Multiple sclerosis: re-expression of a developmental pathway that restricts oligodendrocyte maturation

During mammalian central nervous system (CNS) development, contact-mediated activation of Notch1 receptors on oligodendrocyte precursors by the ligand Jagged1 induces Hes5, which inhibits maturation of these cells. Here we tested whether the Notch pathway is re-expressed in the adult CNS in multiple sclerosis (MS), an inflammatory demyelinating disease in which remyelination is typically limited. We found that transforming growth factor-beta 1 (TGF-beta 1), a cytokine upregulated in MS, specifically re-induced Jagged1 in primary cultures of human astrocytes. Within and around active MS plaques lacking remyelination, Jagged1 was expressed at high levels by hypertrophic astrocytes, whereas Notch1 and Hes5 localized to cells with an immature oligodendrocyte phenotype, and TGF-beta 1 was associated with perivascular extracellular matrix in the same areas. In contrast, there was negligible Jagged1 expression in remyelinated lesions. Experiments in vitro showed that Jagged1 signaling inhibited process outgrowth from primary human oligodendrocytes. These data are the first to implicate the Notch pathway in the limited remyelination in MS. Thus, Notch may represent a potential target for therapeutic intervention in this disease.     

A simple water-filled plethysmograph for measurement of limb blood flow in humans

Fundamental principles underpinning the study of cardiovascular physiology can be emphasized by measuring blood flow. Plethysmography is an appropriate, noninvasive technique to use but may not be available to some institutions. Therefore, for measurement of blood flow in human limbs, we developed a simple water-filled plethysmograph that may be built with minimal technical support. The device is formed from a plastic cylinder and houses a latex sleeve sealed at either end by means of circular flanges and rubber O-ring seals. Limb volume changes are transcribed using an air-filled piston recorder. This instrument proves to be sensitive and accurately determines limb volume changes over time. Utilizing an appropriate venous occlusion protocol, predicted vascular responses to postural challenge and physical exercise may be followed. In response to a questionnaire, a majority of students (n = 33) agreed that performing blood flow measurements succeeded in relating theory to practice, improved technical and observational skills, and made the learning experience real. This modified plethysmograph proves to be a valuable teaching tool in human physiology classes.     

Hypothesis: hyperstructures regulate initiation in Escherichia coli and other bacteria

Hyperstructures or modules have been proposed to constitute a level of organisation intermediate between macromolecules and whole cells. In this model of intracellular organisation, hyperstructures compete and collaborate for existence within the membrane and cytoplasm. Those directly involved in the cell cycle include initiation, replication and division hyperstructures based on DnaA, SeqA and the 2-minute cluster, respectively. During the run-up to initiation, the mass to DNA ratio increases and, we contend, differential gene expression leads to some hyperstructures becoming more active and stable than others. This results in a drop in the diversity of hyperstructures, some of which release DnaA as they dissociate, and a DnaA-initiation hyperstructure forms. Subsequent DNA replication and cell division generate different daughter cells containing different hyperstructures. This has the advantage of increasing the phenotypic diversity of the population. In developing this model, we also invoke hyperstructures in the partitioning of origins of replication.     

Modelling autocatalytic networks with artificial microbiology

Cells can usefully be equated to autocatalytic networks that increase in mass and then divide. To begin to model relationships between autocatalytic networks and cell division, we have written a program of artificial chemistry that simulates a cell fed by monomers. These monomers are symbols that can be assembled into linear (non-branched) polymers to give different lengths. A reaction is catalysed by a particular polymer or 'enzyme' that may itself be a reactant of that reaction (autocatalysis). These reactions are only studied within the confines of the 'cell' or 'reaction chamber'. There is a flux of material through the cell and eventually the mass of polymers reaches a threshold at which we analyse the cell. Our results indicate a similarity between the connectivity of the reaction network and that of real metabolic networks. Developing the model will entail attributing increased probabilities of reactions to polymers that are colocalised to evaluate the consequences of the dynamics of large assemblies of diverse molecules (hyperstructures) and of cell division.     

Factors that Influence the Way Communities Respond to Proposals for Major Changes to Local Emergency Services: A Qualitative Study

Objective

According to policy commentators, decisions about how best to organise care involve trade-offs between factors relating to care quality, workforce, cost, and patient access. In England, proposed changes such as Emergency Department closures often face public opposition. This study examined the way communities respond to plans aimed at reorganising emergency services, including the trade-offs inherent in such decisions.

