Efficient accommodation of local minima in watershed model calibration

The Gauss-Marquardt-Levenberg (GML) method of computer-based parameter estimation, in common with other gradient-based approaches, suffers from the drawback that it may become trapped in local objective function minima, and thus report optimized parameter values that are not, in fact, optimized at all. This can seriously degrade its utility in the calibration of watershed models where local optima abound. Nevertheless, the method also has advantages, chief among these being its model-run efficiency, and its ability to report useful information on parameter sensitivities and covariances as a by-product of its use. It is also easily adapted to maintain this efficiency in the face of potential numerical problems (that adversely affect all parameter estimation methodologies) caused by parameter insensitivity and/or parameter correlation. The present paper presents two algorithmic enhancements to the GML method that retain its strengths, but which overcome its weaknesses in the face of local optima. Using the first of these methods an intelligent search for better parameter sets is conducted in parameter subspaces of decreasing dimensionality when progress of the parameter estimation process is slowed either by numerical instability incurred through problem ill-posedness, or when a local objective function minimum is encountered. The second methodology minimizes the chance of successive GML parameter estimation runs finding the same objective function minimum by starting successive runs at points that are maximally removed from previous parameter trajectories. As well as enhancing the ability of a GML-based method to find the global objective function minimum, the latter technique can also be used to find the locations of many non-global optima (should they exist) in parameter space. This can provide a useful means of inquiring into the well-posedness of a parameter estimation problem, and for detecting the presence of bimodal parameter and predictive probability distributions. The new methodologies are demonstrated by calibrating a Hydrological Simulation Program-FORTRAN (HSPF) model against a time series of daily flows. Comparison with the SCE-UA method in this calibration context demonstrates a high level of comparative model run efficiency for the new method. (c) 2006 Elsevier B.V. All rights reserved.

KRAS variation and risk of endometriosis

Endometriosis is a common gynaecological disease with symptoms of pelvic pain and infertility which affects 7-10% of women in their reproductive years. Activation of an oncogenic allele of Kirsten rat sarcoma viral oncogene homologue (KRAS) in the reproductive tract of mice resulted in the development of endometriosis. We hypothesized that variation in KRAS may influence risk of endometriosis in humans. Thirty tagSNPs spanning a region of 60.7 kb across the KRAS locus were genotyped using iPLEX chemistry on a MALDI-TOF MassARRAY platform in 959 endometriosis cases and 959 unrelated controls, and data were analysed for association with endometriosis. Genotypes were obtained for most individuals with a mean completion rate of 99.1%. We identified six haplotype blocks across the KRAS locus in our sample. There were no significant differences between cases and controls in the frequencies of individual single-nucleotide polymorphisms (SNPs) or haplotypes. We also developed a rapid method to screen for 11 common KRAS and BRAF mutations on the Sequenom MassARRAY system. The assay detected all mutations previously identified by direct sequencing in a panel of positive controls. No germline variants for KRAS or BRAF were detected. Our results demonstrate that any risk of endometriosis in women because of common variation in KRAS must be very small.

A new relaxation method for roll forming problems

Finite element analysis (FEA) of nonlinear problems in solid mechanics is a time consuming process, but it can deal rigorously with the problems of both geometric, contact and material nonlinearity that occur in roll forming. The simulation time limits the application of nonlinear FEA to these problems in industrial practice, so that most applications of nonlinear FEA are in theoretical studies and engineering consulting or troubleshooting. Instead, quick methods based on a global assumption of the deformed shape have been used by the roll-forming industry. These approaches are of limited accuracy. This paper proposes a new form-finding method - a relaxation method to solve the nonlinear problem of predicting the deformed shape due to plastic deformation in roll forming. This method involves applying a small perturbation to each discrete node in order to update the local displacement field, while minimizing plastic work. This is iteratively applied to update the positions of all nodes. As the method assumes a local displacement field, the strain and stress components at each node are calculated explicitly. Continued perturbation of nodes leads to optimisation of the displacement field. Another important feature of this paper is a new approach to consideration of strain history. For a stable and continuous process such as rolling and roll forming, the strain history of a point is represented spatially by the states at a row of nodes leading in the direction of rolling to the current one. Therefore the increment of the strain components and the work-increment of a point can be found without moving the object forward. Using this method we can find the solution for rolling or roll forming in just one step. This method is expected to be faster than commercial finite element packages by eliminating repeated solution of large sets of simultaneous equations and the need to update boundary conditions that represent the rolls.

