Holocene floodplain palaeoecology of the Humberhead Levels; implications for regional wetland development

The acquisition of high quality, well-dated local site records is essential for progressing regional environmental reconstructions. As part of a wider study designed to examine intra- and extra- site ecosystem responses to environmental change, this paper presents new palaeoecological data from the floodplain of the River Torne in the Humberhead Levels, South Yorkshire. The sampling site lies adjacent to the lowland raised mire of Hatfield Moors, a location with a long history of palaeoecological investigations. The potential of using floodplain records to reconstruct local variations in ecosystem response to environmental change is also considered. Coleoptera and pollen are used to reconstruct floodplain ecosystem dynamics, whilst chronologies are established using Bayesian age–depth modelling. Between 10,200 cal BP and 2300 cal BP, the floodplain experienced multiple phases of ecological change. At 10,200–9910 cal BP, a cut-off channel began to infill with peat, while the surrounding floodplain remained relatively dry with Pinus forest growing nearby. Between 9630–9500 cal BP and 7270–7020 cal BP, a depositional hiatus occurred in the sedimentary record. By the end of this period, the local woodland had diversified and expanded to mixed deciduous tree cover. A wet shift identified at 6870–6160 cal BP was shortly followed by a rise in Alnus and Tilia from 6410–6160 cal BP. At this time, widespread floodplain paludification had occurred in the Humberhead Levels, which was largely controlled by relative sea-level (RSL) rise and the associated rise in regional water tables. Floodplain expansion also resulted in the widespread occurrence of Alnus dominated fen woodland. The local Torne floodplain experienced varying levels of wetness that influenced the decline and subsequent regeneration of the woodland from 5870–5640 cal BP. At this time, the Ulmus decline is identified in the pollen stratigraphic record. Floodplain hydrology appears to have been controlled by a combination of water table fluctuations and changes in channel pattern/flow, both of which can be linked to RSL variations recorded in the Humber Estuary. Floodplain alluviation, also linked to rising water tables, is dated to 4360–4160 cal BP. Anthropogenic woodland clearance further upstream may have further compounded this event.

Keratinocyte Growth-Factor Promotes Epithelial Survival and Resolution in a Human Model of Lung Injury

Rationale: Increasing epithelial repair and regeneration may hasten resolution of lung injury in patients with the Acute Respiratory Distress Syndrome (ARDS). In animal models of ARDS, Keratinocyte Growth Factor (KGF) reduces injury and increases epithelial proliferation and repair. The effect of KGF in the human alveolus is unknown.

Objectives: To test whether KGF can attenuate alveolar injury in a human model of ARDS.

Methods: Volunteers were randomized to intravenous KGF (60 μg/kg) or placebo for 3 days, before inhaling 50μg lipopolysaccharide. Six hours later, subjects underwent bronchoalveolar lavage (BAL) to quantify markers of alveolar inflammation and cell-specific injury.

Measurements and Main Results: KGF did not alter leukocyte infiltration or markers of permeability in response to LPS. KGF increased BAL concentrations of Surfactant Protein D (SP-D), MMP-9, IL-1Ra, GM-CSF and CRP. In vitro, BAL fluid from KGF-treated subjects (KGF BAL) inhibited pulmonary fibroblast proliferation, but increased alveolar epithelial proliferation. Active MMP-9 increased alveolar epithelial wound repair. Finally, BAL from the KGF pre-treated group enhanced macrophage phagocytic uptake of apoptotic epithelial cells and bacteria compared with BAL from the placebo-treated group. This effect was blocked by inhibiting activation of the GM-CSF receptor.

Conclusions: KGF treatment increases BAL SP-D, a marker of type II alveolar epithelial cell proliferation in a human model of ALI. Additionally KGF increases alveolar concentrations of the anti-inflammatory cytokine IL-1Ra, and mediators that drive epithelial repair (MMP-9) and enhance macrophage clearance of dead cells and bacteria (GM-CSF).

Population pharmacokinetic and pharmacogenetic analysis of tacrolimus in paediatric liver transplant patients

Aims: To build a population pharmacokinetic model that describes the apparent clearance of tacrolimus and the potential demographic, clinical and genetically controlled factors that could lead to inter-patient pharmacokinetic variability within children following liver transplantation.

Methods: The present study retrospectively examined tacrolimus whole blood pre-dose concentrations (n = 628) of 43 children during their first year post-liver transplantation. Population pharmacokinetic analysis was performed using the non-linear mixed effects modelling program (nonmem) to determine the population mean parameter estimate of clearance and influential covariates.

