Repurposing small molecules to target ppar-γ as new therapies for peripheral nerve injuries

The slow rate of neuronal regeneration that follows peripheral nerve repair results in poor recovery, particularly where reinnervation of muscles is delayed, leading to atrophy and permanent loss of function. There is a clear clinical need to develop drug treatments that can accelerate nerve regeneration safely, restoring connections before the target tissues deteriorate irreversibly. The identification that the Rho/Rho-associated kinase (ROCK) pathway acts to limit neuronal growth rate is a promising advancement towards the development of drugs. Targeting Rho or ROCK directly can act to suppress the activity of this pathway; however, the pathway can also be modulated through the activation of upstream receptors; one of particular interest being peroxisome proliferator-activated receptor gamma (PPAR-γ). The connection between the PPAR-γ receptor and the Rho/ROCK pathway is the suppression of the conversion of inactive guanosine diphosphate (GDP)-Rho to active guanosine triphosphate GTP-Rho, resulting in the suppression of Rho/ROCK activity. PPAR-γ is known for its role in cellular metabolism that leads to cell growth and differentiation. However, more recently there has been a growing interest in targeting PPAR-γ in peripheral nerve injury (PNI). The localisation and expression of PPAR-γ in neural cells following a PNI has been reported and further in vitro and in vivo studies have shown that delivering PPAR-γ agonists following injury promotes nerve regeneration, leading to improvements in functional recovery. This review explores the potential of repurposing PPAR-γ agonists to treat PNI and their prospective translation to the clinic

A critical study of academic acceleration in the early years in Singapore

In Singapore, there is an extensive shadow system of commercial enrichment schools and tuition centres that provide extracurricular lessons to young children. Unfortunately, acceleration has often been associated with negative perceptions. It has been described as stressful or developmentally inappropriate. There have been concerns that it contributes to intergenerational social immobility too. In this dissertation, I undertook a qualitative study to examine and analyse academic acceleration in the preschool years in Singapore. 12 sets of parents and children across three socioeconomic groups were interviewed, as well as 10 of the kindergarten teachers who taught these children in their regular preschool settings. Lessons in 5 out of 7 of the enrichment centres attended by the children were observed as well. Using Foucault’s notion of “governmentality” and Bourdieu’s conceptions of “habitus” and “capital”, the study found that meritocracy and pragmatism are widely referenced in Singapore. However, socioeconomic class mediates the extent and manner of ideological uptake across individual families and children. At the same time, the neoliberal ethos that has given rise to the free market of enrichment schools in Singapore has contributed to a perpetuation of socioeconomic inequalities. Enrichment centres have themselves become geospatial sites for the performance and reproduction of “habitus” and various kinds of symbolic “capital”. Although alternate possibilities exist, especially in the light of human agency, reforms to resolve these issues are constrained by the deeply embedded assumptions and political “technologies” that have led to the present sociocultural and educational context for parents, young children and kindergarten teachers in Singapore. Whilst parents resisted ideological tenets occasionally, their resistance was primarily verbal and not enacted. Kindergarten teachers tended to maintain a silence about acceleration practices, even though they disapproved of them in private

Quantifying regeneration in patients following peripheral nerve injury

Healthy nerve function provides humans with the control of movement, sensation (such as pain, touch and temperature) and the quality of skin, hair and nails. Injury to this complex system creates a deficit in function which is slow to recover and rarely, if ever, returns to what patients consider to be normal. Despite promising preclinical experiments in animals, a significant limitation in the translation of emerging therapies is the lack of effective measures with which to quantify nerve regeneration in patients and to relate this to clinical recovery. In animal models, tissue can be obtained interventionally following treatment to quantify muscle mass and structure and the number of axons in nerve. This would incur a significant functional deficit if undertaken in humans, and furthermore, quantification of such biological features does not necessarily reflect patient experience of functional recovery. This article presents a combined commentary of current practice from a specialist clinical unit and research team in regard to laboratory and clinic quantification of nerve regeneration. We highlight how electrophysiological diagnostic methods (which are used with significant recognised limitations in assessment of clinical medicine) can potentially be used with more validity to interpret and assess the processes of neural regeneration in the clinical context. Thus throwing light on the factors at play in translating lab advances into the clinic

Engineered neural tissue made using clinical-grade human neural stem cells supports regeneration in a long gap peripheral nerve injury model

A surgical autograft remains the clinical gold-standard therapy for gap repair following peripheral nerve injury, however, challenges remain with achieving full recovery and reducing donor-site morbidity. Engineered neural tissue (EngNT) manufactured using differentiated CTX0E03 human stem cells (EngNT-CTX) has been developed as a potential ‘off the shelf’ allogeneic autograft replacement. Ensheathed within a collagen membrane developed to facilitate biomechanical integration, EngNT-CTX was used to bridge a critical-length (15 mm) sciatic nerve gap injury in athymic nude rats. The effectiveness of EngNT-CTX was compared to an autograft using outcome measures that assessed neuronal regeneration and functional recovery at 8 and 16 weeks. At both time points EngNT-CTX restored electrophysiological nerve conduction and functional reinnervation of downstream muscles to the same extent as the autograft. Histological analysis confirmed that more motor neurons had successfully regenerated through the repair in EngNT-CTX in comparison to the autograft at 8 weeks, which was consistent with the electrophysiology, with the number of motor neurons similar in both groups by 16 weeks. The total number of neurons (motor + sensory) was greater in autografts than EngNT-CTX at 8 weeks, indicating that more sensory fibres may have sprouted in those animals at this time point. In conclusion, this study provides evidence to support the effectiveness of EngNT-CTX as a replacement for the nerve autograft, as the functional regeneration assessed through histological and electrophysiological outcome measures demonstrated equivalent performance

