Cytogenetic effects of irradiation on somatic and germ cells

This paper summarizes the results obtained in two of the research projects carried out in our laboratory within the radiation protection programs of the Consejo de Seguridad Nuclear and the European Union. These two research lines are fundamentally interconnected, since the analysis of the cytogenetic effects of radiation on somatic cells studies the consequences of occupational or accidental exposure to radiation for the individual, especially from the point of view of developing some type of malignancy, while the studies carried out in germ cells evaluate the risk of exposure for future generations, through the transmission of chromosome abnormalities via affected spermatozoa. In both cases these studies, which were mainly carried out during the last six years, in addition to providing basic data for the assessment of the consequences of radiation exposure and defining the steps to be taken to prevent the transmission of chromosome anomalies to the offspring in cases of therapeutic exposure, have also been fundamental in developing more effective techniques for the evaluation of the cytogenetic consequences of exposure to radiation

The history and evolution of the clinical effectiveness of haemophilia type a treatment: a systematic review.

First evidence of cases of haemophilia dates from ancient Egypt, but it was when Queen Victoria from England in the 19th century transmitted this illness to her descendants, when it became known as the "royal disease". Last decades of the 20th century account for major discoveries that improved the life expectancy and quality of life of these patients. The history and evolution of haemophilia healthcare counts ups and downs. The introduction of prophylactic schemes during the 1970s have proved to be more effective that the classic on-demand replacement of clotting factors, nevertheless many patients managed with frequent plasma transfusions or derived products became infected with the Human Immunodeficiency Virus (HIV) and Hepatitis C virus during the 1980s and 1990s. Recombinant factor VIII inception has decreased the risk of blood borne infections and restored back longer life expectancies. Main concerns for haemophilia healthcare are shifting from the pure clinical aspects to the economic considerations of long-term replacement therapy. Nowadays researchers' attention has been placed on the future costs and cost-effectiveness of costly long-term treatment. Equity considerations are relevant as well, and alternative options for less affluent countries are under the scope of further research. The aim of this review was to assess the evidence of different treatment options for haemophilia type A over the past four decades, focusing on the most important technological advances that have influenced the natural course of this "royal disease"

Synthesis, in Vitro Profiling, and in Vivo Evaluation of Benzohomoadamantane-Based Ureas for Visceral Pain: A New Indication for Soluble Epoxide Hydrolase Inhibitors

The soluble epoxide hydrolase (sEH) has been suggested as a pharmacological target for the treatment of several diseases, including pain-related disorders. Herein, we report further medicinal chemistry around new benzohomoadamantane-based sEH inhibitors (sEHI) in order to improve the drug metabolism and pharmacokinetics properties of a previous hit. After an extensive in vitro screening cascade, molecular modeling, and in vivo pharmacokinetics studies, two candidates were evaluated in vivo in a murine model of capsaicin-induced allodynia. The two compounds showed an anti-allodynic effect in a dose-dependent manner. Moreover, the most potent compound presented robust analgesic efficacy in the cyclophosphamide-induced murine model of cystitis, a well-established model of visceral pain. Overall, these results suggest painful bladder syndrome as a new possible indication for sEHI, opening a new range of applications for them in the visceral pain field

Progressive Telomere Dysfunction Causes Cytokinesis Failure and Leads to the Accumulation of Polyploid Cells

Most cancer cells accumulate genomic abnormalities at a remarkably rapid rate, as they are unable to maintain their chromosome structure and number. Excessively short telomeres, a known source of chromosome instability, are observed in early human-cancer lesions. Besides telomere dysfunction, it has been suggested that a transient phase of polyploidization, in most cases tetraploidization, has a causative role in cancer. Proliferation of tetraploids can gradually generate subtetraploid lineages of unstable cells that might fire the carcinogenic process by promoting further aneuploidy and genomic instability. Given the significance of telomere dysfunction and tetraploidy in the early stages of carcinogenesis, we investigated whether there is a connection between these two important promoters of chromosomal instability. We report that human mammary epithelial cells exhibiting progressive telomere dysfunction, in a pRb deficient and wild-type p53 background, fail to complete the cytoplasmatic cell division due to the persistence of chromatin bridges in the midzone. Flow cytometry together with fluorescence in situ hybridization demonstrated an accumulation of binucleated polyploid cells upon serial passaging cells. Restoration of telomere function through hTERT transduction, which lessens the formation of anaphase bridges by recapping the chromosome ends, rescued the polyploid phenotype. Live-cell imaging revealed that these polyploid cells emerged after abortive cytokinesis due to the persistence of anaphase bridges with large intervening chromatin in the cleavage plane. In agreement with a primary role of anaphase bridge intermediates in the polyploidization process, treatment of HMEC-hTERT cells with bleomycin, which produces chromatin bridges through illegimitate repair, resulted in tetraploid binucleated cells. Taken together, we demonstrate that human epithelial cells exhibiting physiological telomere dysfunction engender tetraploid cells through interference of anaphase bridges with the completion of cytokinesis. These observations shed light on the mechanisms operating during the initial stages of human carcinogenesis, as they provide a link between progressive telomere dysfunction and tetraploidy

