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

Modelling the photo-Fenton oxidation of the pharmaceutical paracetamol in water including the effect of photon absorption (VRPA)

A new model is proposed for the photo-Fenton oxidation of water contaminants including the effect of photon absorption (volumetric rate of photon absorption, VRPA), the effect of the geometry of the reactor and the illuminated volume to total volume ratio (Ri) in the reaction system. Fe(III) was found to be the main species in the aqueous solution responsible for photon absorption provided that hydrogen peroxide was not totally consumed. Paracetamol was used as model pollutant at a concentration of 1 mM to validate the model. The illuminated part of the raceway reactor configuration (total length of 80 cm) was operated at two liquid depths (5.0 and 2.5 cm) equivalent to two irradiated reactor volumes (2 and 1 L) and using Ri ratios in the range 0.30–0.65, which changed the dark reactor volume. These values are commonly found in photo-Fenton pilot plants for water treatment and purification. The model successfully fitted the temporal evolution of the dissolved oxygen (O2) and the hydrogen peroxide (H2O2) concentrations and the evolution of the total organic carbon (TOC) in solution in both reactor geometries and for different illuminated volume to total volume ratios. The model can be easily extended to model other water contaminants and provides a robust method for process design, process control and optimization

Clinical implication of FMR1 intermediate alleles in a Spanish population

FMR1 premutation carriers (55-200 CGGs) are at risk of developing Fragile X-associated primary ovarian insufficiency as well as Fragile X-associated tremor/ataxia syndrome. FMR1 premutation alleles are also associated with a variety of disorders, including psychiatric, developmental, and neurological problems. However, there is a major concern regarding clinical implications of smaller CGG expansions known as intermediate alleles (IA) or gray zone alleles (45-54 CGG). Although several studies have hypothesized that IA may be involved in the etiology of FMR1 premutation associated phenotypes, this association still remains unclear. The aim of this study was to provide new data on the clinical implications of IA. We reviewed a total of 17 011 individuals: 1142 with primary ovarian insufficiency, 478 with movement disorders, 14 006 with neurodevelopmental disorders and 1385 controls. Similar IA frequencies were detected in all the cases and controls (cases 1.20% vs controls 1.39%, P =.427). When comparing the allelic frequencies of IA = 50CGGs, a greater, albeit not statistically significant, number of alleles were detected in all the cohorts of patients. Therefore, IA below 50 CGGs should not be considered as risk factors for FMR1 premutation-associated phenotypes, at least in our population. However, the clinical implication of IA = 50CGGs remains to be further elucidated

Synchronization of Hamiltonian motion and dissipative effects in optical lattices: Evidence for a stochastic resonance

We theoretically study the influence of the noise strength on the excitation of the Brillouin propagation modes in a dissipative optical lattice. We show that the excitation has a resonant behavior for a specific amount of noise corresponding to the precise synchronization of the Hamiltonian motion on the optical potential surfaces and the dissipative effects associated with optical pumping in the lattice. This corresponds to the phenomenon of stochastic resonance. Our results are obtained by numerical simulations and correspond to the analysis of microscopic quantities (atomic spatial distributions) as well as macroscopic quantities (enhancement of spatial diffusion and pump-probe spectra). We also present a simple analytical model in excellent agreement with the simulations

Maximising embryo production in endangered sheep breeds: in vitro procedures that complement in vivo techniques