Knowledge, attitudes and practices regarding iodine among patients with hyperthyroidism in the Free State, South Africa

Objectives: To gather baseline information on the knowledge, attitudes and practices regarding iodine and iodised salt among patients with hyperthyroidism in the Free State.Subjects and Setting: The study was part of a large cohort study that included the first 96 patients aged 13 years or older diagnosed with hyperthyroidism and referred to Universitas Academic Hospital in Bloemfontein, South Africa during 2005.Methods: The patients were interviewed in their language using a structured validated questionnaire. Descriptive statistics were used fordata analysis.Results: The majority of the patients (86.9%) did not know what iodine was. Similarly, a higher percentage of patients (76.7%) were unaware of the most important or main source of iodine in the food of South Africans. Regarding knowledge of the most important harmful effect on the health of children if they did not get enough iodine, almost all of the patients (89.1%) did not know what it was. Ninety-five per cent of salt was obtained from the local shops, and only 36.1% of the patients read the labelling on the package during purchase. A very small proportion of patients (1.6%) stored salt in closed containers and away from sunlight, while about half of them (49.2%) stored salt in open containers without lids, 36.1% stored it in rigid plastic containers with holes at the top, and 13.1% stored it in the open plastic bags in which the salt was bought.Conclusions: Patients with hyperthyroidism lacked knowledge of iodine, as well as of the storage of iodised salt, and this could have contributed to the persisting endemic goitre reported in previous studies. An aggressive awareness programme, targeting policy makers and the public, is recommended to ensure sustainable elimination of iodine deficiency disorders in South Africa.  Keywords: hyperthyroidism; iodine; iodised salt; knowledge-attitude-practice study; South Afric

Unshifting the baseline: a framework for documenting historical population changes and assessing long-term anthropogenic impacts

Ecological baselines—reference states of species' distributions and abundances—are key to the scientific arguments underpinning many conservation and management interventions, as well as to the public support to such interventions. Yet societal as well as scientific perceptions of these baselines are often based on ecosystems that have been deeply transformed by human actions. Despite increased awareness about the pervasiveness and implications of this shifting baseline syndrome, ongoing global assessments of the state of biodiversity do not take into account the long-term, cumulative, anthropogenic impacts on biodiversity. Here, we propose a new framework for documenting such impacts, by classifying populations according to the extent to which they deviate from a baseline in the absence of human actions. We apply this framework to the bowhead whale (Balaena mysticetus) to illustrate how it can be used to assess populations with different geographies and timelines of known or suspected impacts. Through other examples, we discuss how the framework can be applied to populations for which there is a wide diversity of existing knowledge, by making the best use of the available ecological, historical and archaeological data. Combined across multiple populations, this framework provides a standard for assessing cumulative anthropogenic impacts on biodiversity

Semantic distillation: a method for clustering objects by their contextual specificity

Techniques for data-mining, latent semantic analysis, contextual search of databases, etc. have long ago been developed by computer scientists working on information retrieval (IR). Experimental scientists, from all disciplines, having to analyse large collections of raw experimental data (astronomical, physical, biological, etc.) have developed powerful methods for their statistical analysis and for clustering, categorising, and classifying objects. Finally, physicists have developed a theory of quantum measurement, unifying the logical, algebraic, and probabilistic aspects of queries into a single formalism. The purpose of this paper is twofold: first to show that when formulated at an abstract level, problems from IR, from statistical data analysis, and from physical measurement theories are very similar and hence can profitably be cross-fertilised, and, secondly, to propose a novel method of fuzzy hierarchical clustering, termed \textit{semantic distillation} -- strongly inspired from the theory of quantum measurement --, we developed to analyse raw data coming from various types of experiments on DNA arrays. We illustrate the method by analysing DNA arrays experiments and clustering the genes of the array according to their specificity.Comment: Accepted for publication in Studies in Computational Intelligence, Springer-Verla

Developing an In Vitro Model to Screen Drugs for Nerve Regeneration

Peripheral nerve injuries (PNI) have a high prevalence and can be debilitating, resulting in life-long loss or disturbance in end-organ function, which compromises quality of life for patients. Current therapies use microsurgical approaches but there is the potential for enhancing recovery through other therapeutic modalities such as; cell-based conduits, gene therapy and small molecules. A number of molecular targets and drugs which have the potential to improve nerve regeneration have been identified, however, there are challenges associated with moving therapies toward clinical translation. Due to the lack of detailed knowledge about the pro-regenerative effect of potential drug treatments, there is a need for effective in vitro models to screen compounds to inform future pre-clinical and clinical studies. The interaction between regenerating neurites and supporting Schwann cells is a key feature of the nerve environment, therefore, in vitro models that mimic this cellular association are useful tools. In this study, we have investigated various cell culture models, including simple monolayer systems and more complex 3D-engineered co-cultures, as models for use in PNI drug development. Anat Rec, 2018. © 2018 The Authors. The Anatomical Record: Advances in Integrative Anatomy and Evolutionary Biology published by Wiley Periodicals, Inc. on behalf of Wiley-Liss, Inc