Levodopa does not affect expression of reinforcement learning in older adults.

Dopamine has been implicated in learning from rewards and punishment, and in the expression of this learning. However, many studies do not fully separate retrieval and decision mechanisms from learning and consolidation. Here, we investigated the effects of levodopa (dopamine precursor) on choice performance (isolated from learning or consolidation). We gave 31 healthy older adults 150 mg of levodopa or placebo (double-blinded, randomised) 1 hour before testing them on stimuli they had learned the value of the previous day. We found that levodopa did not affect the overall accuracy of choices, nor the relative expression of positively or negatively reinforced values. This contradicts several studies and suggests that overall dopamine levels may not play a role in the choice performance for values learned through reinforcement learning in older adults.

A prospective multicentre phase III validation study of AZGP1 as a biomarker in localized prostate cancer.

BACKGROUND: Prostate cancers (PCs) with similar characteristics at the time of diagnosis can have very different disease outcomes. Conventional biomarkers of PC still lack precision in identifying individuals at high risk of PC recurrence. While many candidate biomarkers are proposed in the literature, few are in clinical practice as they lack rigorous validation. This study prospectively enrolled an independent phase III cohort to evaluate the clinical utility of zinc-alpha 2-glycoprotein (AZGP1) as a prognostic biomarker in localized PC. PATIENTS AND METHODS: In our multicentre, prospective phase III study, AZGP1 status in 347 radical prostatectomy specimens was assayed by immunohistochemistry in a NATA-accredited laboratory. The AZGP1 score was assessed in a multivariable model incorporating established prognostic factors. We also report extended outcomes from our previous phase II study. The primary endpoint was biochemical relapse-free survival (BRFS). Secondary endpoints were metastasis-free survival (MFS) and PC-specific survival (PCSS). RESULTS: In the phase II cohort, with a median follow-up of 15.8 years, low/absent AZGP1 expression was an independent predictor of poor BRFS (HR, 1.4; 95% CI, 1.1-1.9; P = 0.03), MFS (HR, 2.8; 95% CI, 1.2-6.6; P = 0.02) and PCSS (HR, 3.8; 95% CI, 1.5-9.5; P = 0.005). These results were validated in our prospective phase III cohort. Low/absent AZGP1 expression independently predicted for BRFS (HR, 1.9; 95% CI, 1.1-3.3; P = 0.02), with shorter MFS (HR, 2.0; 95% CI, 1.1-3.4; P = 0.02). AZGP1 improved the discriminatory value when incorporated into existing prognostic risk models. CONCLUSION: Our study provides prospective phase III validation that absent/low AZGP1 expression provides independent prognostic value in PC. This study provides robust evidence for the incorporation of this biomarker into clinical practice.

Mechanical Cell-Cell Communication in Fibrous Networks: The Importance of Network Geometry.

Cells contracting in extracellular matrix (ECM) can transmit stress over long distances, communicating their position and orientation to cells many tens of micrometres away. Such phenomena are not observed when cells are seeded on substrates with linear elastic properties, such as polyacrylamide (PA) gel. The ability for fibrous substrates to support far reaching stress and strain fields has implications for many physiological processes, while the mechanical properties of ECM are central to several pathological processes, including tumour invasion and fibrosis. Theoretical models have investigated the properties of ECM in a variety of network geometries. However, the effects of network architecture on mechanical cell-cell communication have received little attention. This work investigates the effects of geometry on network mechanics, and thus the ability for cells to communicate mechanically through different networks. Cell-derived displacement fields are quantified for various network geometries while controlling for network topology, cross-link density and micromechanical properties. We find that the heterogeneity of response, fibre alignment, and substrate displacement fields are sensitive to network choice. Further, we show that certain geometries support mechanical communication over longer distances than others. As such, we predict that the choice of network geometry is important in fundamental modelling of cell-cell interactions in fibrous substrates, as well as in experimental settings, where mechanical signalling at the cellular scale plays an important role. This work thus informs the construction of theoretical models for substrate mechanics and experimental explorations of mechanical cell-cell communication.

Formation of a carbapenemase resistance detection algorithm for use in the routine laboratory.

