even to show hypothermia, reducing costs of thermoregulation and diverting the energy saved to other components of the immune system. Environmental thermal quality, and therefore the thermoregulation cost/benefit balance, varies geographically. Hence, we hypothesize that, in alpine habitats, immune-challenged ectotherms should show no thermal response, given that (1) hypothermia would be very costly, as the temporal window for reproduction is extremely small, and (2) fever would have a prohibitive cost, as heat acquisition is limited in such habitat. However, in temperate habitats, immune-challenged ectotherms might show a febrile response, due to lower cost/benefit balance as a consequence of a more suitable thermal environment. We tested this hypothesis in Psammodromus algirus lizards from Sierra Nevada (SE Spain), by testing body temperature preferred by alpine and non-alpine lizards, before and after activating their immune system with a typical innocuous pyrogen. Surprisingly, non-alpine lizards responded to immune challenge by decreasing preferential body-temperature, presumably allowing them to save energy and reduce exposure to predators. On the contrary, as predicted, immune-challenged alpine lizards maintained their body-temperature preferences. These results match with increased costs of no thermoregulation with elevation, due to the reduced window of time for reproduction in alpine environment.This work was funded by the Spanish Ministerio de Ciencia e Innovación [project CGL2009-13185]. FJZC [AP2009-3505] and SR [AP2009-1325] were supported by two pre-doctoral grants from the Ministerio de Ciencia e Innovación (FPU programme). FJZC was partially supported by a Ramón Areces Foundation postdoctoral fellowship. GMR was partially supported by a grant of the Ministerio de Ciencia e Innovación (Juan de la Cierva programme)

Evolutionary rates vary among rRNA structural elements

Understanding patterns of rRNA evolution is critical for a number of fields, including structure prediction and phylogeny. The standard model of RNA evolution is that compensatory mutations in stems make up the bulk of the changes between homologous sequences, while unpaired regions are relatively homogeneous. We show that considerable heterogeneity exists in the relative rates of evolution of different secondary structure categories (stems, loops, bulges, etc.) within the rRNA, and that in eukaryotes, loops actually evolve much faster than stems. Both rates of evolution and abundance of different structural categories vary with distance from functionally important parts of the ribosome such as the tRNA path and the peptidyl transferase center. For example, fast-evolving residues are mainly found at the surface; stems are enriched at the subunit interface, and junctions near the peptidyl transferase center. However, different secondary structure categories evolve at different rates even when these effects are accounted for. The results demonstrate that relative rates and patterns of evolution are lineage specific, suggesting that phylogenetically and structurally specific models will improve evolutionary and structural predictions