Motor skill acquisition in children with poor motor coordination

Physical Activity is essential for growth, development and wellbeing. Children with poor motor coordination are known to have lower levels of participation in physical activity and exercise in comparison to their typically developing peers, at least partly due to the difficulty in acquiring the motor skills they need for participation. Reduced participation in physical activity in childhood increases the risk of developing obesity, cardiovascular disease and psychosocial problems which persist throughout adolescence and adulthood. Poor motor coordination in these children has been largely attributed to their difficulty in acquiring and performing motor skills. However, motor skill acquisition is not yet well understood in this group, in particular whether these children are able to improve the quality of their movement and the pattern of motor skill acquisition. The following thesis aims to investigate the motor skill acquisition in a group of children with motor coordination difficulties and is comprised of two main studies. The first one aims at creating a simple and easy tool for screening coordination in large cohorts of children in mainstream schools in order to identify children with poor motor coordination. The second study is a pilot/feasibility study aimed at informing the implementation of a fully powered follow-up motor learning intervention trial. It involved detection of a sample of children with poor motor coordination using the designed screening tool in 3 mainstream schools and recruiting them into a physical training intervention with an embedded practice of a novel rhythmic stepping task. The characteristics of their performance throughout the training program were investigated by instrumenting the stepping ask and comparing the performance with a group of children with normal motor coordination. Applying a reduction analysis on a large set of motor screening data (which included test items from The Bruininks-Oseretsky Test of Motor Proficiency-Short Form (BOT-SF) as well as Fundamental Movement Skill), we successfully designed a test which has face validity for detection of children with poor coordination. Using this test, we screened a total of 571 students (273 females and 298 males) from 3 main stream schools in Oxfordshire and invited students who scored below the 25th percentile on our screening test (117; 53 girls and 64 boys) to an 11 week training intervention. Thirty-three students attended the intervention (21 girls and 12 boys) with a great difference in recruitment and retention rates between the schools. The learning of the novel motor skill was measured by analysis of the participants’ performance on a novel stepping task, in which they stepped rhythmically in accordance to a sequence of visual stimuli presented on a computer screen. The performance (movement time), measured using accelerometry, was significantly worse in children with coordination problems (p<.001) mean±SD= 1.193±.036. Importantly, children with poor motor coordination were able to improve their performance on the task with no significant differences between the groups. However, we observed a tendency for difference in the pattern of improvement over time (p=.06). Given the nature of the conducted studies, i.e. as feasibility studies, our findings don’t allow of a straightforward generalisation. Still, they entail important implications in clinical and school-based training interventions, directed towards children with poor motor coordination, and it is recommended that a follow-up trial take place which takes into account the suggestions mentioned in this thesis with regards to the involvement of schools, importance of applying successful recruitment strategy and the requirements of successful intervention

Methods for Treating Neuropathic Pain

Provided are methods for using bis-quaternary ammonium compounds to treat inflammatory pain, neuropathic pain and nociceptive pain

Oncogenic RIT1 mutations in lung adenocarcinoma

Lung adenocarcinoma is comprised of distinct mutational subtypes characterized by mutually exclusive oncogenic mutations in RTK/RAS pathway members KRAS, EGFR, BRAF and ERBB2, and translocations involving ALK, RET and ROS1. Identification of these oncogenic events has transformed the treatment of lung adenocarcinoma via application of therapies targeted toward specific genetic lesions in stratified patient populations. However, such mutations have been reported in only ∼55% of lung adenocarcinoma cases in the United States, suggesting other mechanisms of malignancy are involved in the remaining cases. Here we report somatic mutations in the small GTPase gene RIT1 in ∼2% of lung adenocarcinoma cases that cluster in a hotspot near the switch II domain of the protein. RIT1 switch II domain mutations are mutually exclusive with all other known lung adenocarcinoma driver mutations. Ectopic expression of mutated RIT1 induces cellular transformation in vitro and in vivo, which can be reversed by combined PI3K and MEK inhibition. These data identify RIT1 as a driver oncogene in a specific subset of lung adenocarcinomas and suggest PI3K and MEK inhibition as a potential therapeutic strategy in RIT1-mutated tumors

Development of a novel definitive scoring system for an enteral feed-only model of necrotizing enterocolitis in piglets

IntroductionNecrotizing enterocolitis (NEC) is a complex inflammatory disorder of the human intestine that most often occurs in premature newborns. Animal models of NEC typically use mice or rats; however, pigs have emerged as a viable alternative given their similar size, intestinal development, and physiology compared to humans. While most piglet NEC models initially administer total parenteral nutrition prior to enteral feeds, here we describe an enteral-feed only piglet model of NEC that recapitulates the microbiome abnormalities present in neonates that develop NEC and introduce a novel multifactorial definitive NEC (D-NEC) scoring system to assess disease severity.MethodsPremature piglets were delivered via Caesarean section. Piglets in the colostrum-fed group received bovine colostrum feeds only throughout the experiment. Piglets in the formula-fed group received colostrum for the first 24 h of life, followed by Neocate Junior to induce intestinal injury. The presence of at least 3 of the following 4 criteria were required to diagnose D-NEC: (1) gross injury score ≥4 of 6; (2) histologic injury score ≥3 of 5; (3) a newly developed clinical sickness score ≥5 of 8 within the last 12 h of life; and (4) bacterial translocation to ≥2 internal organs. Quantitative reverse transcription polymerase chain reaction was performed to confirm intestinal inflammation in the small intestine and colon. 16S rRNA sequencing was performed to evaluate the intestinal microbiome.ResultsCompared to the colostrum-fed group, the formula-fed group had lower survival, higher clinical sickness scores, and more severe gross and histologic intestinal injury. There was significantly increased bacterial translocation, D-NEC, and expression of IL-1α and IL-10 in the colon of formula-fed compared to colostrum-fed piglets. Intestinal microbiome analysis of piglets with D-NEC demonstrated lower microbial diversity and increased Gammaproteobacteria and Enterobacteriaceae.ConclusionsWe have developed a clinical sickness score and a new multifactorial D-NEC scoring system to accurately evaluate an enteral feed-only piglet model of NEC. Piglets with D-NEC had microbiome changes consistent with those seen in preterm infants with NEC. This model can be used to test future novel therapies to treat and prevent this devastating disease