This study investigated the use of previously superovulated ovaries as a source of oocytes, assessing the competence of them for in vitro embryo production. Two superovulatory treatments were performed: equine Chorionic Gonadotrophin (eCG) plus porcine Follicle-Stimulating Hormone (pFSH) in a single dose or the conventional protocol of six decreasing doses of pFSH. Thirty donor ewes of the endangered Ojalada breed were given either the simplified (group S; n=15) or the decreasing-dose (group D; n=15) treatments three times at intervals of ≥50 days. Ovaries were recovered on day 7 after the oestrus following the third treatment, just after embryo flushing, and the oocytes were collected to assess in vitro maturation, fertilisation and development to the blastocyst stage. The two superovulatory treatments did not differ in the mean number of oocytes selected for maturation (7.1±1.2 and 8.5±1.5 per ewe in the D and S groups, respectively). The oocytes recovered from ewes in Group D (87.5%) had a significantly (p<0.05) higher maturation rate than did those recovered from ewes in group S (75%), but no differences were found in fertilisation rate (94% and 94.6% in the D and S groups, respectively); both groups did not differ in their blastocyst rates and the total number of cells in in vitro-produced blastocysts. In the two experimental groups, 1.7 (D) and 1.8 (S) in vitro-produced blastocysts were generated per ewe, which indicate that it is feasible to combine in vivo and in vitro techniques to maximise embryo production in endangered sheep breeds.EEA ChubutFil: Forcada, Fernando. Universidad de Zaragoza. Instituto de Investigación de Ciencias Ambientales de Aragón. Grupo de Biología y Fisiología de la Reproducción; EspañaFil: Buffoni, Andres. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Chubut; ArgentinaFil: Abecia, José Alfonso. Universidad de Zaragoza. Instituto de Investigación de Ciencias Ambientales de Aragón. Grupo de Biología y Fisiología de la Reproducción; EspañaFil: Asenjo, B. Universidad de Valladolid. Escuela Universitaria de Ingenierías Agrarias de Soria; EspañaFil: Palacin, José Ignacio. Universidad de Zaragoza. Instituto de Investigación de Ciencias Ambientales de Aragón. Grupo de Biología y Fisiología de la Reproducción; EspañaFil: Vázquez, M.I. Universidad de Zaragoza. Instituto de Investigación de Ciencias Ambientales de Aragón. Grupo de Biología y Fisiología de la Reproducción; EspañaFil: Rodriguez Castillo, José del Carmen. Benemérita Universidad Autónoma de Puebla. Facultad de Medicina Veterinaria y Zootecnia; MéxicoFil: Sanchez Prieto, L. Universidad de Zaragoza. Instituto de Investigación de Ciencias Ambientales de Aragón. Grupo de Biología y Fisiología de la Reproducción; EspañaFil: Casao, A. Universidad de Zaragoza. Instituto de Investigación de Ciencias Ambientales de Aragón. Grupo de Biología y Fisiología de la Reproducción; Españ

A Comprehensive Analysis of Choroideremia: From Genetic Characterization to Clinical Practice.

Choroideremia (CHM) is a rare X-linked disease leading to progressive retinal degeneration resulting in blindness. The disorder is caused by mutations in the CHM gene encoding REP-1 protein, an essential component of the Rab geranylgeranyltransferase (GGTase) complex. In the present study, we evaluated a multi-technique analysis algorithm to describe the mutational spectrum identified in a large cohort of cases and further correlate CHM variants with phenotypic characteristics and biochemical defects of choroideremia patients. Molecular genetic testing led to the characterization of 36 out of 45 unrelated CHM families (80%), allowing the clinical reclassification of four CHM families. Haplotype reconstruction showed independent origins for the recurrent p.Arg293* and p.Lys178Argfs*5 mutations, suggesting the presence of hotspots in CHM, as well as the identification of two different unrelated events involving exon 9 deletion. No certain genotype-phenotype correlation could be established. Furthermore, all the patients´ fibroblasts analyzed presented significantly increased levels of unprenylated Rabs proteins compared to control cells; however, this was not related to the genotype. This research demonstrates the major potential of the algorithm proposed for diagnosis. Our data enhance the importance of establish a differential diagnosis with other retinal dystrophies, supporting the idea of an underestimated prevalence of choroideremia. Moreover, they suggested that the severity of the disorder cannot be exclusively explained by the genotype

Effectiveness of an mHealth intervention combining a smartphone app and smart band on body composition in an overweight and obese population: Randomized controlled trial (EVIDENT 3 study)