Design

Cross-sectional study involving in-depth interviews. Participants selected their priorities for emergency care, including aspects they might be prepared to have ‘less’ of (e.g. rapid access) if it meant having ‘more’ of another (e.g. consultant-delivered care). A thematic analysis was carried out, combining inductive and deductive approaches, drawing on theories about risk perception.

Setting

Two urban areas of England; one where changes to emergency services were under consideration (‘Greenville’), and one where they were not (‘Hilltown’).

Participants

28 participants in total. Greenville interviewees included more common emergency service users - parents of young children (n=5) and older people (n=6) - plus patient representatives and individuals campaigning against service closures (n=9). Hilltown interviewees (n=8) received outpatient care for Chronic Obstructive Pulmonary Disease, an important cause of emergency admission.

Results

Most participants, in both areas, were not willing to accommodate the trade-offs involved in consolidating emergency services, principally because of the belief that timely access is associated with better outcomes. Participants did not consider the proposed improvements as gains worth having; interviewees believed care quality would be adversely impact, partly because increased patient numbers would place staff under greater pressure and result in longer waiting times.

Conclusions

Visible clinical leadership and detailed explanation of the case for change were insufficient to overcome opposition to the reconfiguration in Greenville, challenging the assumption that communities can be persuaded by evidence. Commissioners should make explicit credible plans to accommodate changes in patient flows, as well as clarifying the roles played by key staff groups.     

Is ‘Self-Medication’ a Useful Term to Retrieve Related Publications in the Literature? A Systematic Exploration of Related Terms

BackgroundSelf-Medication (SM), i.e. using medications to treat oneself, is a major concern for health researchers and policy makers. The terms “self medication” or “self-medication” (SM terms) have been used to explain various concepts while several terms have also been employed to define this practice. Hence, retrieving relevant publications would require exhaustive literature screening. So, we assessed the current situation of SM terms in the literature to improve the relevancy of search outcomes.MethodsIn this Systematic exploration, SM terms were searched in the 6 following databases and publisher’s portals till April 2012: Web of Science, Scopus, PubMed, Google scholar, ScienceDirect, and Wiley. A simple search query was used to include only publications with SM terms. We used Relative-Risk (RR) to estimate the probability of SM terms use in related compared to unrelated publications. Sensitivity and specificity of SM terms as keywords in search query were also calculated. Relevant terms to SM practice were extracted and their Likelihood Ratio positive and negative (LR+/-) were calculated to assess their effect on the probability of search outcomes relevancy in addition to previous search queries. We also evaluated the content of unrelated publications. All mentioned steps were performed in title (TI) and title or abstract (TIAB) of publications.Results1999 related and 1917 unrelated publications were found. SM terms RR was 4.5 in TI and 2.1 in TIAB. SM terms sensitivity and specificity respectively were 55.4% and 87.7% in TI and 84.0% and 59.5% in TIAB. “OTC” and “Over-The-Counter Medication”, with LR+ 16.78 and 16.30 respectively, provided the most conclusive increase in the probability of the relevancy of publications. The most common unrelated SM themes were self-medication hypothesis, drug abuse and Zoopharmacognosy.ConclusionsDue to relatively low specificity or sensitivity of SM terms, relevant terms should be employed in search queries and clear definitions of SM applications should be applied to improve the relevancy of publications.     

Ashtanga-Based Yoga Therapy Increases the Sensory Contribution to Postural Stability in Visually-Impaired Persons at Risk for Falls as Measured by the Wii Balance Board: A Pilot Randomized Controlled Trial

Objective

Persons with visual impairment (VI) are at greater risk for falls due to irreparable damage to visual sensory input contributing to balance. Targeted training may significantly improve postural stability by strengthening the remaining sensory systems. Here, we evaluate the Ashtanga-based Yoga Therapy (AYT) program as a multi-sensory behavioral intervention to develop postural stability in VI.