Assembly processes of invertebrate communities in springs across different spatial scales

Il presente lavoro ha lo scopo di comprendere i processi sottesi ai pattern di coesistenza tra le specie di invertebrati sorgentizi, distinguendo tra dinamiche stocastiche e deterministiche. Le sorgenti sono ecosistemi complessi e alcune loro caratteristiche (ad esempio l’insularità, la stabilità termica, la struttura ecotonale “a mosaico”, la frequente presenza di specie rare ed endemiche, o l’elevata diversità in taxa) le rendono laboratori naturali utili allo studio dei processi ecologici, tra cui i processi di assembly. Al fine di studiare queste dinamiche è necessario un approccio multi-scala, per questo motivi sono state prese in considerazione tre scale spaziali. A scala locale è stato compiuto un campionamento stagionale su sette sorgenti (quattro temporanee e tre permanenti) del Monte Prinzera, un affioramento ofiolitico vicino alla città di Parma. In questa area sono stati valutati l’efficacia e l’impatto ambientale di diversi metodi di campionamento e sono stati analizzati i drivers ecologici che influenzano le comunità. A scala più ampia sono state campionate per due volte 15 sorgenti della regione Emilia Romagna, al fine di identificare il ruolo della dispersione e la possibile presenza di un effetto di niche-filtering. A scala continentale sono state raccolte informazioni di letteratura riguardanti sorgenti dell’area Paleartica occidentale, e sono stati studiati i pattern biogeografici e l’influenza dei fattori climatici sulle comunità. Sono stati presi in considerazione differenti taxa di invertebrati (macroinvertebrati, ostracodi, acari acquatici e copepodi), scegliendo tra quelli che si prestavano meglio allo studio dei diversi processi in base alle loro caratteristiche biologiche e all’approfondimento tassonomico raggiungibile. I campionamenti biologici in sorgente sono caratterizzati da diversi problemi metodologici e possono causare impatti sugli ambienti. In questo lavoro sono stati paragonati due diversi metodi: l’utilizzo del retino con un approccio multi-habitat proporzionale e l’uso combinato di trappole e lavaggio di campioni di vegetazione. Il retino fornisce dati più accurati e completi, ma anche significativi disturbi sulle componenti biotiche e abiotiche delle sorgenti. Questo metodo è quindi raccomandato solo se il campionamento ha come scopo un’approfondita analisi della biodiversità. D’altra parte l’uso delle trappole e il lavaggio della vegetazione sono metodi affidabili che presentano minori impatti sull’ecosistema, quindi sono adatti a studi ecologici finalizzati all’analisi della struttura delle comunità. Questo lavoro ha confermato che i processi niche-based sono determinanti nello strutturare le comunità di ambienti sorgentizi, e che i driver ambientali spiegano una rilevante percentuale della variabilità delle comunità. Infatti le comunità di invertebrati del Monte Prinzera sono influenzate da fattori legati al chimismo delle acque, alla composizione e all’eterogeneità dell’habitat, all’idroperiodo e alle fluttuazioni della portata. Le sorgenti permanenti mostrano variazioni stagionali per quanto riguarda le concentrazioni dei principali ioni, mentre la conduttività, il pH e la temperatura dell’acqua sono più stabili. È probabile che sia la stabilità termica di questi ambienti a spiegare l’assenza di variazioni stagionali nella struttura delle comunità di macroinvertebrati. L’azione di niche-filtering delle sorgenti è stata analizzata tramite lo studio della diversità funzionale delle comunità di ostracodi dell’Emilia-Romagna. Le sorgenti ospitano più del 50% del pool di specie regionale, e numerose specie sono state rinvenute esclusivamente in questi habitat. Questo è il primo studio che analizza la diversità funzionale degli ostracodi, è stato quindi necessario stilare una lista di tratti funzionali. Analizzando il pool di specie regionale, la diversità funzionale nelle sorgenti non è significativamente diversa da quella misurata in comunità assemblate in maniera casuale. Le sorgenti non limitano quindi la diversità funzionale tra specie coesistenti, ma si può concludere che, data la soddisfazione delle esigenze ecologiche delle diverse specie, i processi di assembly in sorgente potrebbero essere influenzati da fattori stocastici come la dispersione, la speciazione e le estinzioni locali. In aggiunta, tutte le comunità studiate presentano pattern spaziali riconoscibili, rivelando una limitazione della dispersione tra le sorgenti, almeno per alcuni taxa. Il caratteristico isolamento delle sorgenti potrebbe essere la causa di questa limitazione, influenzando maggiormente i taxa a dispersione passiva rispetto a quelli a dispersione attiva. In ogni caso nelle comunità emiliano-romagnole i fattori spaziali spiegano solo una ridotta percentuale della variabilità biologica totale, mentre tutte le comunità risultano influenzate maggiormente dalle variabili ambientali. Il controllo ambientale è quindi prevalente rispetto a quello attuato dai fattori spaziali. Questo risultato dimostra che, nonostante le dinamiche stocastiche siano importanti in tutte le comunità studiate, a questa scala spaziale i fattori deterministici ricoprono un ruolo prevalente. I processi stocastici diventano più influenti invece nei climi aridi, dove il disturbo collegato ai frequenti eventi di disseccamento delle sorgenti provoca una dinamica source-sink tra le diverse comunità. Si è infatti notato che la variabilità spiegata dai fattori ambientali diminuisce all’aumentare dell’aridità del clima. Disturbi frequenti potrebbero provocare estinzioni locali seguite da ricolonizzazioni di specie provenienti dai siti vicini, riducendo la corrispondenza tra gli organismi e le loro richieste ambientali e quindi diminuendo la quantità di variabilità spiegata dai fattori ambientali. Si può quindi concludere che processi deterministici e stocastici non si escludono mutualmente, ma contribuiscono contemporaneamente a strutturare le comunità di invertebrati sorgentizi. Infine, a scala continentale, le comunità di ostracodi sorgentizi mostrano chiari pattern biogeografici e sono organizzate lungo gradienti ambientali principalmente collegati altitudine, latitudine, temperatura dell’acqua e conducibilità. Anche la tipologia di sorgente (elocrena, reocrena o limnocrena) è influente sulla composizione delle comunità. La presenza di specie rare ed endemiche inoltre caratterizza specifiche regioni geografiche.