The increasing prevalence of carbapenem non-susceptible Gram negative organisms demands prompt and accurate identification of resistance mechanisms to limit their transmission. The aim of this study is to evaluate the rapid CARB screen (Rosco Diagnostica, Denmark), the 'KPC/MBL in P. aeruginosa/Acinetobacter Confirm Kit' (Rosco Diagnostica), Check-MDR Carba and Check-Direct CPE kits (Check-Points, The Netherlands). The purpose of this study is the formation of a carbapenemase resistance detection algorithm that can be used in the routine laboratory. Results of the rapid CARB screen kit were improved when isolates were tested from Muller Hinton agar with a meropenem 10 µg disc instead of blood agar. The rapid CARB screen (performed in 2-3 h) demonstrated overall 98.7% sensitivity and 87.7% specificity (n = 133). The KPC/MBL in P. aeruginosa/Acinetobacter Confirm Kit (which requires overnight incubation) demonstrated a high number of false-positive results giving 38.6% specificity and 100% sensitivity (n = 44). The Check-MDR Carba (performed in 5 h), detecting carbapenemase presence, provides a cabapenemase-positive or -negative result demonstrated 96.7% specificity and 98.6% sensitivity (n = 132). The Check-Direct CPE (performed in 3 h), which identifies KPC, NDM/VIM or OXA-48 type carbapenemases, demonstrated 96.5% specificity and 97.1% sensitivity (n = 97). The Check-Direct CPE, however, failed to detect dual carbapenemase genes present in two out of four isolates. The principal conclusion is the recommendation of the rapid CARB screen and Check-MDR Carba for incorporation into a carbapenemase detection algorithm which, when used in combination, will yield results with 97.3% sensitivity and 99.6% specificity.

Computational micromechanics of bioabsorbable magnesium stents.

Magnesium alloys are a promising candidate material for an emerging generation of absorbable metal stents. Due to its hexagonal-close-packed lattice structure and tendency to undergo twinning, the deformation behaviour of magnesium is quite different to that of conventional stent materials, such as stainless steel 316L and cobalt chromium L605. In particular, magnesium exhibits asymmetric plastic behaviour (i.e. different yield behaviours in tension and compression) and has lower ductility than these conventional alloys. In the on-going development of absorbable metal stents it is important to assess how the unique behaviour of magnesium affects device performance. The mechanical behaviour of magnesium stent struts is investigated in this study using computational micromechanics, based on finite element analysis and crystal plasticity theory. The plastic deformation in tension and bending of textured and non-textured magnesium stent struts with different numbers of grains through the strut dimension is investigated. It is predicted that, unlike 316L and L605, the failure risk and load bearing capacity of magnesium stent struts during expansion is not strongly affected by the number of grains across the strut dimensions; however texturing, which may be introduced and controlled in the manufacturing process, is predicted to have a significant influence on these measures of strut performance.

A physical corrosion model for bioabsorbable metal stents.

Absorbable metal stents (AMSs) are an emerging technology in the treatment of heart disease. Computational modelling of AMS performance will facilitate the development of this technology. In this study a physical corrosion model is developed for AMSs based on the finite element method and adaptive meshing. The model addresses a gap between currently available phenomenological corrosion models for AMSs and physical corrosion models that have been developed for more simple geometries than those of a stent. The model developed in this study captures the changing surface of a corroding three-dimensional AMS structure for the case of diffusion-controlled corrosion. Comparisons are made between model predictions and those of previously developed phenomenological corrosion models for AMSs in terms of predicted device geometry and mechanical performance during corrosion. Relationships between alloy solubility and diffusivity in the corrosion environment and device performance during corrosion are also investigated.

TNF superfamily member TL1A elicits type 2 innate lymphoid cells at mucosal barriers.

Immune responses at mucosal barriers are regulated by innate type 2 lymphoid cells (ILC2s) that elaborate effector cytokines interleukins 5 and 13 (IL5 and IL13). IL25 and IL33 are key cytokines that support ILC2s; however, mice deficient in these pathways retain some functional ILC2s. Analysis of human and murine cells revealed that ILC2s highly express tumor necrosis factor (TNF)-receptor superfamily member DR3 (TNFRSF25). Engagement of DR3 with cognate ligand TL1A promoted ILC2 expansion, survival, and function. Exogenous protein or genetic overexpression of TL1A activated ILC2s independent of IL25 or IL33. Dr3(-/-) mice failed to control gut helminthic infections, and failed to mount ILC2 responses in the lung after nasal challenge with papain. Our data demonstrate a key role for TL1A in promoting ILC2s at mucosal barriers.

A novel flow chamber for biodegradable alloy assessment in physiologically realistic environments.

