La realidad virtual como entorno fortalecedor para el cambio personal: la contribución del laboratorio de tecnología aplicada a la neuropsicología

When we exercise real choice, we gain increased control over our lives and are able to change ourselves. However for many subjects it is not easy to exercise effective choices: patients often don’t have the knowledge, skills, assertiveness, or self esteem needed. In this situation Virtual Reality (VR), an artificial reality that projects the user into a 3D space generated by the computer, may offer a critical advantage to the therapist. The enriched experience and the total level of control on its features, transform VR in an “empowering environment”, where patients can start to explore and act without feeling actually threatened. The attempt of defining, developing and testing VR tools supporting personal empowerment is the main goal of the Applied Technology for Neuro-Psychology Laboratory –ATN-P Lab– at the Istituto Auxologico Italiano. The paper describes the actual work done by the ATN-P Lab. in this area. Specifically, the open source "NeuroVR" system and its potential clinical applications –anxiety disorders, obesity and eating disorders– are presented and discussed.La capacidad de elección nos proporciona control sobre nuestras vidas y nos ofrece posibilidades de cambio. Sin embargo, para muchas personas no es fácil realizar elecciones efectivas; por ejemplo, los pacientes carecen muchas veces del conocimiento, la habilidad, la asertividad o autoestima necesarias. En esas situaciones, la realidad virtual (RV), una realidad artificial que coloca al sujeto en un espacio generado por el ordenador, puede ser para el terapeuta un recurso decisivo. La experiencia enriquecida y el control total sobre todos sus aspectos transforman la RV en un “entorno fortalecedor”, en el que los pacientes pueden comenzar a explorar y actuar sin sentirse amenazados. El principal objetivo del “Applied Technology for Neuro-Psychology Laboratory” (ATN-P Lab), perteneciente al Instituto Auxologico Italiano, es intentar definir, desarrollar y probar aplicaciones basadas en RV que faciliten el fortalecimiento personal. En este artículo se describe el trabajo que se viene realizando sobre este tema en ese laboratorio. Se presenta y discute, específicamente, el sistema de código abierto denominado “NeuroVR”, así como sus aplicaciones clínicas potenciales sobre los trastornos de ansiedad, la obesidad y los trastornos alimentarios

La realidad virtual como entorno fortalecedor para el cambio personal: la contribución del laboratorio de tecnología aplicada a la neuropsicología

When we exercise real choice, we gain increased control over our lives and are able to change ourselves. However for many subjects it is not easy to exercise effective choices: patients often don’t have the knowledge, skills, assertiveness, or self esteem needed. In this situation Virtual Reality (VR), an artificial reality that projects the user into a 3D space generated by the computer, may offer a critical advantage to the therapist. The enriched experience and the total level of control on its features, transform VR in an “empowering environment”, where patients can start to explore and act without feeling actually threatened. The attempt of defining, developing and testing VR tools supporting personal empowerment is the main goal of the Applied Technology for Neuro-Psychology Laboratory –ATN-P Lab– at the Istituto Auxologico Italiano. The paper describes the actual work done by the ATN-P Lab. in this area. Specifically, the open source "NeuroVR" system and its potential clinical applications –anxiety disorders, obesity and eating disorders– are presented and discussed.La capacidad de elección nos proporciona control sobre nuestras vidas y nos ofrece posibilidades de cambio. Sin embargo, para muchas personas no es fácil realizar elecciones efectivas; por ejemplo, los pacientes carecen muchas veces del conocimiento, la habilidad, la asertividad o autoestima necesarias. En esas situaciones, la realidad virtual (RV), una realidad artificial que coloca al sujeto en un espacio generado por el ordenador, puede ser para el terapeuta un recurso decisivo. La experiencia enriquecida y el control total sobre todos sus aspectos transforman la RV en un “entorno fortalecedor”, en el que los pacientes pueden comenzar a explorar y actuar sin sentirse amenazados. El principal objetivo del “Applied Technology for Neuro-Psychology Laboratory” (ATN-P Lab), perteneciente al Instituto Auxologico Italiano, es intentar definir, desarrollar y probar aplicaciones basadas en RV que faciliten el fortalecimiento personal. En este artículo se describe el trabajo que se viene realizando sobre este tema en ese laboratorio. Se presenta y discute, específicamente, el sistema de código abierto denominado “NeuroVR”, así como sus aplicaciones clínicas potenciales sobre los trastornos de ansiedad, la obesidad y los trastornos alimentarios

Italian National Health Service immunized by Covid-19?

