A genetically engineered thermally responsive sustained release curcumin depot to treat neuroinflammation.

Radiculopathy, a painful neuroinflammation that can accompany intervertebral disc herniation, is associated with locally increased levels of the pro-inflammatory cytokine tumor necrosis factor alpha (TNFα). Systemic administration of TNF antagonists for radiculopathy in the clinic has shown mixed results, and there is growing interest in the local delivery of anti-inflammatory drugs to treat this pathology as well as similar inflammatory events of peripheral nerve injury. Curcumin, a known antagonist of TNFα in multiple cell types and tissues, was chemically modified and conjugated to a thermally responsive elastin-like polypeptide (ELP) to create an injectable depot for sustained, local delivery of curcumin to treat neuroinflammation. ELPs are biopolymers capable of thermally-triggered in situ depot formation that have been successfully employed as drug carriers and biomaterials in several applications. ELP-curcumin conjugates were shown to display high drug loading, rapidly release curcumin in vitro via degradable carbamate bonds, and retain in vitro bioactivity against TNFα-induced cytotoxicity and monocyte activation with IC50 only two-fold higher than curcumin. When injected proximal to the sciatic nerve in mice via intramuscular (i.m.) injection, ELP-curcumin conjugates underwent a thermally triggered soluble-insoluble phase transition, leading to in situ formation of a depot that released curcumin over 4days post-injection and decreased plasma AUC 7-fold

Horizontal force production and multi-segment foot kinematics during the acceleration phase of bend sprinting

This paper investigated horizontal force production, foot kinematics and metatarsophalangeal (MTP) joint push-off axis use during acceleration in bend (anti-clockwise) and straight-line sprinting. It was hypothesised that bend sprinting would cause the left step push-off to occur about the oblique axis, resulting in a decrease in propulsive force. Three-dimensional kinematic and ground reaction force data were collected from nine participants during sprinting on the bend (36.5 m radius) and straight. Anteroposterior force was reduced at 38-44% of stance during bend sprinting compared with the straight. This coincided with an increase in mediolateral force for the majority of the stance phase (3-96%) on the bend compared with the straight. In addition, a lower propulsive impulse was reported on the bend compared with the straight. Analysis of multi-segment foot kinematics provides insight into the possible mechanisms behind these changes in force production. Mean mediolateral centre of pressure position was more lateral in relation to the second metatarsal head in the left step on the bend compared with the straight, indicating the oblique axis was used for push-off at the MTP joint. Greater peak joint angles of the left foot were also reported, in particular, an increase in left step midfoot eversion and internal ankle rotation. It is possible these changes in joint kinematics are associated with the observed decrease in propulsive force. Therefore, practitioners should seek to strengthen muscles such as tibialis posterior in frontal and sagittal planes and ensure specificity of training which may aid in addressing these force reductions

Members of the chloride intracellular ion channel protein family demonstrate glutaredoxin-like enzymatic activity

© 2015 Al Khamici et al. The Chloride Intracellular Ion Channel (CLIC) family consists of six evolutionarily conserved proteins in humans. Members of this family are unusual, existing as both monomeric soluble proteins and as integral membrane proteins where they function as chloride selective ion channels, however no function has previously been assigned to their soluble form. Structural studies have shown that in the soluble form, CLIC proteins adopt a glutathione S-transferase (GST) fold, however, they have an active site with a conserved glutaredoxin monothiol motif, similar to the omega class GSTs. We demonstrate that CLIC proteins have glutaredoxin-like glutathione-dependent oxidoreductase enzymatic activity. CLICs 1, 2 and 4 demonstrate typical glutaredoxin-like activity using 2-hydroxyethyl disulfide as a substrate. Mutagenesis experiments identify cysteine 24 as the catalytic cysteine residue in CLIC1, which is consistent with its structure. CLIC1 was shown to reduce sodium selenite and dehydroascorbate in a glutathione-dependent manner. Previous electrophysiological studies have shown that the drugs IAA-94 and A9C specifically block CLIC channel activity. These same compounds inhibit CLIC1 oxidoreductase activity. This work for the first time assigns a functional activity to the soluble form of the CLIC proteins. Our results demonstrate that the soluble form of the CLIC proteins has an enzymatic activity that is distinct from the channel activity of their integral membrane form. This CLIC enzymatic activity may be important for protecting the intracellular environment against oxidation. It is also likely that this enzymatic activity regulates the CLIC ion channel function

An approximate model for cancellous bone screw fixation

This is the author's accepted manuscript. The final published article is available from the link below. Copyright @ 2013 Taylor & Francis.This paper presents a finite element (FE) model to identify parameters that affect the performance of an improved cancellous bone screw fixation technique, and hence potentially improve fracture treatment. In cancellous bone of low apparent density, it can be difficult to achieve adequate screw fixation and hence provide stable fracture fixation that enables bone healing. Data from predictive FE models indicate that cements can have a significant potential to improve screw holding power in cancellous bone. These FE models are used to demonstrate the key parameters that determine pull-out strength in a variety of screw, bone and cement set-ups, and to compare the effectiveness of different configurations. The paper concludes that significant advantages, up to an order of magnitude, in screw pull-out strength in cancellous bone might be gained by the appropriate use of a currently approved calcium phosphate cement

