Pharmacological Interventions to Ameliorate Neuropathological Symptoms in a Mouse Model of Lafora Disease

14 páginas; 9 figuras.Lafora disease (LD, OMIM 254780) is a rare fatal neurodegenerative disorder that usually occurs during childhood with generalized tonic-clonic seizures, myoclonus, absences, drop attacks or visual seizures. Unfortunately, at present, available treatments are only palliatives and no curative drugs are available yet. The hallmark of the disease is the accumulation of insoluble polyglucosan inclusions, called Lafora bodies (LBs), within the neurons but also in heart, muscle and liver cells. Mouse models lacking functional EPM2A or EPM2B genes (the two major loci related to the disease) recapitulate the Lafora disease phenotype: they accumulate polyglucosan inclusions, show signs of neurodegeneration and have a dysregulation of protein clearance and endoplasmic reticulum stress response. In this study, we have subjected a mouse model of LD (Epm2b-/-) to different pharmacological interventions aimed to alleviate protein clearance and endoplasmic reticulum stress. We have used two chemical chaperones, trehalose and 4-phenylbutyric acid. In addition, we have used metformin, an activator of AMP-activated protein kinase (AMPK), as it has a recognized neuroprotective role in other neurodegenerative diseases. Here, we show that treatment with 4-phenylbutyric acid or metformin decreases the accumulation of Lafora bodies and polyubiquitin protein aggregates in the brain of treated animals. 4-Phenylbutyric acid and metformin also diminish neurodegeneration (measured in terms of neuronal loss and reactive gliosis) and ameliorate neuropsychological tests of Epm2b-/- mice. As these compounds have good safety records and are already approved for clinical uses on different neurological pathologies, we think that the translation of our results to the clinical practice could be straightforward.This work was supported by grants from the Spanish Ministry of Education and Science SAF2011-27442, Fundació La Marato de TV3 (ref. 100130) and an ACCI2012 action from CIBERER. A.B. holds a postdoctoral fellowship from the Program “Junta para la Ampliación de Estudios” (JAE-Doc) co-funded by the European Social Fund (ESF).Peer reviewe

Innovación y estrategias de intervención en acoso escolar

Los problemas de convivencia escolar, violencia escolar, bullying y cyberbullying, en los centros españoles son una realidad y, por tanto, es necesario que los futuros docentes cuenten con estrategias específicas para el abordaje de estas situaciones cuando se enfrenten a la realidad de las aulas. En este manual, profesionales del área de la convivencia escolar presentan las actuaciones, programas y herramientas disponibles que en estos momentos se están poniendo en práctica en los centros escolares con resultados positivos. Así, se pretende ampliar el conocimiento teórico-práctico en el ámbito de la convivencia, gestión de conflictos y violencia escolar.EducaciónPsicologí

Cluster analysis of Health-related lifestyles in university students

Health-related lifestyles in young adults are a public health concern because they affect the risk for developing noncommunicable diseases. Although unhealthy lifestyles tend to cluster together, most studies have analyzed their effects as independent factors. This study assessed the prevalence association, and clustering of health-related lifestyles (smoking, alcohol consumption, physical activity, and quality of diet) among university students. This cross-sectional study examined a sample of student participants from the University of the Balearic Islands (n = 444; 67.8% females; mean age: 23.1 years). A self-reported questionnaire was used to assess health-related lifestyles. Men that consumed more alcohol, had less healthy diets, were more likely to be overweight, and performed more physical activity. Women had a higher prevalence of low weight and performed less physical activity. Physical activity had a negative association with time using a computer (OR: 0.85; 95% CI: 0.76, 0.95) and a positive association with adherence to the Mediterranean diet (OR: 1.16; 95% CI: 1.02, 1.32). Adherence to the Mediterranean diet had a negative association with tobacco consumption (OR: 0.52; 95% CI: 0.30, 0.91), and positive associations with having breakfast every day (OR: 1.70; 95% CI: 1.05, 2.76) and consuming more daily meals (OR: 1.43; 95% CI: 1.10, 1.87). Cluster analysis indicated the presence of three distinct groups: Unhealthy lifestyles with moderate risk; unhealthy lifestyles with high risk; and healthy lifestyles with low risk. Health promotion interventions in the university environment that focus on multiple lifestyles could have a greater effect than interventions that target any single lifestyle. Keywords: lifestyle; clustering; risk factors; university students; physical activity; diet; smoking; alcohol; mediterranean diet; health-related behavior