Results: The final model identified time post-transplantation and CYP3A5*1 allele as influential covariates on tacrolimus apparent clearance according to the following equation:

TVCL=12.9×(Weight /13.2)^0.75×EXP(-0.00158×TPT)×EXP(0.428×CYP3A5)

where TVCL is the typical value for apparent clearance, TPT is time post-transplantation in days and the CYP3A5 is 1 where*1 allele is present and 0 otherwise. The population estimate and inter-individual variability (%CV) of tacrolimus apparent clearance were found to be 0.977 l h kg (95% CI 0.958, 0.996) and 40.0%, respectively, while the residual variability between the observed and predicted concentrations was 35.4%.

Conclusion: Tacrolimus apparent clearance was influenced by time post-transplantation and CYP3A5 genotypes. The results of this study, once confirmed by a large scale prospective study, can be used in conjunction with therapeutic drug monitoring to recommend tacrolimus dose adjustments that take into account not only body weight but also genetic and time-related changes in tacrolimus clearance. © 2013 The British Pharmacological Society.

Multi-Fidelity Multidisciplinary Whole Engine Thermo-Mechanical Design Optimization

Traditionally, the optimization of a turbomachinery engine casing for tip clearance has involved either twodimensional transient thermomechanical simulations or three-dimensional mechanical simulations. This paper illustrates that three-dimensional transient whole-engine thermomechanical simulations can be used within tip clearance optimizations and that the efficiency of such optimizations can be improved when a multifidelity surrogate modeling approach is employed. These simulations are employed in conjunction with a rotor suboptimization using surrogate models of rotor-dynamics performance, stress, mass and transient displacements, and an engine parameterization.

Tip Leakage Flow and Heat Transfer on Turbine Stage Tip and Casing: Effect of Unsteady Stator-Rotor Interactions

Unsteady simulations were performed to investigate time dependent behaviors of the leakage flow structures and heat transfer on the rotor blade tip and casing in a single stage gas turbine engine. This paper mainly illustrates the unsteady nature of the leakage flow and heat transfer, particularly, that caused by the stator–rotor interactions. In order to obtain time-accurate results, the effects of varying the number of time steps, sub iterations, and the number of vane passing periods was firstly examined. The effect of tip clearance height and rotor speeds was also examined. The results showed periodic patterns of the tip leakage flow and heat transfer rate distribution for each vane passing. The relative position of the vane and vane trailing edge shock with respect to time alters the flow conditions in the rotor domain, and results in significant variations in the tip leakage flow structures and heat transfer rate distributions. It is observed that the trailing edge shock phenomenon results in a critical heat transfer region on the blade tip and casing. Consequently, the turbine blade tip and casing are subjected to large fluctuations of Nusselt number (about Nu = 2000 to 6000 and about Nu = 1000 to 10000, respectively) at a high frequency (coinciding with the rotor speed).

Efficient Drug Delivery and Induction of Apoptosis in Colorectal Tumors Using a Death Receptor 5-Targeted Nanomedicine

Death Receptor 5 (DR5) is a pro-apoptotic cell-surface receptor that is a potential therapeutic target in cancer. Despite the potency of DR5-targeting agents in preclinical models, the translation of these effects into the clinic remains disappointing. Herein, we report an alternative approach to exploiting DR5 tumor expression using antibody-targeted, chemotherapy-loaded nanoparticles. We describe the development of an optimized polymer-based nanotherapeutic incorporating both a functionalized polyethylene glycol (PEG) layer and targeting antibodies to limit premature phagocytic clearance whilst enabling targeting of DR5-expressing tumor cells. Using the HCT116 colorectal cancer model, we show that following binding to DR5, the nanoparticles activate caspase 8, enhancing the anti-tumor activity of the camptothecin payload both in vitro and in vivo. Importantly, the combination of nanoparticle-induced DR5 clustering with camptothecin delivery overcomes resistance to DR5-induced apoptosis caused by loss of BAX or overexpression of anti-apoptotic FLIP. This novel approach may improve the clinical activity of DR5-targeted therapeutics while increasing tumor-specific delivery of systemically toxic chemotherapeutics.Molecular Therapy (2014); doi:10.1038/mt.2014.137.