In order to better understand the in vivo corrosion of biodegradable alloys, it is necessary to replicate the physiological environment as closely as possible. In this study, a novel flow chamber system is developed that allows the investigation of biodegradable alloy corrosion in a simulated physiological environment. The system is designed to reproduce flow conditions encountered in coronary arteries using a parallel plate setup and to allow the culturing of cells. Computational fluid dynamics and analytical methods are used as part of the design process to ensure that suitable flow conditions are maintained in the test region. The system is used to investigate the corrosion behavior of AZ31 alloy foils of different thickness, in test media with and without proteins and in static and dynamic solutions. It is observed that pulsatile flows, similar to those in the coronary arteries, significantly increase corrosion rates and lead to a different corrosion surface morphologies relative to static immersion tests.

Influence of statistical size effects on the plastic deformation of coronary stents.

The dimensions of coronary stent struts are similar to those of the metallic grains of their constituent alloys. This means that statistical size effects (SSEs), which are evident in polycrystals with few grains through their dimensions, can have detrimental effects on the mechanical performance of stent struts undergoing large plastic deformation. Current trends in coronary stent design are towards thinner struts, potentially increasing the influence of SSEs. In order to maintain adequate device performance with decreasing strut thickness, it is therefore important to assess the role of SSEs in the plastic deformation of stents. In this study, finite element modelling and crystal plasticity theory are used to investigate SSEs in the deformation of struts in tension and bending. The relationships between SSEs and microstructure morphology, alloy strain hardening behaviour and secondary phases are also investigated. It is predicted that reducing the number of grains through the strut cross section and increasing the number of grains along the strut length have detrimental effects on mechanical performance. The magnitudes of these effects are predicted to be independent of the uniformity of the studied microstructures, but dependent on alloy strain hardening behaviour. It is believed that model predictions will aid in identifying a lower bound on suitable strut thicknesses in coronary stents for a range of alloys and microstructures.

Computational modelling of the mechanics of trabecular bone and marrow using fluid structure interaction techniques.

Bone marrow found within the porous structure of trabecular bone provides a specialized environment for numerous cell types, including mesenchymal stem cells (MSCs). Studies have sought to characterize the mechanical environment imposed on MSCs, however, a particular challenge is that marrow displays the characteristics of a fluid, while surrounded by bone that is subject to deformation, and previous experimental and computational studies have been unable to fully capture the resulting complex mechanical environment. The objective of this study was to develop a fluid structure interaction (FSI) model of trabecular bone and marrow to predict the mechanical environment of MSCs in vivo and to examine how this environment changes during osteoporosis. An idealized repeating unit was used to compare FSI techniques to a computational fluid dynamics only approach. These techniques were used to determine the effect of lower bone mass and different marrow viscosities, representative of osteoporosis, on the shear stress generated within bone marrow. Results report that shear stresses generated within bone marrow under physiological loading conditions are within the range known to stimulate a mechanobiological response in MSCs in vitro. Additionally, lower bone mass leads to an increase in the shear stress generated within the marrow, while a decrease in bone marrow viscosity reduces this generated shear stress.

Comparing coronary stent material performance on a common geometric platform through simulated bench testing.

Absorbable metallic stents (AMSs) are a newly emerging cardiovascular technology which has the potential to eliminate long-term patient health risks associated with conventional permanent stents. AMSs developed to date have consisted of magnesium alloys or iron, materials with inferior mechanical properties to those used in permanent stents, such as stainless steel and cobalt-chromium alloys. However, for AMSs to be feasible for widespread clinical use it is important that their performance is comparable to modern permanent stents. To date, the performances of magnesium, iron, and permanent stent materials have not been compared on a common stent platform for a range of stent performance metrics, such as flexibility, radial strength, and recoil. In this study, this comparison is made through simulated bench testing, based on finite-element modelling. The significance of this study is that it allows potential limitations in current AMS performance to be identified, which will aid in focusing future AMS design. This study also allows the identification of limitations in current AMS materials, thereby informing the on-going development of candidate biodegradable alloys. The results indicate that the AMSs studied here can match the recoil characteristics and radial strength of modern permanent stents; however, to achieve this, larger strut dimensions are required. It is also predicted that the AMSs studied are inferior to permanent stents in terms of maximum absolute curvature and longitudinal stiffness.

A corrosion model for bioabsorbable metallic stents.

In this study a numerical model is developed to predict the effects of corrosion on the mechanical integrity of bioabsorbable metallic stents. To calibrate the model, the effects of corrosion on the integrity of biodegradable metallic foils are assessed experimentally. In addition, the effects of mechanical loading on the corrosion behaviour of the foil samples are determined. A phenomenological corrosion model is developed and applied within a finite element framework, allowing for the analysis of complex three-dimensional structures. The model is used to predict the performance of a bioabsorbable stent in an idealized arterial geometry as it is subject to corrosion over time. The effects of homogeneous and heterogeneous corrosion processes on long-term stent scaffolding ability are contrasted based on model predictions.