Haemostatic function measured by thromboelastography and metabolic activity of platelets treated with riboflavin and UV light

[eng] Background: Pathogen reduction technology (PRT) may damage platelet (PLT) components. To study this, metabolic activity and haemostatic function of buffy coat (BC) PLT concentrates, with or without riboflavin and UV light PRT treatment, were compared. Material and methods: Twenty-four BC PLT concentrates, leukoreduced and diluted in additive solution, were grouped into 12 type-matched pairs, which were pooled and divided into 12 non-PRT-treated BC PLT concentrates (control units) and 12 riboflavin and UV PRT-treated BC PLT concentrates (test units). Haemostatic function and metabolic parameters were monitored by thrombelastography at days 1, 3, 7 and 14 post collection in both PLT groups. Results: Loss of PLT discoid shape, glucose consumption, lactate production, and decrease in pH were greater in the PRT-treated PLTs than in control PLTs over time (p<0.001). PLT haemostatic function evaluated by clot strength was also significantly weaker in PRT-treated PLTs compared with the excellent clot quality of control PLTs at day 7 (maximum amplitude: 41.27 vs 64.27; p<0.001), and even at day 14 (21.16 vs 60.39; p<0.001) of storage. Discussion: Pathogen reduction technology treatment accelerates and increases platelet storage lesion, resulting in glucose depletion, lactate accumulation, PLT acidification, and discoid shape loss. The clots produced by control PLTs at day 14 were still remarkably strong, whereas at day 7 PRT-treated PLTs produced weaker clots compared to the control group. Clinical trials investigating the efficacy of PRT-treated PLTs transfused at the end of the storage period (day 7), when the in vitro clot strength is weaker, are needed.

High NOR-1 (Neuron-Derived Orphan Receptor 1) Expression Strengthens the Vascular Wall Response to Angiotensin II Leading to Aneurysm Formation in Mice

[eng] No drug therapy has shown to limit abdominal aortic aneurysm (AAA) growth or rupture, and the understanding of the disease biology is incomplete; whereby, one challenge of vascular medicine is the development of good animal models and therapies for this life-threatening condition. The nuclear receptor NOR-1 (neuron-derived orphan receptor 1) controls biological processes involved in AAA; however, whether it plays a role in this pathology is unknown. Through a gain-of-function approach we assessed the impact of NOR-1 expression on the vascular response to Ang II (angiotensin II). We used 2 mouse models that overexpress human NOR-1 in the vasculature, one of them specifically in vascular smooth muscle cells. NOR-1 transgenesis amplifies the response to Ang II enhancing vascular inflammation (production of proinflammatory cytokines, chemokines, and reactive oxygen species), increasing MMP (matrix metalloproteinase) activity and disturbing elastin integrity, thereby broking the resistance of C57BL/6 mice to Ang II-induced AAA. Genes encoding for proteins critically involved in AAA formation (Il [interleukin]-6, Il-1β, Cxcl2, [C-X-C motif chemokine ligand 2], Mcp-1 [monocyte chemoattractant protein 1], and Mmp2) were upregulated in aneurysmal tissues. Both animal models show a similar incidence and severity of AAA, suggesting that high expression of NOR-1 in vascular smooth muscle cell is a sufficient condition to strengthen the response to Ang II. These alterations, including AAA formation, were prevented by the MMP inhibitor doxycycline. Microarray análisis identified gene sets that could explain the susceptibility of transgenic animals to Ang II-induced aneurysms, including those related with extracellular matrix remodeling, inflammatory/immune response, sympathetic activity, and vascular smooth muscle cell differentiation. These results involve NOR-1 in AAA and validate mice overexpressing this receptor as useful experimental models

Genetic mapping of semi-polar metabolites in pepper fruits (Capsicum sp.): towards unravelling the molecular regulation of flavonoid quantitative trait loci

