Developmental Expression of Kv Potassium Channels at the Axon Initial Segment of Cultured Hippocampal Neurons

Axonal outgrowth and the formation of the axon initial segment (AIS) are early events in the acquisition of neuronal polarity. The AIS is characterized by a high concentration of voltage-dependent sodium and potassium channels. However, the specific ion channel subunits present and their precise localization in this axonal subdomain vary both during development and among the types of neurons, probably determining their firing characteristics in response to stimulation. Here, we characterize the developmental expression of different subfamilies of voltage-gated potassium channels in the AISs of cultured mouse hippocampal neurons, including subunits Kv1.2, Kv2.2 and Kv7.2. In contrast to the early appearance of voltage-gated sodium channels and the Kv7.2 subunit at the AIS, Kv1.2 and Kv2.2 subunits were tethered at the AIS only after 10 days in vitro. Interestingly, we observed different patterns of Kv1.2 and Kv2.2 subunit expression, with each confined to distinct neuronal populations. The accumulation of Kv1.2 and Kv2.2 subunits at the AIS was dependent on ankyrin G tethering, it was not affected by disruption of the actin cytoskeleton and it was resistant to detergent extraction, as described previously for other AIS proteins. This distribution of potassium channels in the AIS further emphasizes the heterogeneity of this structure in different neuronal populations, as proposed previously, and suggests corresponding differences in action potential regulation

A Screening Pipeline for Antiparasitic Agents Targeting Cryptosporidium Inosine Monophosphate Dehydrogenase

Persistent diarrhea is a leading cause of illness and death among impoverished children, and a growing share of this disease burden can be attributed to the parasite Cryptosporidium. There are no vaccines to prevent Cryptosporidium infection, and the treatment options are limited and unreliable. Critically, no effective treatment exists for children or adults suffering from AIDS. Cryptosporidium presents many technical obstacles for drug discovery; perhaps the most important roadblock is the difficulty of monitoring drug action. Here we have developed a set of methods to accelerate the drug discovery process for cryptosporidiosis. We exploit the opportunities for experimental manipulation in the related parasite Toxoplasma to genetically engineer a Cryptosporidium model. This new model parasite mirrors the metabolism of Cryptosporidium for a particularly promising drug target that supplies the building blocks for DNA and RNA. Drug effectiveness can be assayed through simple fluorescence measurements for many candidates. Using this assay as an initial filter, and adapting other assays to a high throughput format, we identify several novel chemical compounds that exhibit markedly improved anti-cryptosporidial activity and excellent selectivity

A scoping study of interventions to increase the uptake of physical activity (PA) amongst individuals with mild-to-moderate depression (MMD)

Background - Depression is the largest contributor to disease burden globally. The evidence favouring physical activity as a treatment for mild-to-moderate depression is extensive and relatively uncontested. It is unclear, however, how to increase an uptake of physical activity amongst individuals experiencing mild-to-moderate depression. This leaves professionals with no guidance on how to help people experiencing mild-to-moderate depression to take up physical activity. The purpose of this study was to scope the evidence on interventions to increase the uptake of physical activity amongst individuals experiencing mild-to-moderate depression, and to develop a model of the mechanisms by which they are hypothesised to work. Methods - A scoping study was designed to include a review of primary studies, grey literature and six consultation exercises; two with individuals with experience of depression, two pre-project consultations with physical activity, mental health and literature review experts, one with public health experts, and one with community engagement experts. Results - Ten papers met the inclusion criteria and were included in the review. Consultation exercises provided insights into the mechanisms of an uptake of physical activity amongst individuals experiencing mild-to-moderate depression; evidence concerning those mechanisms is (a) fragmented in terms of design and purpose; (b) of varied quality; (c) rarely explicit about the mechanisms through which the interventions are thought to work. Physical, environmental and social factors that may represent mediating variables in the uptake of physical activity amongst people experiencing mild-to-moderate depression are largely absent from studies. Conclusions - An explanatory model was developed. This represents mild-to-moderate depression as interfering with (a) the motivation to take part in physical activity and (b) the volition that it is required to take part in physical activity. Therefore, both motivational and volitional elements are important in any intervention to increase physical activity in people with mild-to-moderate depression. Furthermore, mild-to-moderate depression-specific factors need to be tackled in any physical activity initiative, via psychological treatments such as Cognitive Behavioural Therapy. We argu