The Rise and Fall of "Respectable" Spanish Liberalism, 1808-1923: An Explanatory Framework

The article focuses on the reasons behind both the consolidation of what I have termed “respectable” liberalism between the 1830s and the 1840s and its subsequent decline and fall between 1900 and 1923. In understanding both processes I study the links established between “respectable” liberals and propertied elites, the monarchy, and the Church. In the first phase these links served to consolidate the liberal polity. However, they also meant that many tenets of liberal ideology were compromised. Free elections were undermined by the operation of caciquismo, monarchs established a powerful position, and despite the Church hierarchy working with liberalism, the doctrine espoused by much of the Church was still shaped by the Counter-Reformation. Hence, “respectable” liberalism failed to achieve a popular social base. And the liberal order was increasingly denigrated as part of the corrupt “oligarchy” that ruled Spain. Worse still, between 1916 and 1923 the Church, monarch, and the propertied elite increasingly abandoned the liberal Monarchist Restoration. Hence when General Primo de Rivera launched his coup the rug was pulled from under the liberals’ feet and there was no one to cushion the fall

Novel phenotypes of feeding and social behaviour and their relationship with individual rabbit growth and feed efficiency

Due to the lack of a recording system for individual consumption of group-housed rabbits, published studies about feeding behaviour are based on information recorded at the group- and not at the individual level and periods covering only a few days or, in some cases, only part of a day. Such information could be used to inform rabbit management systems but cannot be used for genetic selection. We aimed to generate and use information from a novel automated feeder for group-housed rabbits to identify new phenotypes for individual animals that could be incorporated into breeding programs to improve feed efficiency and social behaviour under different feeding regimens. At 39 d of age, rabbits from 15 batches were placed in cages and fed ad libitum to become used to the electronic feeder. From 42 to 58–59 d, one group of 1 086 rabbits was fed ad libitum (AL), while another group of 1 134 rabbits was fed on a restricted feeding schedule (R) by limiting the feeding time to the period between 1800 and 0600 h of the following day. We implemented a reliable multivariate method to remove anomalous feeding behaviour records. We then defined novel traits for feeding behaviour that apply to both types of feeding regimes, and for social behaviour that indicates an animal’s rank within the cage hierarchy. We based these traits on feeder records and a biologically sound definition of a meal. Finally, we estimated the phenotypic correlations of those traits with growth and feed efficiency traits. Our findings demonstrate that variables about resource distribution among cage mates and an animal's priority for feed access were found to be good indicators of an animal's dominant or subordinate status within the cage. Based on results obtained in R animals (results were similar in AL animals), the most efficient animals were those that ate less frequently (phenotypic correlation with feed conversion ratio, rho = 0.6), and consumed smaller amounts per meal (rho = 0.7), spent less time at the feeder (rho = 0.4), and appeared to be subordinate, as they did not have priority access to the feeder (rho = −0.3), and had the smallest share of resources (range of rho = 0.2–0.6). We conclude that quantifying feeding and social behaviour traits can enhance the understanding of the mechanisms through which individuals exert their effects on the performance of their cage mates.This work has been funded by the Feed-a-Gene (grant agreement no. 633531), Genef (RTA2014-00015-C02), Genef2 (RTI2018-097610-R-I00) and Genef3 (PID2021-128173OR-C21) projects.info:eu-repo/semantics/publishedVersio