Untargeted LCMS profiling of semi-polar metabolites followed by metabolite quantitative trait locus (mQTL) analysis was performed in ripe pepper fruits of 113 F2 plants derived from a cross between Capsicum annuum AC1979 (no. 19) and Capsicum chinense No. 4661 Selection (no. 18). The parental accessions were selected based on their variation in fruit morphological characteristics and fruit content of some target phytonutrients. Clear segregation of fruit colour and fruit metabolite profiles was observed in the F2 population. The F2 plants formed three clusters based on their metabolite profiles. Of the total of 542 metabolites, 52 could be annotated, including a range of flavonoids, such as flavone C-glycosides, flavonol O-glycosides and naringenin chalcone, as well as several phenylpropanoids, a capsaicin analogue, fatty acid derivatives and amino acid derivatives. Interval mapping revealed 279 mQTLs in total. Two mQTL hotspots were found on chromosome 9. These two chromosomal regions regulated the relative levels of 35 and 103 metabolites, respectively. Analysis also revealed an mQTL for a capsaicin analogue, located on chromosome 7. Confirmation of flavonoid mQTLs using a set of six flavonoid candidate gene markers and their corresponding expression data (expression QTLs) indicated the Ca-MYB12 transcription factor gene on chromosome 1 and the gene encoding flavone synthase (FS-2) on chromosome 6 as likely causative genes determining the variation in naringenin chalcone and flavone C-glycosides, respectively, in this population. The combination of large-scale metabolite profiling and QTL analysis provided valuable insight into the genomic regions and genes important for the production of (secondary) metabolites in pepper fruit. This will impact breeding strategies aimed at optimising the content of specific metabolites in pepper frui

Prominence seismology using small amplitude oscillations

Quiescent prominences are thin slabs of cold, dense plasma embedded in the much hotter and rarer solar corona. Although their global shape is rather irregular, they are often characterised by an internal structure consisting of a large number of thin, parallel threads piled together. Prominences often display periodic disturbances mostly observed in the Doppler displacement of spectral lines and with an amplitude typically of the order of or smaller than 2--3 km s$^{-1}$, a value which seems to be much smaller than the characteristic speeds of the prominence plasma (namely the Alfv\'en and sound velocities). Two particular features of these small amplitude prominence oscillations is that they seem to damp in a few periods and that they seem not to affect the whole prominence structure. In addition, in high spatial resolution observations, in which threads can be discerned, small amplitude oscillations appear to be clearly associated to these fine structure constituents. Prominence seismology tries to bring together the results from these observations (e.g. periods, wavelengths, damping times) and their theoretical modeling (by means of the magnetohydrodynamic theory) to gain insight into physical properties of prominences that cannot be derived from direct observation. In this paper we discuss works that have not been described in previous reviews, namely the first seismological application to solar prominences and theoretical advances on the attenuation of prominence oscillations

Nuclear Interactions Of Super High Energy Cosmic-rays Observed In Mountain Emulsion Chambers