Vibrational dynamics and structure of natural feldspars

The present study gives a contribution to the knowledge on the Na-feldspar and plagioclases, extending the database of the Raman spectra of plagioclases with different chemical compositions and structural orders. This information may be used for the future planetary explorations by “rovers”, for the investigation of ceramics nanocrystal materials and for the mineralogical phase identification in sediments. Na-feldspar and plagioclase solid solution have been investigated by Raman spectroscopy in order to determine the relationships between the vibrational changes and the plagioclase crystal chemistry and structure. We focused on the Raman micro-spectroscopy technique, being a non-destructive method, suited for contactless analysis with high spatial resolution. Chemical and structural analyses have been performed on natural samples to test the usefulness of Raman spectroscopy as a tool in the study of the pressure-induced structural deformations, the disordering processes due to change in the Al-Si distribution in the tetrahedral sites and, finally, in the determination of the anorthitic content (Anx) in plagioclase minerals. All the predicted 39 Ag Raman active modes have been identified and assigned to specific patterns of atomic vibrational motion. A detailed comparison between experimental and computed Raman spectra has been performed and previous assignments have been revised, solving some discrepancies reported in recent literature. The ab initio calculation at the hybrid HF/DFT level with the WC1LYP Hamiltonian has proven to give excellent agreement between calculated and experimentally measured Raman wavenumbers and intensities in triclinic minerals. A short digression on the 36 infrared active modes of Na-feldspar has been done too. The identification of all 39 computed Raman modes in the experimentally measured spectra of the fully ordered Na-feldspar, known as low albite, along with the detailed description of each vibrational mode, has been essential to extend the comparative analysis to the high pressure and high temperature structural forms of albite, which reflect the physical–chemical conditions of the hosting rocks. The understanding of feldspar structure response to pressure and temperature is crucial in order to constrain crustal behaviour. The compressional behaviour of the Na-feldspar has been investigated for the first time by Raman spectroscopy. The absence of phase transitions and the occurrence of two secondary compression mechanisms acting at different pressures have been confirmed. Moreover, Raman data suggest that the internal structural changes are confined to a small pressure interval, localized around 6 GPa, not spread out from 4 to 8 GPa as suggested by previous X-rays studies on elasticity. The dominant compression mechanisms act via tetrahedral tilting, while the T-O bond lengths remain nearly constant at moderate compressional regimes. At the spectroscopic level, this leads to the strong pressure dependencies of T-O-T bending modes, as found for the four modes at 478, 508, 578 and 815 cm-1. The Al-Si distribution in the tetrahedral sites affects also the Raman spectrum of Na-feldspar. In particular, peak broadening is more sensitive than peak position to changes in the degree of order. Raman spectroscopy is found to be a good probe for local ordering, in particular being sensitive to the first annealing steps, when the macroscopic order parameter is still high. Even though Raman data are scattered and there are outliers in the estimated values of the degree of order, the average peak linewidths of the Na-feldspar characteristic doublet band, labelled here as υa and υb, as a function of the order parameter Qod show interesting trends: both peak linewidths linearly increase until saturation. From Qod values lower than 0.6, peak broadening is no more affected by the Al-Si distribution. Moreover, the disordering process is found to be heterogeneous. SC-XRD and Raman data have suggested an inter-crystalline inhomogeneity of the samples, i.e., the presence of regions with different defect density on the micrometric scale. Finally, the influence of Ca-Na substitution in the plagioclase Raman spectra has been investigated. Raman spectra have been collected on a series of well characterized natural, low structural plagioclases. The variations of the Raman modes as a function of the chemical composition and the structural order have been determined. The number of the observed Raman bands at each composition gives information about the unit-cell symmetry: moving away from the C1 structures, the number of the Raman bands enhances, as the number of formula units in the unit cell increases. The modification from an “albite-like” Raman spectrum to a more “anorthite-like” spectrum occurs from sample An78 onwards, which coincides with the appearance of c reflections in the diffraction patterns of the samples. The evolution of the Raman bands υa and υb displays two changes in slope at ~An45 and ~An75: the first one occurs between e2 and e1 plagioclases, the latter separates e1 and I1 plagioclases with only b reflections in their diffraction patterns from I1 and P1 