Enhanced magnetic properties in ZnCoAlO caused by exchangecoupling to Co nanoparticles

We report the results of a sequence of magnetisation and magneto-optical studies on laser ablated thin films of ZnCoAlO and ZnCoO that contain a small amount of metallic cobalt. The results are compared to those expected when all the magnetization is due to isolated metallic clusters of cobalt and with an oxide sample that is almost free from metallic inclusions. Using a variety of direct magnetic measurements and also magnetic circular dichroism we find that there is ferromagnetism within both the oxide and the metallic inclusions, and furthermore that these magnetic components are exchange-coupled when aluminium is included. This enhances both the coercive field and the remanence. Hence the presence of a controlled quantity of metallic nanoparticles in ZnAlO can improve the magnetic response of the oxide, thus giving great advantages for applications in spintronics

Know your tuberculosis epidemic–Is it time to add Mycobacterium tuberculosis immunoreactivity back into global surveillance?

Tuberculosis (TB) still causes 1.5 million deaths globally each year. Over recent decades, slow and uneven declines in TB incidence have resulted in a falling prevalence of TB disease, which increasingly concentrates in vulnerable populations. Falling prevalence, while welcome, poses new challenges for TB surveillance. Cross-sectional disease surveys require very large sample sizes to accurately estimate disease burden, and even more participants to detect trends over time or identify high-risk areas or populations, making them prohibitively resource-intensive. In the past, tuberculin skin surveys measuring Mycobacterium tuberculosis (Mtb) immunoreactivity were widely used to monitor TB epidemiology in high-incidence settings, but were limited by challenges with both delivering and interpreting the test. Here we argue that the shifting epidemiology of tuberculosis, and the development of new tests for Mtb infection, make it timely and important to revisit the strategy of TB surveillance based on infection or immunoreactivity. Mtb infection surveys carry their own operational challenges and fundamental questions, for example: around survey design and frequency; which groups should be included; how the prevalence of immunoreactivity in a population should be used to estimate force of infection; how individual results should be interpreted and managed; and how surveillance can be delivered efficiently and ethically. However, if these knowledge gaps are addressed, the relative feasibility and lower costs of Mtb infection surveillance offer a powerful and affordable opportunity to better “know your TB epidemic”, understand trends, identify high-risk and underserved communities, and tailor public health responses to dynamic epidemiology

Pan-cancer analysis of whole genomes identifies driver rearrangements promoted by LINE-1 retrotransposition

About half of all cancers have somatic integrations of retrotransposons. Here, to characterize their role in oncogenesis, we analyzed the patterns and mechanisms of somatic retrotransposition in 2,954 cancer genomes from 38 histological cancer subtypes within the framework of the Pan-Cancer Analysis of Whole Genomes (PCAWG) project. We identified 19,166 somatically acquired retrotransposition events, which affected 35% of samples and spanned a range of event types. Long interspersed nuclear element (LINE-1; L1 hereafter) insertions emerged as the first most frequent type of somatic structural variation in esophageal adenocarcinoma, and the second most frequent in head-and-neck and colorectal cancers. Aberrant L1 integrations can delete megabase-scale regions of a chromosome, which sometimes leads to the removal of tumor-suppressor genes, and can induce complex translocations and large-scale duplications. Somatic retrotranspositions can also initiate breakage–fusion–bridge cycles, leading to high-level amplification of oncogenes. These observations illuminate a relevant role of L1 retrotransposition in remodeling the cancer genome, with potential implications for the development of human tumors

Challenges of neural interfaces for stroke motor rehabilitation

More than 85% of stroke survivors suffer from different degrees of disability for the rest of their lives. They will require support that can vary from occasional to full time assistance. These conditions are also associated to an enormous economic impact for their families and health care systems. Current rehabilitation treatments have limited efficacy and their long-term effect is controversial. Here we review different challenges related to the design and development of neural interfaces for rehabilitative purposes. We analyze current bibliographic evidence of the effect of neuro-feedback in functional motor rehabilitation of stroke patients. We highlight the potential of these systems to reconnect brain and muscles. We also describe all aspects that should be taken into account to restore motor control. Our aim with this work is to help researchers designing interfaces that demonstrate and validate neuromodulation strategies to enforce a contingent and functional neural linkage between the central and the peripheral nervous system. We thus give clues to design systems that can improve or/and re-activate neuroplastic mechanisms and open a new recovery window for stroke patients