Neurodegeneration and Epilepsy in a Zebrafish Model of CLN3 Disease (Batten Disease)

The neuronal ceroid lipofuscinoses are a group of lysosomal storage disorders that comprise the most common, genetically heterogeneous, fatal neurodegenerative disorders of children. They are characterised by childhood onset, visual failure, epileptic seizures, psychomotor retardation and dementia. CLN3 disease, also known as Batten disease, is caused by autosomal recessive mutations in the CLN3 gene, 80–85% of which are a ~1 kb deletion. Currently no treatments exist, and after much suffering, the disease inevitably results in premature death. The aim of this study was to generate a zebrafish model of CLN3 disease using antisense morpholino injection, and characterise the pathological and functional consequences of Cln3 deficiency, thereby providing a tool for future drug discovery. The model was shown to faithfully recapitulate the pathological signs of CLN3 disease, including reduced survival, neuronal loss, retinopathy, axonopathy, loss of motor function, lysosomal storage of subunit c of mitochondrial ATP synthase, and epileptic seizures, albeit with an earlier onset and faster progression than the human disease. Our study provides proof of principle that the advantages of the zebrafish over other model systems can be utilised to further our understanding of the pathogenesis of CLN3 disease and accelerate drug discovery

Transfer of learning between unimanual and bimanual rhythmic movement coordination: transfer is a function of the task dynamic.

Under certain conditions, learning can transfer from a trained task to an untrained version of that same task. However, it is as yet unclear what those certain conditions are or why learning transfers when it does. Coordinated rhythmic movement is a valuable model system for investigating transfer because we have a model of the underlying task dynamic that includes perceptual coupling between the limbs being coordinated. The model predicts that (1) coordinated rhythmic movements, both bimanual and unimanual, are organised with respect to relative motion information for relative phase in the coupling function, (2) unimanual is less stable than bimanual coordination because the coupling is unidirectional rather than bidirectional, and (3) learning a new coordination is primarily about learning to perceive and use the relevant information which, with equal perceptual improvement due to training, yields equal transfer of learning from bimanual to unimanual coordination and vice versa [but, given prediction (2), the resulting performance is also conditioned by the intrinsic stability of each task]. In the present study, two groups were trained to produce 90° either unimanually or bimanually, respectively, and tested in respect to learning (namely improved performance in the trained 90° coordination task and improved visual discrimination of 90°) and transfer of learning (to the other, untrained 90° coordination task). Both groups improved in the task condition in which they were trained and in their ability to visually discriminate 90°, and this learning transferred to the untrained condition. When scaled by the relative intrinsic stability of each task, transfer levels were found to be equal. The results are discussed in the context of the perception–action approach to learning and performance

High-resolution DNA copy number and gene expression analyses distinguish chromophobe renal cell carcinomas and renal oncocytomas

Contains fulltext : 80487.pdf (publisher's version ) (Open Access)BACKGROUND: The diagnosis of benign renal oncocytomas (RO) and chromophobe renal cell carcinomas (RCC) based on their morphology remains uncertain in several cases. METHODS: We have applied Affymetrix GeneChip Mapping 250 K NspI high-density oligoarrays to identify small genomic alterations, which may occur beyond the specific losses of entire chromosomes, and also Affymetrix GeneChip HG-U133 Plus2.0 oligoarrays for gene expression profiling. RESULTS: By analysing of DNA extracted from 30 chRCCs and 42 ROs, we have confirmed the high specificity of monosomies of chromosomes 1, 2, 6, 10, 13, 17 and 21 in 70-93% of the chRCCs, while ROs displayed loss of chromosome 1 and 14 in 24% and 5% of the cases, respectively. We demonstrated that chromosomal gene expression biases might correlate with chromosomal abnormalities found in chromophobe RCCs and ROs. The vast majority genes downregulated in chromophobe RCC were mapped to chromosomes 2, 6, 10, 13 and 17. However, most of the genes overexpressed in chromophobe RCCs were located to chromosomes without any copy number changes indicating a transcriptional regulation as a main event. CONCLUSION: The SNP-array analysis failed to detect recurrent small deletions, which may mark loci of genes involved in the tumor development. However, we have identified loss of chromosome 2, 10, 13, 17 and 21 as discriminating alteration between chromophobe RCCs and ROs. Therefore, detection of these chromosomal changes can be used for the accurate diagnosis in routine histology