Potential of Microneedles in Enhancing Delivery of Photosensitising Agents for Photodynamic Therapy

Photodynamic therapy can be used in the treatment of pre-malignant and malignant diseases. It offers advantages over other therapies currently used in the treatment of skin lesions including avoidance of damage to surrounding tissue and minimal or no scarring. Unfortunately, systemic delivery of photosensitising agents can result in adverse effects, such as prolonged cutaneous photosensitivity; while topical administration lacks efficacy in the clearance of deeper skin lesions and those with a thick overlying keratotic layer. Therefore, enhancement of conventional photosensitiser delivery is desired. However, the physicochemical properties of photosensitising agents, such as extreme hydrophilicity or lipophilicity and large molecular weights make this challenging. This paper reviews the potential of microneedles as a viable method to overcome these delivery-limiting physicochemical characteristics and discusses the current benefits and limitations of solid, dissolving and hydrogel-forming microneedles. Clinical studies in which microneedles have successfully improved photodynamic therapy are also discussed, along with benefits which microneedles offer, such as precise photosensitiser localisation, painless application and reduction in waiting times between photosensitiser administration and irradiation highlighted.

Type-I interferons induce lung protease responses following respiratory syncytial virus infection via RIG-I-like receptors

The role of proteases in viral infection of the lung is poorly understood. Thus, we examined matrix metalloproteinases (MMPs) and cathepsin proteases in respiratory syncytial virus (RSV)-infected mouse lungs. RSV-induced gene expression for MMPs -2, -3, -7, -8, -9, -10, -12, -13, -14, -16, -17, -19, -20, -25, -27, and -28 and cathepsins B, C, E, G, H, K, L1, S, W, and Z in the airways of Friend leukemia virus B sensitive strain mice. Increased proteases were present in the bronchoalveolar lavage fluid (BALF) and lung tissue during infection. Mitochondrial antiviral-signaling protein (MAVS) and TIR-domain-containing adapter-inducing interferon-β-deficient mice were exposed to RSV. Mavs-deficient mice had significantly lower expression of airway MMP-2, -3, -7, -8, -9, -10, -12, -13, and -28 and cathepsins C, G, K, S, W, and Z. In lung epithelial cells, retinoic acid-inducible gene-1 (RIG-I) was identified as the major RIG-I-like receptor required for RSV-induced protease expression via MAVS. Overexpression of RIG-I or treatment with interferon-β in these cells induced MMP and cathepsin gene and protein expression. The significance of RIG-1 protease induction was demonstrated by the fact that inhibiting proteases with batimastat, E64 or ribavirin prevented airway hyperresponsiveness and enhanced viral clearance in RSV-infected mice.

An Observational Study of Blood Concentrations and Kinetics of Methyl- and Propyl-Parabens in Neonates

Purpose: Systemic exposure to parabens in the neonatal population, in particular propyl-parabens (PPB), remains a concern. Blood concentrations and kinetics of methyl-parabens (MPB) and PPB were therefore determined in neonates receiving medicines containing these excipients.

Methods: A multi-centre, non-interventional, observational study of excipient-kinetics in neonates. ‘Dried Blood Spot’ samples were collected opportunistically at the same time as routine samples and the observations modelled using a non-linear mixed effects approach.

Results: A total of 841 blood MPB and PPB concentration data were available for evaluation from 181 pre- and term-neonates. Quantifiable blood concentrations of MPB and PPB were observed in 99% and 49% of patients, and 55% and 25% of all concentrations were above limit of detection (10 ng/ml), respectively. Only MPB data was amenable to modelling. Oral bioavailability was influenced by type of formulation and disposition was best described by a two compartment model with clearance (CL) influenced by post natal age (PNA); CL_{PNA<21 days} 0.57 versus CL_PNA>21days 0.88 L/h.

Conclusions: Daily repeated administration of parabens containing medicines can result in prolonged systemic exposure to the parent compound in neonates. Animal toxicology studies of PPB that specifically address the neonatal period are required before a permitted daily exposure for this age group can be established.

Development of Novel Activity-Based Probes for the Detection of Serine Proteases

Cystic Fibrosis (CF) is a genetic disease featuring a chronic cycle of inflammation and infection in the airways of sufferers. Mutations lead to altered ion transport, which in turn causes dehydrated airways and reduced mucociliary clearance which predisposes the patient to infection, resulting in a severe immune response and tissue destruction (1). Airway dehydration is primarily caused by the hyperabsorption of sodium by the epithelial sodium channel (ENaC) (2). ENaC is activated by the action of a number of predominantly trypsin-like Channel Activating Proteases (CAPs) including prostasin, matriptase and furin (3). Additional proteases known to activate ENaC include human airway trypsin (3), plasmin, neutrophil elastase and chymotrypsin (4).