Pertussis outbreak in northwest Ireland, January - June 2010.

We report a community pertussis outbreak that occurred in a small town located in the northwest of Ireland. Epidemiological investigations suggest that waning immunity and the absence of a booster dose during the second year of life could have contributed to the outbreak. The report also highlights the need to reinforce the surveillance of pertussis in Ireland and especially to improve the clinical and laboratory diagnosis of cases.

Multi-component adsorption model for pellicle formation: the influence of salivary proteins and non-salivary phospho proteins on the binding of histatin 5 onto hydroxyapatite.

The acquired enamel pellicle formed by selective adsorption of proteins in whole saliva is a protective integument on the tooth surface. The purpose of the present study was to investigate the formation of human acquired enamel pellicle using an in vitro hydroxyapatite (HA) model and 3H-histatin 5 to allow accurate measurement of histatin 5 binding in a multi-component experimental system. A binary system was employed by mixing 3H-histatin 5 with one unlabeled protein prior to incubation with HA or by first incubating 3H-histatin 5 with the HA which had been pre-coated with one of a panel of unlabeled proteins (human albumin, salivary amylase, lysozyme, acidic PIFs, statherin, the N-terminal fragment of statherin, and egg yolk phosvitin). A ternary system was employed by mixing 3H-histatin 5 with HA sequentially pre-coated with two different unlabeled proteins, including recombinant histatin 1. The results showed that only salivary statherin and egg yolk phosvitin promote histatin 5 adsorption significantly. The amount of histatin 5 adsorbed was also found to increase as a function of the amount of phosvitin and statherin used to pre-coat HA up to a maximum level that was two- to four-fold greater than that observed on untreated HA. These data suggest that specific protein-protein interactions may play important roles in pellicle formation in vivo.

Prospective comparison of methods of closure of the coronal flap after craniofacial surgery in children.

The coronal flap in children may be closed with clips or sutures. The results of closure with clips in patients treated during 1 year at the paediatric craniofacial unit, Liverpool, UK, were audited. Eight of 43 required a further general anaesthetic for removal of clips. A prospective audit the following year of patients whose wounds were closed with a rapidly-absorbed polyglactin suture (Vicryl rapide) showed that 3 out of 39 required re-suture of the wound in theatre (two following trauma from falls). There was one infection in each group. Neither of these patients required formal debridement of the wound in theatre. Rapidly-absorbed polyglactin is a safe alternative to clips for wound closure after craniofacial surgery in children and the morbidity is less because fewer patients have to return to theatre than closure with surgical clips.

Physical parameters of hydroxyapatite adsorption and effect on candidacidal activity of histatins.

Histatins 1, 3 and 5 are the major members of a histidine-rich protein family present in human salivary secretions. These proteins are distinct from many salivary proteins in their high positive charge density at neutral pH, and their antibacterial and antifungal properties. In this study, the hydroxyapatite adsorption characteristics of histatin 1, containing a single phosphoserine residue, recombinantly expressed histatin 1, native histatin 3, synthetic histatin 5 and an internal 12-residue sequence of histatin 5 were investigated. A Langmuir-type model was used to analyse the adsorption. A comparison of the affinities and binding sites of phosphorylated and recombinant histatin 1 provided an estimate of the positive influence of the single phosphoseryl group on mineral adsorption. Furthermore, an apparent correlation was shown to exist between peptide chain length and the number of binding sites. The influence of histatin 5 adsorption on its anticandidal activity was also investigated by performing Candida albicans killing assays with histatin 5 and histatin 5/hydroxyapatite suspensions. A decrease in killing activity was observed with the increase of hydroxyapatite present. The results suggest that the anticandidal properties of histatin 5 could be impaired by the conformations resulting from mineral adsorption, or that putative cellular receptors necessary for candidacidal activity are inaccessible when histatin 5 is adsorbed on hydroxyapatite.

Modulation of blood fluke development in the liver by hepatic CD4+ lymphocytes.

We have identified an alternate developmental pathway in the life cycle of the trematode pathogen Schistosoma mansoni. This pathway is used in immunodeficient hosts in which the parasite fails to receive appropriate signals from the host immune system. Helminth development is altered at an early stage during infection, resulting in the appearance of attenuated forms that prolong survival of host and parasite. Hepatic CD4+ T lymphocyte populations are an integral component of the immune signal recognized by the parasite.