The functional response of a generalist predator

Peer reviewedPublisher PD

The impact of sediment flux and calibre on flood risk in the Kathmandu Valley, Nepal

AbstractThis paper investigates how variations in sediment supply, grain size distribution and climate change affect channel morphology and flood inundation in the Nakkhu River, Kathmandu, Nepal. Climate change‐induced extreme rainfall is expected to increase flood intensity and frequency, causing severe flooding in the Kathmandu basin. The upper reaches of the Nakkhu River are susceptible to landslides and have been impacted by large‐scale sand mining. We simulate potential erosion and deposition scenarios along a 14 km reach of the Nakkhu River using the landscape evolution model CAESAR‐Lisflood with a 10 m digital elevation model, field‐derived sediment grain size data, daily discharge records and flood forecast models. In a series of numerical experiments, we compare riverbed profiles, cross‐sections, flood extent and flow depths for three scenarios (1.2‐, 85‐ and 1000‐year return period floods). For each scenario, the model is first run without sediment transport and then with sediment transport for three grain size distributions (GSDs) (observed average, finer and coarser). In all cases, the inclusion of sediment led to predicted floods of a larger extent than estimated without sediment. The sediment grain size distribution was found to have a significant influence on predicted river morphology and flood inundation, especially for lower magnitude, higher probability flood events. The results emphasise the importance of including sediment transport in hydrological models when predicting flood inundation in sediment‐rich rivers such as those in and around the Himalaya.</jats:p

Unintended Consequences of Conservation Actions: Managing Disease in Complex Ecosystems

Infectious diseases are increasingly recognised to be a major threat to biodiversity. Disease management tools such as control of animal movements and vaccination can be used to mitigate the impact and spread of diseases in targeted species. They can reduce the risk of epidemics and in turn the risks of population decline and extinction. However, all species are embedded in communities and interactions between species can be complex, hence increasing the chance of survival of one species can have repercussions on the whole community structure. In this study, we use an example from the Serengeti ecosystem in Tanzania to explore how a vaccination campaign against Canine Distemper Virus (CDV) targeted at conserving the African lion (Panthera leo), could affect the viability of a coexisting threatened species, the cheetah (Acinonyx jubatus). Assuming that CDV plays a role in lion regulation, our results suggest that a vaccination programme, if successful, risks destabilising the simple two-species system considered, as simulations show that vaccination interventions could almost double the probability of extinction of an isolated cheetah population over the next 60 years. This work uses a simple example to illustrate how predictive modelling can be a useful tool in examining the consequence of vaccination interventions on non-target species. It also highlights the importance of carefully considering linkages between human-intervention, species viability and community structure when planning species-based conservation actions

Multi-centre parallel arm randomised controlled trial to assess the effectiveness and cost-effectiveness of a group-based cognitive behavioural approach to managing fatigue in people with multiple sclerosis

Abstract (provisional) Background Fatigue is one of the most commonly reported and debilitating symptoms of multiple sclerosis (MS); approximately two-thirds of people with MS consider it to be one of their three most troubling symptoms. It may limit or prevent participation in everyday activities, work, leisure, and social pursuits, reduce psychological well-being and is one of the key precipitants of early retirement. Energy effectiveness approaches have been shown to be effective in reducing MS-fatigue, increasing self-efficacy and improving quality of life. Cognitive behavioural approaches have been found to be effective for managing fatigue in other conditions, such as chronic fatigue syndrome, and more recently, in MS. The aim of this pragmatic trial is to evaluate the clinical and cost-effectiveness of a recently developed group-based fatigue management intervention (that blends cognitive behavioural and energy effectiveness approaches) compared with current local practice. Methods This is a multi-centre parallel arm block-randomised controlled trial (RCT) of a six session group-based fatigue management intervention, delivered by health professionals, compared with current local practice. 180 consenting adults with a confirmed diagnosis of MS and significant fatigue levels, recruited via secondary/primary care or newsletters/websites, will be randomised to receive the fatigue management intervention or current local practice. An economic evaluation will be undertaken alongside the trial. Primary outcomes are fatigue severity, self-efficacy and disease-specific quality of life. Secondary outcomes include fatigue impact, general quality of life, mood, activity patterns, and cost-effectiveness. Outcomes in those receiving the fatigue management intervention will be measured 1 week prior to, and 1, 4, and 12 months after the intervention (and at equivalent times in those receiving current local practice). A qualitative component will examine what aspects of the fatigue management intervention participants found helpful/unhelpful and barriers to change. Discussion This trial is the fourth stage of a research programme that has followed the Medical Research Council guidance for developing and evaluating complex interventions. What makes the intervention unique is that it blends cognitive behavioural and energy effectiveness approaches. A potential strength of the intervention is that it could be integrated into existing service delivery models as it has been designed to be delivered by staff already working with people with MS. Service users will be involved throughout this research. Trial registration: Current Controlled Trials ISRCTN7651747