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Leber's Hereditary Optic Neuropathy (LHON) Pathogenic Mutations Induce Mitochondrial-dependent Apoptotic Death in Transmitochondrial Cells Incubated with Galactose Medium

Leber's hereditary optic neuropathy (LHON), a maternally inherited form of central vision loss, is associated with mitochondrial DNA pathogenic point mutations affecting different subunits of complex I. We here report that osteosarcoma-derived cytoplasmic hybrids (cybrid) cell lines harboring one of the three most frequent LHON pathogenic mutations, at positions 11778/ND4, 3460/ND1, and 14484/ND6, undergo cell death when galactose replaces glucose in the medium, contrary to control cybrids that maintain some growth capabilities. This is a well known way to produce a metabolic stress, forcing the cells to rely on the mitochondrial respiratory chain to produce ATP. We demonstrate that LHON cybrid cell death is apoptotic, showing chromatin condensation and nuclear DNA laddering. Moreover, we also document the mitochondrial involvement in the activation of the apoptotic cascade, as shown by the increased release of cytochrome c into the cytosol in LHON cybrid cells as compared with controls. Cybrids bearing the 3460/ND1 and 14484/ND6 mutations seemed more readily prone to undergo apoptosis as compared with the 11778/ND4 mutation. In conclusion, LHON cybrid cells forced by the reduced rate of glycolytic flux to utilize oxidative metabolism are sensitized to an apoptotic death through a mechanism involving mitochondria

Respiratory function in cybrid cell lines carrying European mtDNA haplogroups: implications for Leber's hereditary optic neuropathy

AbstractThe possibility that some combinations of mtDNA polymorphisms, previously associated with Leber's hereditary optic neuropathy (LHON), may affect mitochondrial respiratory function was tested in osteosarcoma-derived transmitochondrial cytoplasmic hybrids (cybrids). In this cellular system, in the presence of the same nuclear background, different exogenous mtDNAs are used to repopulate a parental cell line previously devoid of its original mtDNA. No detectable differences in multiple parameters exploring respiratory function were observed when mtDNAs belonging to European haplogroups X, H, T and J were used. Different possible explanations for the previously established association between haplogroup J and LHON 11778/ND4 and 14484/ND6 pathogenic mutations are discussed, including the unconventional proposal that mtDNA haplogroup J may exert a protective rather than detrimental effect

Protection against oxidant-induced apoptosis by exogenous glutathione in Leber hereditary optic neuropathy cybrids

PURPOSE. To use different paradigms of oxidative and metabolic stress in a cellular model of Leber hereditary optic neuropathy (LHON), with the aim of evaluating the efficacy of potentially therapeutic molecules for the treatment of this disease. METHODS. Cybrids bearing one of the three most common LHON pathogenic mutations (11778/ND4, 3460/ND1, 14484/ ND6) were incubated with two compounds known to induce oxidative injury, tert-butyl hydroperoxide (t-BH) and rotenone. To mimic metabolic stress, cells were incubated in a glucosefree medium containing galactose. Cell viability was determined using the MTT assay. To identify the apoptotic type of cell death, nuclear morphology was examined after cell loading with Hoechst. Cellular glutathione (GSH), and oxidized glutathione (GSSG) levels were measured enzymatically. RESULTS. Incubation with t-BH caused apoptotic cell death of control and LHON cybrids, whereas only LHON cybrids were damaged by rotenone concentrations up to 2.5 M. Both types of stress caused a marked imbalance in the glutathione levels, but an increase in the GSSG/GSHϩGSSG ratio was detected only after rotenone treatment. The efficacy of several antioxidant and antiapoptotic compounds was then assessed in cells exposed to these two oxidative paradigms. Only exogenous GSH remarkably protected the t-BH-and rotenone-treated cybrids from cell death. In contrast, GSH was unable to increase the viability of cybrids exposed to metabolic stress. CONCLUSIONS. These results suggest that GSH is an effective antioxidant compound to be tested as a potential treatment for LHON. (Invest Ophthalmol Vis Sci. 2008;49:671-676

The Background of Mitochondrial DNA Haplogroup J Increases the Sensitivity of Leber's Hereditary Optic Neuropathy Cells to 2,5-Hexanedione Toxicity