Design

A randomized, waitlist-controlled, single-blind clinical trial

Methods

The trial was conducted between October 2012 and December 2013. Twenty-one legally blind participants were randomized to an 8-week AYT program (n = 11, mean (SD) age = 55(17)) or waitlist control (n=10, mean (SD) age = 55(10)). AYT subjects convened for one group session at a local yoga studio with an instructor and two individual home-based practice sessions per week for a total of 8 weeks. Subjects completed outcome measures at baseline and post-8 weeks of AYT. The primary outcome, absolute Center of Pressure (COP), was derived from the Wii Balance Board (WBB), a standalone posturography device, in 4 sensory conditions: firm surface, eyes open (EO); firm surface, eyes closed (EC); foam surface, EO; and foam surface, EC. Stabilization Indices (SI) were computed from COP measures to determine the relative visual (SI_firm, SI_foam), somatosensory (SI_EO, SI_EC) and vestibular (SI_V, i.e., Foam_EC vs. Firm_EO) contributions to balance. This study was not powered to detect between group differences, so significance of pre-post changes was assessed by paired samples t-tests within each group.

Results

Groups were equivalent at baseline (all p > 0.05). In the AYT group, absolute COP significantly increased in the Foam_EO (t(8) = -3.66, p = 0.01) and Foam_EC (t(8) = -3.90, p = 0.01) conditions. Relative somatosensory SI_EO (t(8) = -2.42, p = 0.04) and SI_EC (t(8) = -3.96, p = 0.01), and vestibular SI_V (t(8) = -2.47, p = 0.04) contributions to balance increased significantly. As expected, no significant changes from EO to EC conditions were found indicating an absence of visual dependency in VI. No significant pre-post changes were observed in the control group (all p > 0.05).

Conclusions

These preliminary results establish the potential for AYT training to develop the remaining somatosensory and vestibular responses used to optimize postural stability in a VI population.

Trial Registration

www.ClinicalTrials.gov NCT01366677     

The summer distribution of net plankton dinoflagellates and their relation to water movements in the NE Atlantic Ocean, west of Ireland

A grid of 28 stations on the continental shelf and slope regionwest of Ireland, which included the Porcupine Bank and the PorcupineSea Bight, was sampled for net phytoplankton in the summer (Juneand July) of 1995. Armoured dinoflagellates were recorded onboth a relative abundance and presence/absence basis. Resultsshowed good agreement with the physical circulation of the region,based on an analysis of seasonal current meter data from theupper 500 m of the water column. The distributions of some dinoflagellatespecies, known to have either a mainly oceanic or warm temperatedistribution, indicated the existence of two separate slopecurrents in the region, one along the Irish Shelf with a sourcein the Bay of Biscay, and the other along the western slopeof the Porcupine Bank fed by the North Atlantic Current waters.The data presented here support the idea that, in summer atleast, the slope current west of Ireland is not entirely coherentin the upper layers of the water column.     

Characterization of nontoxic and toxin-producing strains of Alexandrium minutum (Dinophyceae) in Irish coastal waters

A comparative analysis of the morphology, toxin composition, and ribosomal DNA (rDNA) sequences was performed on a suite of clonal cultures of the potentially toxic dinoflagellate Alexandrium minutum Halim. These were established from resting cysts or vegetative cells isolated from sediment and water samples taken from the south and west coasts of Ireland. Results revealed that strains were indistinguishable, both morphologically and through the sequencing of the D1-D2 domain of the large subunit and the ITS1-5.8S-ITS2 regions of the rDNA. High-performance liquid chromatography fluorescence detection analysis, however, showed that only strains derived from retentive inlets on the southern Irish coast synthesized paralytic shellfish poisoning (PSP) toxins (GTX2 and GTX3), whereas all strains of A. minutum isolated from the west coast were nontoxic. Toxin analysis of net hauls, taken when A. minutum vegetative cells were in the water column, revealed no PSP toxins in samples from Killary Harbor (western coast), whereas GTX2 and GTX3 were detected in samples from Cork Harbor (southern coast). These results confirm the identity of A. minutum as the most probable causative organism for historical occurrences of contamination of shellfish with PSP toxins in Cork Harbor. Finally, random amplification of polymorphic DNA was carried out to determine the degree of polymorphism among strains. The analysis showed that all toxic strains from Cork Harbor clustered together and that a separate cluster grouped all nontoxic strains from the western coast.