Activity profiling is a valuable technique which involves the use of small inhibitory molecules called Activity-Based Probes (ABPs) which can be used to covalently label the active site of proteases and provide a range of information regarding its structure, catalytic mechanism, location and function within biological systems. The development of novel ABPs for CAPs, would enhance understanding of the role of these proteases in CF airways disease and in particular their role in ENaC activation and airway dehydration. This project investigates the application of a range of novel broad-spectrum ABPs targeting the various subclasses of serine proteases, to include those proteases involved in ENaC activation. Additionally, the application of more selective ABPs in detecting specific serine proteases is investigated.

Compounds were synthesised by Solid-Phase Peptide Synthesis (SPPS) using a standard Fmoc/tBu strategy. Kinetic evaluation of synthesised ABPs against various serine proteases was determined by fluorogenic steady-state enzyme assays. Furthermore, application of ABPs and confirmation of irreversible nature of the compounds was carried out through SDS-PAGE and electroblotting techniques.

Synthesised compounds showed potent irreversible inhibition of serine proteases within their respective targeting class (NAP855 vs Trypsin k3/Ki = 2.60 x 106 M-1 min-1, NFP849 vs Chymotrypsin k3/Ki = 1.28 x 106 M-1 min-1 and NVP800 vs Neutrophil Elastase k3/Ki = 6.41 x 104 M-1 min-1). Furthermore ABPs showed little to no cross-reactivity between classes and so display selectivity between classes. The irreversible nature of compounds was further demonstrated through labelling of proteases, followed by separation and detection via SDS-PAGE and electroblotting techniques. Targeted labelling of active proteases only, was demonstrated by failure of ABPs to detect previously inactivated proteases. Extension of the substrate recognition site within probes resulted in an increased potency and selectivity in the detection of the target proteases. Successful detection of neutrophil elastase from CF sputum samples by NVP800, demonstrated the application of compounds within biological samples and their potential use in identifying further proteases involved in ENaC activation and airway dehydration in CF patients.

Plasma Clusterin Levels and the rs11136000 Genotype in Individuals with Mild Cognitive Impairment and Alzheimer's Disease

Aim: Substantial evidence links atherosclerosis and Alzheimer's disease (AD). Apolipoproteins, such as apolipoprotein E, have a causal relationship with both diseases. The rs11136000 SNP within the CLU gene, which encodes clusterin (apolipoprotein J), is also associated with increased AD risk. The aim of this study was to investigate the relationship between plasma clusterin and the rs11136000 genotype in mild cognitive impairment (MCI) and AD.

Methods: Plasma and DNA samples were collected from control, MCI and AD subjects (n=142, 111, 154, respectively). Plasma clusterin was determined by ELISA and DNA samples were genotyped for rs11136000 by TaqMan assay.

Results: Plasma clusterin levels were higher in MCI and AD subjects vs. controls (222.3 +/- 61.3 and 193.6 +/- 58.2 vs. 178.6 +/- 52.3 mu g/ml, respectively; p

Conclusion: This study examined control, MCI and AD subjects, identifying for the first time that plasma clusterin levels were influenced, not only by the presence of AD, but also the transitional stage of MCI, while rs11136000 genotype only influenced plasma clusterin levels in the control group. The increase in plasma clusterin in MCI and AD subjects may occur in response to the disease process and would be predicted to increase binding capacity for amyloid-beta peptides in plasma, enhancing their removal from the brain.

Unsteady tip leakage characteristics and heat transfer on turbine blade tip and casing

An unsteady numerical investigation was performed to examine time dependent behaviors of the tip leakage flow structures and heat transfer on the rotor blade tip and casing in a single stage gas turbine engine. A transonic, high-pressure
turbine stage was modeled and simulated using a stage pressure ratio of 3.2. The rotor’s tip clearance was 1.2 mm in height (3% of the rotor span) and its speed was set at 9500 rpm. Periodic flow is observed for each vane passing period. Tip leakage flow as well as heat transfer data showed highly time dependent behaviors. A stator trailing edge shock appears as the turbine stage is operating at transonic conditions. The shock alters the flow condition in the rotor section, namely, the tip leakage flow structures and heat transfer rate distributions. The instantaneous Nusselt number distributions are compared to the time averaged and steady-state results. The same patterns in tip leakage flow
structures and heat transfer rate distributions were observed in both unsteady and steady simulations. However, the unsteady simulation captured the locally time-dependent high heat transfer phenomena caused by the unsteady interaction with the upstream vane trailing-edge shock and the passing wake.

Treatment adherence and health outcomes in patients with bronchiectasis

Background: We aimed to determine adherence to inhaled antibiotics, other respiratory medicines and airway clearance and to determine the association between adherence to these treatments and health outcomes (pulmonary exacerbations, lung function and Quality of Life Questionnaire-Bronchiectasis [QOL-B]) in bronchiectasis after 12 months.