samples having b and c reflections too. The first variation represents exactly the e2→e1 phase transitions, whereas the second one corresponds in good approximation to the C1→I1 transition, which has been determined at ~An70 by previous works. The I1→P1 phase transition in the anorthite-rich side of the solid solution is not highlighted in the collected Raman spectra. Variations in peak broadening provide insights into the behaviour of the order parameter on a local scale, suggesting an increase in the structural disorder within the solid solution, as the structures have to incorporate more Al atoms to balance the change from monovalent to divalent cations. All the information acquired on these natural plagioclases has been used to produce a protocol able to give a preliminary estimation of the chemical composition of an unknown plagioclase from its Raman spectrum. Two calibration curves, one for albite-rich plagioclases and the other one for the anorthite-rich plagioclases, have been proposed by relating the peak linewidth of the most intense Raman band υa and the An content. It has been pointed out that the dependence of the composition from the linewidth can be obtained only for low structural plagioclases with a degree of order not far away from the references. The proposed tool has been tested on three mineralogical samples, two of meteoric origin and one of volcanic origin. Chemical compositions by Raman spectroscopy compare well, within an error of about 10%, with those obtained by elemental techniques. Further analyses on plagioclases with unknown composition will be necessary to validate the suggested method and introduce it as routine tool for the determination of the chemical composition from Raman data in planetary missions.

Spring Phenology of Butterflies : The role of seasonal variation in life-cycle regulation

Animals and plants in temperate regions must adapt their life cycle to pronounced seasonal variation. The research effort that has gone into studying these cyclical life history events, or phenological traits, has increased greatly in recent decades. As phenological traits are often correlated to temperature, they are relevant to study in terms of understanding the effect of short term environmental variation as well as long term climate change. Because of this, changes in phenology are the most obvious and among the most commonly reported responses to climate change. Moreover, phenological traits are important for fitness as they determine the biotic and abiotic environment an individual encounters. Fine-tuning of phenology allows for synchronisation at a local scale to mates, food resources and appropriate weather conditions. On a between-population scale, variation in phenology may reflect regional variation in climate. Such differences can not only give insights to life cycle adaptation, but also to how populations may respond to environmental change through time. This applies both on an ecological scale through phenotypic plasticity as well as an evolutionary scale through genetic adaptation. In this thesis I have used statistical and experimental methods to investigate both the larger geographical patterns as well as mechanisms of fine-tuning of phenology of several butterfly species. The main focus, however, is on the orange tip butterfly, Anthocharis cardamines, in Sweden and the United Kingdom. I show a contrasting effect of spring temperature and winter condition on spring phenology for three out of the five studied butterfly species. For A. cardamines there are population differences in traits responding to these environmental factors between and within Sweden and the UK that suggest adaptation to local environmental conditions. All populations show a strong negative plastic relationship between spring temperature and spring phenology, while the opposite is true for winter cold duration. Spring phenology is shifted earlier with increasing cold duration. The environmental variables show correlations, for example, during a warm year a short winter delays phenology while a warm spring speeds phenology up. Correlations between the environmental variables also occur through space, as the locations that have long winters also have cold springs. The combined effects of these two environmental variables cause a complex geographical pattern of phenology across the UK and Sweden. When predicting phenology with future climate change or interpreting larger geographical patterns one must therefore have a good enough understanding of how the phenology is controlled and take the relevant environmental factors in to account. In terms of the effect of phenological change, it should be discussed with regards to change in life cycle timing among interacting species. For example, the phenology of the host plants is important for A. cardamines fitness, and it is also the main determining factor for oviposition. In summary, this thesis shows that the broad geographical pattern of phenology of the butterflies is formed by counteracting environmental variables, but that there also are significant population differences that enable fine-tuning of phenology according to the seasonal progression and variation at the local scale.