Here we present a summary of joint discussions on the results of three mountain experiments with large-scale emulsion chambers, at Pamir, Mt. Fuji and Chacaltaya. Observations cover gamma quanta, hadrons and their clusters (called "families"). The following topics are covered, concerning the characteristics of nuclear interactions the energy region 1014-1016 eV: (i) rapid dissipation seen in atmospheric diffusion of high-energy cosmic-rays; (ii) multiplicity and Pt increase in produced pi-mesons in the fragmentation region; (iii) existence of large-Pt jets, (iv) extremely hadron-rich family of the Centauro type; (v) exotic phenomena in the extremely high energy region beyond 1016 eV. © 1981.1911125(1977) Acta Univ. Lodz ser. II, (60)(1973) 13th Int. Cosmic-ray Conf., 3, p. 2228(1975) 14th Int. Cosmic-Ray Conf., 7, p. 2365(1979) AIP Conf. Proc. no. 49, p. 334(1979) 16th Int. Cosmic-ray Conf., 6, p. 344(1979) 16th Int. Cosmic-ray Conf., 7, p. 6816th Int. Cosmic-ray Conf. (1979) 16th Int. Cosmic-ray Conf., 7, p. 284(1979) 16th Int. Cosmic-ray Conf., 7, p. 294(1979) 16th Int. Cosmic-ray Conf., 13, p. 87(1979) 16th Int. Cosmic-ray Conf., 13, p. 92(1979) 16th Int. Cosmic-ray Conf., 13, p. 98(1979) AIP Conf. Proc. no. 49, p. 94(1979) AIP Conf. Proc. no. 49, p. 145(1979) AIP Conf. Proc. no. 49, p. 317(1979) 16th Int. Cosmic-ray Conf., 6, p. 350(1979) 16th Int. Cosmic-ray Conf., 6, p. 356(1979) 16th Int. Cosmic-ray Conf., 6, p. 362Nikolsky, Proc. 9th Int. High-energy Symp. (1978) CSSR, 21. , ToborMiyake, (1978) Proc. 19th Int. Conf. on High-energy physics, p. 433Vernov, (1977) Physica, 3, p. 1601Khristiansen, (1978) JETP Lett., 28, p. 124(1973) 13th Int. Cosmic-ray Conf., 3, p. 2219Izv. Acad. Nauk USSR, ser Phys. (1974) Izv. Acad. Nauk USSR, ser Phys., 38, p. 918(1975) 14th Int. Cosmic-ray Conf., 7, p. 2365(1979) 16th Int. Cosmic-ray Conf., 7, p. 68Dunaevsky, Urysson, Emelyanov, Shorin, Tashimov, (1975) FIAN preprint no. 150Dunaevsky, Urysson, Emelyanov, Shorin, Tashinov, (1979) Acta Univ. Lodz ser. II, (60), p. 199Ivanenko, Kanevskya, Roganova, (1978) JETP Lett., 40, p. 704Ivanenko, Kanevsky, Roganova, (1979) 16th Int. Cosmic-ray Conf., 7, p. 101Ivanenko, Kanevsky, Roganova, (1979) 16th Int. Cosmic-ray Conf., 7, p. 198Wrotniak, (1977) Acta Univ. Lodz ser. II, (60), p. 165Krys, Tomaszevski, Wrotniak, (1979) 16th Int. Cosmic-ray Conf., 7, p. 182Krys, Tomaszevski, Wrotniak, (1979) 16th Int. Cosmic-ray Conf., 7, p. 186Fomin, Kempa, Khristiansen, Levina, Piotrowska, Wdowczyk, (1977) 15th Int. Cosmic-ray Conf., 7, p. 248Fomin, Kempa, Khristiansen, Levina, Piotrowska, Wdowczyk, (1979) 16th Int. Cosmic-ray Conf., 13, p. 82Azimov, Mullazhanov, Yuldashbayev, (1979) 16th Int. Cosmic-ray Conf., 7, p. 262Azimov, Mullazhanov, Yuldashbayev, (1977) Acta Univ. Lodz ser. II, (60), p. 275Kasahara, Torri, Yuda, (1979) 16th Int. Cosmic-ray Conf., 13, p. 70Kasahara, Torii, Yuda, (1979) 16th Int. Cosmic-ray Conf., 13, p. 79Shibata, (1979) 16th Int. Cosmic-ray Conf., 7, p. 176H. Semba, T. Shibata and T. Tabuki, Suppl. Prog. Theor. Phys., to be publishedZhdanov, Roinishvilli, Smorodin, Tomaszevski, (1975) FIAN preprint no. 163Lattes, Fujimoto, Hasegawa, Hadronic interactions of high energy cosmic-ray observed by emulsion chambers (1980) Physics Reports, 65, p. 152Ellsworth, Gaisser, Yodh, (1981) Phys. Rev., 23 D, p. 764Baradzei, Smorodin, (1974) FIAN preprint nos. 103, 104Baradzei, Smorodin, (1977) Acta Univ. Lodz ser. II, (60), p. 51Zhdanov, (1980) FIAN preprint no. 140H. Semba, T. Shibata and T. Tabuki, Suppl. Prog. Theor. Phys., to be publishedShibata, (1980) Phys. Rev., 22 D, p. 100Slavatinsky, (1980) Proc. 7th European Symp. on Cosmic rays, , Leningrad, to be published(1979) AIP Conference Proc. no. 49, p. 145Azimov, Abduzhamilov, Chudakov, (1963) JETP (Sov. Phys.), 45, p. 40713th Int. Cosmic-ray Conf. (1973) 13th Int. Cosmic-ray Conf., 5, p. 326Acharya, Rao, Sivaprasad, Rao, (1979) 16th Int. Cosmic-ray Conf., 6, p. 289Ellsworth, Goodman, Yodh, Gaisser, Stanev, (1981) Phys. Rev., 23 D, p. 771Bariburina, Guseva, Denisova, (1980) Acta Univ. Lodz, 1, p. 9415th Int. Cosmic-ray Conf. (1977) 15th Int. Cosmic-ray Conf., 7, p. 184(1979) AIP Conf. Proc. no. 49, p. 33