Apyrase treatment of myocardial infarction according to a clinically applicable protocol fails to reduce myocardial injury in a porcine model

<p>Abstract</p> <p>Background</p> <p>Ectonucleotidase dependent adenosine generation has been implicated in preconditioning related cardioprotection against ischemia-reperfusion injury, and treatment with a soluble ectonucleotidase has been shown to reduce myocardial infarct size (IS) when applied prior to induction of ischemia. However, ectonucleotidase treatment according to a clinically applicable protocol, with administration only after induction of ischemia, has not previously been evaluated. We therefore investigated if treatment with the ectonucleotidase apyrase, according to a clinically applicable protocol, would reduce IS and microvascular obstruction (MO) in a large animal model.</p> <p>Methods</p> <p>A percutaneous coronary intervention balloon was inflated in the left anterior descending artery for 40 min, in 16 anesthetized pigs (40-50 kg). The pigs were randomized to 40 min of 1 ml/min intracoronary infusion of apyrase (10 U/ml, n = 8) or saline (0.9 mg/ml, n = 8), twenty minutes after balloon inflation. Area at risk (AAR) was evaluated by <it>ex vivo </it>SPECT. IS and MO were evaluated by <it>ex vivo </it>MRI.</p> <p>Results</p> <p>No differences were observed between the apyrase group and saline group with respect to IS/AAR (75.7 ± 4.2% vs 69.4 ± 5.0%, p = NS) or MO (10.7 ± 4.8% vs 11.4 ± 4.8%, p = NS), but apyrase prolonged the post-ischemic reactive hyperemia.</p> <p>Conclusion</p> <p>Apyrase treatment according to a clinically applicable protocol, with administration of apyrase after induction of ischemia, does not reduce myocardial infarct size or microvascular obstruction.</p

Comparing the Functional Independence Measure and the interRAI/MDS for use in the functional assessment of older adults: a review of the literature

<p>Abstract</p> <p>Background</p> <p>The rehabilitation of older persons is often complicated by increased frailty and medical complexity - these in turn present challenges for the development of health information systems. Objective investigation and comparison of the effectiveness of geriatric rehabilitation services requires information systems that are comprehensive, reliable, valid, and sensitive to clinically relevant changes in older persons. The Functional Independence Measure is widely used in rehabilitation settings - in Canada this is used as the central component of the National Rehabilitation Reporting System of the Canadian Institute of Health Information. An alternative system has been developed by the interRAI consortium. We conducted a literature review to compare the development and measurement properties of these two systems.</p> <p>Methods</p> <p>English language literature published between 1983 (initial development of the FIM) and 2008 was searched using Medline and CINAHL databases, and the reference lists of retrieved articles. Relevant articles were summarized and charted using the criteria proposed by Streiner. Additionally, attention was paid to the ability of the two systems to address issues particularly relevant to older rehabilitation clients, such as medical complexity, comorbidity, and responsiveness to small but clinically meaningful improvements.</p> <p>Results</p> <p>In total, 66 articles were found that met the inclusion criteria. The majority of FIM articles studied inpatient rehabilitation settings; while the majority of interRAI/MDS articles focused on nursing home settings. There is evidence supporting the reliability of both instruments. There were few articles that investigated the construct validity of the interRAI/MDS.</p> <p>Conclusion</p> <p><b>A</b>dditional psychometric research is needed on both the FIM and MDS, especially with regard to their use in different settings and with different client groups.</p