A Novel 31.1 kb α-Thalassemia Deletion (– –MEX3) Found in a Mexican Family

α-Thalassemia (α-thal), a genetic disease characterized by microcytosis, hypochromia and anemia, is predominantly caused by deletions of the α-globin genes, HBA2 and HBA1. In this study, we describe a novel 31.1?kb α-thal deletion, – –^MEX3 (NC_000016.10: g.151479_182582del), observed in a Mexican family, probably originated from non homologous recombination between two Alu sequences; the 5′ Alu element has been involved in at least two other α-thal deletions [– –^FIL (NG_000006.1: g.11684_43534del) and – –^KOL] and possesses a core homologous sequence next to the – –^MEX3 breakpoint. In addition, a 286?bp insertion in an Alu sequence downstream to the – –^MEX3 3′ breakpoint was found in the studied family, – –^FIL carriers, and healthy subjects, suggesting a common genetic variation in the Mexican population. We highlight the involvement of Alu elements and their core sequence in the origin of deletions in the α-globin gene cluster, and the importance of characterizing rare mutations, to better understand DNA rearrangement origins.     

New clinical trials regulation in Spain: analysis of royal decree 1090/2015

The coming into force of Directive 2001/20/EC represented a step forward in harmonising clinical trial regulation in European countries, guaranteeing a uniform protection of subjects participating in clinical research across Europe. However, it led to a disproportionate increase in the bureaucratization, and thus, it became evident that procedures needed to be simplified without detriment to patient’s safety. Thus, Regulation 536/2014, that repealed Directive 2001/20/EC, with the aim of decreasing the growing bureaucratization and stimulating clinical research in Europe, established simplified procedures, such as regulating a common procedure for authorising trials in Europe, the institution of strict assessment timelines, or the definition of new concepts, such as “low-intervention clinical trial”. The legal form of a Regulation allowed the norm to be directly applied to Member States without the need for transposition. By means of the new Royal Decree, the national legislation is adapted to make the application of the regulation feasible and it allows the development of the aspects that the Regulation leaves to national legislation. Both documents seek to stimulate clinical research with medicinal products to foster knowledge, facilitate transparency, and reinforce subjects’ safety. This will surely be the case, but with this revision, we will look at the novelties and key aspects that are most relevant to investigators and we will analyse the consequences for all parties involved in clinical research.     

Modification of the Host Cell Lipid Metabolism Induced by Hypolipidemic Drugs Targeting the Acetyl Coenzyme A Carboxylase Impairs West Nile Virus Replication

West Nile virus (WNV) is a neurotropic flavivirus transmitted by the bite of mosquitoes that causes meningitis and encephalitis in humans, horses, and birds. Several studies have highlighted that flavivirus infection is highly dependent on cellular lipids for virus replication and infectious particle biogenesis. The first steps of lipid synthesis involve the carboxylation of acetyl coenzyme A (acetyl-CoA) to malonyl-CoA that is catalyzed by the acetyl-CoA carboxylase (ACC). This makes ACC a key enzyme of lipid synthesis that is currently being evaluated as a therapeutic target for different disorders, including cancers, obesity, diabetes, and viral infections. We have analyzed the effect of the ACC inhibitor 5-(tetradecyloxy)-2-furoic acid (TOFA) on infection by WNV. Lipidomic analysis of TOFA-treated cells confirmed that this drug reduced the cellular content of multiple lipids, including those directly implicated in the flavivirus life cycle (glycerophospholipids, sphingolipids, and cholesterol). Treatment with TOFA significantly inhibited the multiplication of WNV in a dose-dependent manner. Further analysis of the antiviral effect of this drug showed that the inhibitory effect was related to a reduction of viral replication. Furthermore, treatment with another ACC inhibitor, 3,3,14,14-tetramethylhexadecanedioic acid (MEDICA 16), also inhibited WNV infection. Interestingly, TOFA and MEDICA 16 also reduced the multiplication of Usutu virus (USUV), a WNV-related flavivirus. These results point to the ACC as a druggable cellular target suitable for antiviral development against WNV and other flaviviruses.     

Genital folliculo‐sebaceous cystic hamartoma: A claim of the stroma as a clue in the diagnosis of proliferations with follicular differentiation

Folliculo‐sebaceous hamartomas comprise a series of entities whose boundaries are imprecise. We present the clinical case of a folliculo‐sebaceous cystic hamartoma of genital localization where the diagnosis was established based on the epithelial proliferation, but mostly, on the characteristic stroma. Because this lesion lacked of the cystic component, we mention the most frequent differential diagnoses and review the literature of the few cases published on this infrequent localization.     

Beta‐amyloid protein (25–35) disrupts hippocampal network activity: Role of Fyn‐kinase

Early cognitive deficit characteristic of early Alzheimer's disease seems to be produced by the soluble forms of β‐amyloid protein. Such cognitive deficit correlates with neuronal network dysfunction that is reflected as alterations in the electroencephalogram of both Alzheimer patients and transgenic murine models of such disease. Correspondingly, recent studies have demonstrated that chronic exposure to βAP affects hippocampal oscillatory properties. However, it is still unclear if such neuronal network dysfunction results from a direct action of βAP on the hippocampal circuit or it is secondary to the chronic presence of the protein in the brain. Therefore, we aimed to explore the effect of acute exposure to βAP_25–35 on hippocampal network activity both in vitro and in vivo, as well as on intrinsic and synaptic properties of hippocampal neurons. We found that βAP_25–35, reversibly, affects spontaneous hippocampal population activity in vitro. Such effect is not produced by the inverse sequence βAP_35–25 and is reproduced by the full‐length peptide βAP_1–42. Correspondingly βAP_25–35, but not the inverse sequence βAP_35–25, reduces theta‐like activity recorded from the hippocampus in vivo. The βAP_25–35‐induced disruption in hippocampal network activity correlates with a reduction in spontaneous neuronal activity and synaptic transmission, as well as with an inhibition in the subthreshold oscillations produced by pyramidal neurons in vitro. Finally, we studied the involvement of Fyn‐kinase on the βAP_25–35‐induced disruption in hippocampal network activity in vitro. Interestingly, we found that such phenomenon is not observed in slices obtained from Fyn‐knockout mice. In conclusion, our data suggest that βAP acutely affects proper hippocampal function through a Fyn‐dependent mechanism. We propose that such alteration might be related to the cognitive impairment observed, at least, during the early phases of Alzheimer's disease. © 2009 Wiley‐Liss, Inc.