Transiting extrasolar planetary candidates in the Galactic bulge

More than 200 extrasolar planets have been discovered around relatively nearby stars, primarily through the Doppler line shifts owing to the reflex motions of their host stars, and more recently through transits of some planets across the face of the host stars. The detection of planets with the shortest known periods, 1.2 to 2.5 days, has mainly resulted from transit surveys which have generally targeted stars more massive than 0.75 M_sun. Here we report the results from a planetary transit search performed in a rich stellar field towards the Galactic bulge. We discovered 16 candidates with orbital periods between 0.4 and 4.2 days, five of which orbit stars of 0.44 to 0.75 M_sun. In two cases, radial-velocity measurements support the planetary nature of the companions. Five candidates have orbital periods below 1.0 day, constituting a new class of ultra-short-period planets (USPPs), which occur only around stars of less than 0.88 M_sun. This indicates that those orbiting very close to more luminous stars might be evaporatively destroyed, or that jovian planets around lower-mass stars might migrate to smaller radii.Comment: To appear in October 5, 2006 issue of Natur

Fatal Prion Disease in a Mouse Model of Genetic E200K Creutzfeldt-Jakob Disease

Genetic prion diseases are late onset fatal neurodegenerative disorders linked to pathogenic mutations in the prion protein-encoding gene, PRNP. The most prevalent of these is the substitution of Glutamate for Lysine at codon 200 (E200K), causing genetic Creutzfeldt-Jakob disease (gCJD) in several clusters, including Jews of Libyan origin. Investigating the pathogenesis of genetic CJD, as well as developing prophylactic treatments for young asymptomatic carriers of this and other PrP mutations, may well depend upon the availability of appropriate animal models in which long term treatments can be evaluated for efficacy and toxicity. Here we present the first effective mouse model for E200KCJD, which expresses chimeric mouse/human (TgMHu2M) E199KPrP on both a null and a wt PrP background, as is the case for heterozygous patients and carriers. Mice from both lines suffered from distinct neurological symptoms as early as 5–6 month of age and deteriorated to death several months thereafter. Histopathological examination of the brain and spinal cord revealed early gliosis and age-related intraneuronal deposition of disease-associated PrP similarly to human E200K gCJD. Concomitantly we detected aggregated, proteinase K resistant, truncated and oxidized PrP forms on immunoblots. Inoculation of brain extracts from TgMHu2ME199K mice readily induced, the first time for any mutant prion transgenic model, a distinct fatal prion disease in wt mice. We believe that these mice may serve as an ideal platform for the investigation of the pathogenesis of genetic prion disease and thus for the monitoring of anti-prion treatments

Depression and physical activity in a sample of nigerian adolescents: levels, relationships and predictors

<p>Abstract</p> <p>Background</p> <p>Physical inactivity is related to many morbidities but the evidence of its link with depression in adolescents needs further investigation in view of the existing conflicting reports.</p> <p>Methods</p> <p>The data for this cross-sectional study were collected from 1,100 Nigerian adolescents aged 12-17 years. Depressive symptomatology and physical activity were assessed using the Children's Depression Inventory (CDI) and the Physical Activity Questionnaire-Adolescent version (PAQ-A) respectively. Independent t tests, Pearson's Moment Correlation and Multi-level logistic regression analyses for individual and school area influences were carried out on the data at p < 0.05.</p> <p>Results</p> <p>The mean age of the participants was 15.20 ± 1.435 years. The prevalence of mild to moderate depression was 23.8%, definite depression was 5.7% and low physical activity was 53.8%. More severe depressive symptoms were linked with lower levels of physical activity (r = -0.82, p < 0.001) and moderate physical activity was linked with reduced risk of depressive symptoms (OR = 0.42, 95% CI = 0.29-0.71). The odds of having depressive symptoms were higher in older adolescents (OR = 2.16, 95% CI = 1.81-3.44) and in females (OR = 2.92, 95% CI = 1.82-3.54). Females had a higher risk of low physical activity than male adolescents (OR = 2.91, 95% CI = 1.51-4.26). Being in Senior Secondary class three was a significant predictor of depressive symptoms (OR = 3.4, 95% CI = 2.55-4.37) and low physical activity.</p> <p>Conclusions</p> <p>A sizable burden of depression and low physical activity existed among the studied adolescents and these were linked to both individual and school factors. Future studies should examine the effects of physical activity among clinical samples of adolescents with depression.</p

The 50s cliff: perceptuo-motor learning rates across the lifespan.

