A strategy for designing inhibitors of alpha-synuclein aggregation and toxicity as a novel treatment for Parkinson's disease and related disorders.

Convergent biochemical and genetic evidence suggests that the formation of alpha-synuclein (alpha-syn) protein deposits is an important and, probably, seminal step in the development of Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). It has been reported that transgenic animals overexpressing human alpha-syn develop lesions similar to those found in the brain in PD, together with a progressive loss of dopaminergic cells and associated abnormalities of motor function. Inhibiting and/or reversing alpha-syn self-aggregation could, therefore, provide a novel approach to treating the underlying cause of these diseases. We synthesized a library of overlapping 7-mer peptides spanning the entire alpha-syn sequence, and identified amino acid residues 64-100 of alpha-syn as the binding region responsible for its self-association. Modified short peptides containing alpha-syn amino acid sequences from part of this binding region (residues 69-72), named alpha-syn inhibitors (ASI), were found to interact with full-length alpha-syn and block its assembly into both early oligomers and mature amyloid-like fibrils. We also developed a cell-permeable inhibitor of alpha-syn aggregation (ASID), using the polyarginine peptide delivery system. This ASID peptide was able to inhibit the DNA damage induced by Fe(II) in neuronal cells transfected with alpha-syn(A53T), a familial PD-associated mutation. ASI peptides without this delivery system did not reverse levels of Fe(II)-induced DNA damage. Furthermore, the ASID peptide increased (P

Molecular dynamics studies of trinucleotide repeat DNA involved in neurodegenerative disorders.

Expansion of trinucleotide repeat DNA of the classes CAG�·CTG, CGG�·CCG and GAA�·TTC are found to be associated with several neurodegenerative disorders. Different mechanisms have been attributed to the expansion of triplets, mainly involving the formation of alternate secondary structures by such repeats. This paper reports the molecular dynamics simulation of triplet repeat DNA sequences to study the basic structural features of DNA that are responsible for the formation of structures such as hairpins and slip-strand DNA leading to expansion. All the triplet repeat sequences studied were found to be more flexible compared to the control sequence unassociated with disease. Moreover, flexibility was found to be in the order CAG�·CTG > CGG�·CCG = GAA�·TTC, the highly flexible CAG�·CTG repeat being the most common cause of neurodegenerative disorders. In another simulation, a single G�·C to T�·A mutation at the 9th position of the CAG�·CTG repeat exhibited a reduction in bending compared to the pure 15-mer CAGâ�¢CTG repeat. EPM1 dodecamer repeat associated with the pathogenesis of progressive myoclonus epilepsy was also simulated and showed flexible nature suggesting a similar expansion mechanism.

Genetic disorders and spermatogenesis.

Male infertility affects one man in twenty and a genetic basis seems likely in at least 30% of those men. Genetic regulation of fertility involves the inter-related processes of testicular development, spermatogenesis (involving germ cell mitosis, meiosis and spermatid maturation), and their endocrine and paracrine regulation. In regard to spermatogenesis, particular attention has been given to the Yq11 region, where some spermatogenesis genes ('azoospermia factors') appear to be located. Several candidate genes have been identified but have not been shown to have a defined or essential role in spermatogenesis. Microdeletions of Yq11 are found in approximately 15% of azoospermic or severely oligospermic men. The complexity of the genetic control of male fertility is demonstrated by the evidence for genes involved in spermatogenesis and sexual differentiation on the X chromosome and autosomes. Better understanding of the genetic regulation of normal spermatogenesis will provide new probes for clinical studies; however, at present the majority of spermatogenic failure remains without an identified genetic linkage. The advent of intracytoplasmic sperm injection permits fertility in many previously sterile men and presents the possibility of their transmission of infertility; appropriate counselling is required.

El uso de la musicoterapia para la mejora de la comunicación de niños con Trastorno del Espectro Autista en Aulas Abiertas Especializadas

Los beneficios que aporta la musicoterapia en alumnos con Trastorno del Espectro Autista, han sido demostrados profusamente por los distintos autores, si bien carecemos de literatura suficiente sobre su utilización en las Aulas Abiertas Especializadas en colegios ordinarios (Aulas TEA). En este sentido, el objetivo del trabajo, ha consistido en analizar qué mejoras aporta la musicoterapia al desarrollo de la comunicación en los alumnos con Trastorno del Espectro Autista dentro de las Aulas Abiertas de los CEIPs de Castilla-La Mancha y la Comunidad Autónoma de Madrid. Para ello, se ha realizado una amplia revisión documental de fuentes de referencia y se ha entrevistado a los docentes responsables de las Aulas Abiertas Especializadas que utilizan actividades de musicoterapia como recurso en el aula. Se concluye el artículo manifestando, en primer lugar, la escasa integración de la musicoterapia en las aulas TEA (menos del 20% de los centros). En aquellas aulas que sí se programa con actividades de musicoterapia, los beneficios que ésta aporta se ven reflejados en un incremento claro de la intención comunicativa en los alumnos. Además, a la hora de planificar las actividades se tiene muy en cuenta conocer las preferencias y la historia musical del niño. No obstante, existen factores que impiden el aprovechamiento total de las posibilidades terapéuticas de la musicoterapia debido, especialmente a: a) una escasa formación del profesorado y b) un espacio inadecuado para poner en práctica una sesión de musicoterapia.

Imitation and 'theory of mind' competencies in discrimination of autism from other neurodevelopmental disorders

Several studies have reported imitative deficits in autism spectrum disorder (ASD). However, it is still debated if imitative deficits are specific to ASD or shared with clinical groups with similar mental impairment and motor difficulties. We investigated whether imitative tasks can be used to discriminate ASD children from typically developing children (TD) and children with general developmental delay (GDD). We applied discriminant function analyses to the performance of these groups on three imitation tasks and tests of dexterity, motor planning, verbal skills, theory of mind (ToM). Analyses revealed two significant dimensions. The first represented impairment of dexterity and verbal ability, and discriminated TD from GDD children. Once these differences were accounted for, differences in ToM and the three imitation tasks accounted for a significant proportion of the remaining intergroup variance and discriminated the ASD group from other groups. Further analyses revealed that inclusion of imitative tasks increased the specificity and sensitivity of ASD classification and that imitative tasks considered alone were able to reliably discriminate ASD, TD and GDD. The results suggest that imitation and theory of mind impairment in autism may stem from a common domain of origin separate from general cognitive and motor skill.

Developing critical social work in theory and in practice: child protection and communicative reason

This paper argues that a critical analysis of the ideologies that inform contemporary child care has been missing from the ‘re-focusing debate’. Such an analysis points up the necessity of reasserting a critical social work position in order to provide a basis for reconstructing practice and engaging with other social actors and their ideologies in an open and creative fashion compatible with Habermas’ aspiration of ‘communicative reason’.