Methods: Patients with bronchiectasis prescribed inhaled antibiotics for Pseudomonas aeruginosa infection were recruited into a one-year study. Participants were categorised as " adherent" to medication (medication possession ratio ≥80% using prescription data) or airway clearance (score ≥80% in the Modified Self-Reported Medication-Taking Scale). Pulmonary exacerbations were defined as treatment with a new course of oral or intravenous antibiotics over the one-year study. Spirometry and QOL-B were completed at baseline and 12 months. Associations between adherence to treatment and pulmonary exacerbations, lung function and QOL-B were determined by regression analyses.

Results: Seventy-five participants were recruited. Thirty-five (53%), 39 (53%) and 31 (41%) participants were adherent to inhaled antibiotics, other respiratory medicines, and airway clearance, respectively. Twelve (16%) participants were adherent to all treatments. Participants who were adherent to inhaled antibiotics had significantly fewer exacerbations compared to non-adherent participants (2.6 vs 4, p = 0.00) and adherence to inhaled antibiotics was independently associated with having fewer pulmonary exacerbations (regression co-efficient = -0.51, 95% CI [-0.81,-0.21], p < 0.001). Adherence to airway clearance was associated with lower QOL-B Treatment Burden (regression co-efficient = -15.46, 95% CI [-26.54, -4.37], p < 0.01) and Respiratory Symptoms domain scores (regression co-efficient = -10.77, 95% CI [-21.45; -0.09], p < 0.05). There were no associations between adherence to other respiratory medicines and any of the outcomes tested. Adherence to treatment was not associated with FEV₁ % predicted.

Conclusions: Treatment adherence is low in bronchiectasis and affects important health outcomes including pulmonary exacerbations. Adherence should be measured as part of bronchiectasis management and future research should evaluate bronchiectasis-specific adherence strategies. 

Colorectal cancer risk following adenoma removal: a large prospective population-based cohort study

Background: Randomised controlled trials have demonstrated significant reductions in colorectal cancer (CRC) incidence and mortality associated with polypectomy. However, little is known about whether polypectomy is effective at reducing CRC risk in routine clinical practice. The aim of this investigation was to quantify CRC risk following polypectomy in a large prospective population-based cohort study.

Methods: Patients with incident colorectal polyps between 2000 and 2005 in Northern Ireland (NI) were identified via electronic pathology reports received to the NI Cancer Registry (NICR). Patients were matched to the NICR to detect CRC and deaths up to 31st December 2010. CRC standardised incidence ratios (SIRs) were calculated and Cox proportional hazards modelling applied to determine CRC risk.

Results: During 44,724 person-years of follow-up, 193 CRC cases were diagnosed amongst 6,972 adenoma patients, representing an annual progression rate of 0.43%. CRC risk was significantly elevated in patients who had an adenoma removed (SIR 2.85; 95% CI: 2.61 to 3.25) compared with the general population. Male sex, older age, rectal site and villous architecture were associated with an increased CRC risk in adenoma patients. Further analysis suggested that not having a full colonoscopy performed at, or following, incident polypectomy contributed to the excess CRC risk.

Conclusions: CRC risk was elevated in individuals following polypectomy for adenoma, outside of screening programmes.

Impact: This finding emphasises the need for full colonoscopy and adenoma clearance, and appropriate surveillance, after endoscopic diagnosis of adenoma.

Predictors of adherence to treatment in bronchiestasis

Objectives

We aimed to determine if beliefs about treatment, clinical factors and quality of life predicted adherence to treatment in patients with bronchiectasis.

Methods

We recruited participants with confirmed bronchiectasis to a one-year study. We calculated adherence to treatment using medication possession ratios and self-report. Baseline Beliefs about Medicines, clinical, demographic and Quality of Life Questionnaire-Bronchiectasis data were collected. We used logistic regression to determine predictors of adherence to treatment during the subsequent year.

Results

Seventy-five participants were recruited. Beliefs about harm, age and total number of prescribed medications were predictors of adherence to inhaled antibiotics. Concerns about medication, age and Quality of Life Questionnaire-Bronchiectasis Treatment Burden were predictors of adherence to other respiratory medicines. Beliefs about necessity of airway clearance and age were predictors of adherence to airway clearance.

Conclusion

Beliefs about treatment, age, number of prescribed medications and perceived treatment burden predicted subsequent adherence in bronchiectasis, thereby, providing potential targets for future interventions in this population. Clinicians can use these data to identify patients with bronchiectasis who might be at risk of non-adherence i.e. those who are younger, have concerns about medications, who do not think airway clearance is necessary or who are prescribed numerous medications.