Background: Mobile health (mHealth) is currently among the supporting elements that may contribute to an improvement in health markers by helping people adopt healthier lifestyles. mHealth interventions have been widely reported to achieve greater weight loss than other approaches, but their effect on body composition remains unclear. Objective: This study aimed to assess the short-term (3 months) effectiveness of a mobile app and a smart band for losing weight and changing body composition in sedentary Spanish adults who are overweight or obese. Methods: A randomized controlled, multicenter clinical trial was conducted involving the participation of 440 subjects from primary care centers, with 231 subjects in the intervention group (IG; counselling with smartphone app and smart band) and 209 in the control group (CG; counselling only). Both groups were counselled about healthy diet and physical activity. For the 3-month intervention period, the IG was trained to use a smartphone app that involved self-monitoring and tailored feedback, as well as a smart band that recorded daily physical activity (Mi Band 2, Xiaomi). Body composition was measured using the InBody 230 bioimpedance device (InBody Co., Ltd), and physical activity was measured using the International Physical Activity Questionnaire. Results: The mHealth intervention produced a greater loss of body weight (–1.97 kg, 95% CI –2.39 to –1.54) relative to standard counselling at 3 months (–1.13 kg, 95% CI –1.56 to –0.69). Comparing groups, the IG achieved a weight loss of 0.84 kg more than the CG at 3 months. The IG showed a decrease in body fat mass (BFM; –1.84 kg, 95% CI –2.48 to –1.20), percentage of body fat (PBF; –1.22%, 95% CI –1.82% to 0.62%), and BMI (–0.77 kg/m2, 95% CI –0.96 to 0.57). No significant changes were observed in any of these parameters in men; among women, there was a significant decrease in BMI in the IG compared with the CG. When subjects were grouped according to baseline BMI, the overweight group experienced a change in BFM of –1.18 kg (95% CI –2.30 to –0.06) and BMI of –0.47 kg/m2 (95% CI –0.80 to –0.13), whereas the obese group only experienced a change in BMI of –0.53 kg/m2 (95% CI –0.86 to –0.19). When the data were analyzed according to physical activity, the moderate-vigorous physical activity group showed significant changes in BFM of –1.03 kg (95% CI –1.74 to –0.33), PBF of –0.76% (95% CI –1.32% to –0.20%), and BMI of –0.5 kg/m2 (95% CI –0.83 to –0.19). Conclusions: The results from this multicenter, randomized controlled clinical trial study show that compared with standard counselling alone, adding a self-reported app and a smart band obtained beneficial results in terms of weight loss and a reduction in BFM and PBF in female subjects with a BMI less than 30 kg/m2 and a moderate-vigorous physical activity level. Nevertheless, further studies are needed to ensure that this profile benefits more than others from this intervention and to investigate modifications of this intervention to achieve a global effect

A personalized intervention to prevent depression in primary care: cost-effectiveness study nested into a clustered randomized trial

Background: Depression is viewed as a major and increasing public health issue, as it causes high distress in the people experiencing it and considerable financial costs to society. Efforts are being made to reduce this burden by preventing depression. A critical component of this strategy is the ability to assess the individual level and profile of risk for the development of major depression. This paper presents the cost-effectiveness of a personalized intervention based on the risk of developing depression carried out in primary care, compared with usual care. Methods: Cost-effectiveness analyses are nested within a multicentre, clustered, randomized controlled trial of a personalized intervention to prevent depression. The study was carried out in 70 primary care centres from seven cities in Spain. Two general practitioners (GPs) were randomly sampled from those prepared to participate in each centre (i.e. 140 GPs), and 3326 participants consented and were eligible to participate. The intervention included the GP communicating to the patient his/her individual risk for depression and personal risk factors and the construction by both GPs and patients of a psychosocial programme tailored to prevent depression. In addition, GPs carried out measures to activate and empower the patients, who also received a leaflet about preventing depression. GPs were trained in a 10- to 15-h workshop. Costs were measured from a societal and National Health care perspective. Qualityadjustedlife years were assessed using the EuroQOL five dimensions questionnaire. The time horizon was 18 months. Results: With a willingness-to-pay threshold of (sic)10, 000 ((sic)8568) the probability of cost-effectiveness oscillated from 83% (societal perspective) to 89% (health perspective). If the threshold was increased to (sic)30, 000 ((sic)25, 704), the probability of being considered cost-effective was 94% (societal perspective) and 96%, respectively (health perspective). The sensitivity analysis confirmed these results. Conclusions: Compared with usual care, an intervention based on personal predictors of risk of depression implemented by GPs is a cost-effective strategy to prevent depression. This type of personalized intervention in primary care should be further developed and evaluated