Leber's hereditary optic neuropathy (LHON) is a maternally inherited blinding disease due to mitochondrial DNA (mtDNA) point mutations in complex I subunit genes, whose incomplete penetrance has been attributed to both genetic and environmental factors. Indeed, the mtDNA background defined as haplogroup J is known to increase the penetrance of the 11778/ND4 and 14484/ND6 mutations. Recently it was also documented that the professional exposure to n-hexane might act as an exogenous trigger for LHON. Therefore, we here investigate the effect of the n-hexane neurotoxic metabolite 2,5-hexanedione (2,5-HD) on cell viability and mitochondrial function of different cell models (cybrids and fibroblasts) carrying the LHON mutations on different mtDNA haplogroups. The viability of control and LHON cybrids and fibroblasts, whose mtDNAs were completely sequenced, was assessed using the MTT assay. Mitochondrial ATP synthesis rate driven by complex I substrates was determined with the luciferine/luciferase method. Incubation with 2,5-HD caused the maximal loss of viability in control and LHON cells. The toxic effect of this compound was similar in control cells irrespective of the mtDNA background. On the contrary, sensitivity to 2,5-HD induced cell death was greatly increased in LHON cells carrying the 11778/ND4 or the 14484/ND6 mutation on haplogroup J, whereas the 11778/ND4 mutation in association with haplogroups U and H significantly improved cell survival. The 11778/ND4 mutation on haplogroup U was also more resistant to inhibition of complex I dependent ATP synthesis by 2,5-HD. In conclusion, this study shows that mtDNA haplogroups modulate the response of LHON cells to 2,5-HD. In particular, haplogroup J makes cells more sensitive to its toxic effect. This is the first evidence that an mtDNA background plays a role by interacting with an environmental factor and that 2,5-HD may be a risk element for visual loss in LHON. This proof of principle has broad implications for other neurodegenerative disorders such as Parkinson's disease

Metabolomics hallmarks OPA1 variants correlating with their in-vitro phenotype and predicting clinical severity

Interpretation of variants of uncertain significance is an actual major challenge. We addressed this question on a set of OPA1 missense variants responsible for variable severity of neurological impairments. We used targeted metabolomics to explore the different signatures of OPA1 variants expressed in Opa1 deleted mouse embryonic fibroblasts (Opa1 12/ 12 MEFs), grown under selective conditions. Multivariate analyses of data discriminated Opa1+/+ from Opa1 12/ 12 MEFs metabolic signatures and classified OPA1 variants according to their in-vitro severity. Indeed, the mild p.I382M hypomorphic variant was segregating close to the wild-type allele, while the most severe p.R445H variant was close to Opa1 12/ 12 MEFs, and the p.D603H and p.G439V alleles, responsible for isolated and syndromic presentations respectively, were intermediary between the p.I382M and the p.R445H variants. The most discriminant metabolic features were hydroxyproline, the spermine/spermidine ratio, amino acid pool and several phospholipids, emphasizing proteostasis, endoplasmic reticulum stress and phospholipid remodeling as the main mechanisms ranking OPA1 allele impacts on metabolism. These results demonstrate the high resolving power of metabolomics in hierarchizing OPA1 missense mutations by their in-vitro severity, fitting clinical expressivity. This suggests that our methodological approach can be used to discriminate the pathological significance of variants in genes responsible for other rare metabolic diseases and may be instrumental to select possible compounds eligible for supplementation treatment

Deciphering OPA1 mutations pathogenicity by combined analysis of human, mouse and yeast cell models

OPA1 is the major gene responsible for Dominant Optic Atrophy (DOA) and the syndromic form DOA “plus”. Over 370 OPA1 mutations have been identified so far, although their pathogenicity is not always clear. We have analyzed one novel and a set of known OPA1 mutations to investigate their impact on protein functions in primary skin fibroblasts and in two “ad hoc” generated cell systems: the MGM1/OPA1 chimera yeast model and the Opa1−/− MEFs model expressing the mutated human OPA1 isoform 1. The yeast model allowed us to confirm the deleterious effects of these mutations and to gain information on their dominance/recessivity. The MEFs model enhanced the phenotypic alteration caused by mutations, nicely correlating with the clinical severity observed in patients, and suggested that the DOA “plus” phenotype could be induced by the combinatorial effect of mitochondrial network fragmentation with variable degrees of mtDNA depletion. Overall, the two models proved to be valuable tools to functionally assess and define the deleterious mechanism and the pathogenicity of novel OPA1 mutations, and useful to testing new therapeutic interventions