We recently found that older adults show reduced learning rates when learning a new pattern of coordinated rhythmic movement. The purpose of this study was to extend that finding by examining the performance of all ages across the lifespan from the 20 s through to the 80 s to determine how learning rates change with age. We tested whether adults could learn to produce a novel coordinated rhythmic movement (90° relative phase) in a visually guided unimanual task. We determined learning rates to quantify changes in learning with age and to determine at what ages the changes occur. We found, as before, that learning rates of participants in their 70 s and 80 s were half those of participants in their 20 s. We also found a gradual slow decline in learning rate with age until approximately age 50, when there was a sudden drop to a reduced learning rate for the 60 though 80 year olds. We discuss possible causes for the "50 s cliff" in perceptuo-motor learning rates and suggest that age related deficits in perception of complex motions may be the key to understanding this result

Avoidable costs of physical treatments for chronic back, neck and shoulder pain within the Spanish National Health Service: a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Back, neck and shoulder pain are the most common causes of occupational disability. They reduce health-related quality of life and have a significant economic impact. Many different forms of physical treatment are routinely used. The objective of this study was to estimate the cost of physical treatments which, despite the absence of evidence supporting their effectiveness, were used between 2004 and 2007 for chronic and non-specific neck pain (NP), back pain (BP) and shoulder pain (SP), within the Spanish National Health Service in the Canary Islands (SNHSCI).</p> <p>Methods</p> <p>Chronic patients referred from the SNHSCI to private physical therapy centres for NP, BP or SP, between 2004 and 2007, were identified. The cost of providing physical therapies to these patients was estimated. Systematic reviews (SRs) and clinical practice guidelines (CPGs) for NP, BP and SP available in the same period were searched for and rated according to the Oxman and AGREE criteria, respectively. Those rated positively for ≥70% of the criteria, were used to categorise physical therapies as Effective; Ineffective; Inconclusive; and Insufficiently Assessed. The main outcome was the cost of physical therapies included in each of these categories.</p> <p>Results</p> <p>8,308 chronic cases of NP, 4,693 of BP and 5,035 of SP, were included in this study. Among prescribed treatments, 39.88% were considered Effective (physical exercise and manual therapy with mobilization); 23.06% Ineffective; 13.38% Inconclusive, and 23.66% Insufficiently Assessed. The total cost of treatments was € 5,107,720. Effective therapies accounted for € 2,069,932.</p> <p>Conclusions</p> <p>Sixty percent of the resources allocated by the SNHSCI to fund physical treatment for NP, BP and SP in private practices are spent on forms of treatment proven to be ineffective, or for which there is no evidence of effectiveness.</p

Epigenetic Differences in Cortical Neurons from a Pair of Monozygotic Twins Discordant for Alzheimer's Disease

DNA methylation [1], [2] is capable of modulating coordinate expression of large numbers of genes across many different pathways, and may therefore warrant investigation for their potential role between genes and disease phenotype. In a rare set of monozygotic twins discordant for Alzheimer's disease (AD), significantly reduced levels of DNA methylation were observed in temporal neocortex neuronal nuclei of the AD twin. These findings are consistent with the hypothesis that epigenetic mechanisms may mediate at the molecular level the effects of life events on AD risk, and provide, for the first time, a potential explanation for AD discordance despite genetic similarities

Elective amputation and bionic substitution restore functional hand use after critical soft tissue injuries

Critical soft tissue injuries may lead to a non-functional and insensate limb. In these cases standard reconstructive techniques will not suffice to provide a useful outcome, and solutions outside the biological arena must be considered and offered to these patients. We propose a concept which, after all reconstructive options have been exhausted, involves an elective amputation along with a bionic substitution, implementing an actuated prosthetic hand via a structured tech-neuro-rehabilitation program. Here, three patients are presented in whom this concept has been successfully applied after mutilating hand injuries. Clinical tests conducted before, during and after the procedure, evaluating both functional and psychometric parameters, document the benefits of this approach. Additionally, in one of the patients, we show the possibility of implementing a highly functional and natural control of an advanced prosthesis providing both proportional and simultaneous movements of the wrist and hand for completing tasks of daily living with substantially less compensatory movements compared to the traditional systems. It is concluded that the proposed procedure is a viable solution for re-gaining highly functional hand use following critical soft tissue injuries when existing surgical measures fail. Our results are clinically applicable and can be extended to institutions with similar resources