Coloring random graphs and maximizing local diversity

We study a variation of the graph coloring problem on random graphs of finite average connectivity. Given the number of colors, we aim to maximize the number of different colors at neighboring vertices (i.e. one edge distance) of any vertex. Two efficient algorithms, belief propagation and Walksat are adapted to carry out this task. We present experimental results based on two types of random graphs for different system sizes and identify the critical value of the connectivity for the algorithms to find a perfect solution. The problem and the suggested algorithms have practical relevance since various applications, such as distributed storage, can be mapped onto this problem.

Local luminance amplitude modulates the interpretation of shape-from-shading in textured surfaces

The pattern of illumination on an undulating surface can be used to infer its 3-D form (shape-from-shading). But the recovery of shape would be invalid if the luminance changes actually arose from changes in reflectance. So how does vision distinguish variation in illumination from variation in reflectance to avoid illusory depth? When a corrugated surface is painted with an albedo texture, the variation in local mean luminance (LM) due to shading is accompanied by a similar modulation in local luminance amplitude (AM). This is not so for reflectance variation, nor for roughly textured surfaces. We used depth mapping and paired comparison methods to show that modulations of local luminance amplitude play a role in the interpretation of shape-from-shading. The shape-from-shading percept was enhanced when LM and AM co-varied (in-phase) and was disrupted when they were out of phase or (to a lesser degree) when AM was absent. The perceptual differences between cue types (in-phase vs out-of-phase) were enhanced when the two cues were present at different orientations within a single image. Our results suggest that when LM and AM co-vary (in-phase) this indicates that the source of variation is illumination (caused by undulations of the surface), rather than surface reflectance. Hence, the congruence of LM and AM is a cue that supports a shape-from-shading interpretation. © 2006 Elsevier Ltd. All rights reserved.

Nuclear magnetic resonance studies of molecular interactions and structures

This thesis is concerned with the investigation, by nuclear magnetic resonance spectroscopy, of the molecular interactions occurring in mixtures of benzene and cyclohexane to which either chloroform or deutero-chloroform has been added. The effect of the added polar molecule on the liquid structure has been studied using spin-lattice relaxation time, 1H chemical shift, and nuclear Overhauser effect measurements. The main purpose of the work has been to validate a model for molecular interaction involving local ordering of benzene around chloroform. A chemical method for removing dissolved oxygen from samples has been developed to encompass a number of types of sample, including quantitative mixtures, and its supremacy over conventional deoxygenation technique is shown. A set of spectrometer conditions, the use of which produces the minimal variation in peak height in the steady state, is presented. To separate the general diluting effects of deutero-chloroform from its effects due to the production of local order a series of mixtures involving carbon tetrachloride, instead of deutero-chloroform, have been used as non-interacting references. The effect of molecular interaction is shown to be explainable using a solvation model, whilst an approach involving 1:1 complex formation is shown not to account for the observations. It is calculated that each solvation shell, based on deutero-chloroform, contains about twelve molecules of benzene or cyclohexane. The equations produced to account for the T1 variations have been adapted to account for the 1H chemical shift variations in the same system. The shift measurements are shown to substantiate the solvent cage model with a cage capacity of twelve molecules around each chloroform molecule. Nuclear Overhauser effect data have been analysed quantitatively in a manner consistent with the solvation model. The results show that discrete shells only exist when the mole fraction of deutero-chloroform is below about 0.08.

Application of the finite element method to problems in fracture mechanics

Numerical techniques have been finding increasing use in all aspects of fracture mechanics, and often provide the only means for analyzing fracture problems. The work presented here, is concerned with the application of the finite element method to cracked structures. The present work was directed towards the establishment of a comprehensive two-dimensional finite element, linear elastic, fracture analysis package. Significant progress has been made to this end, and features which can now be studied include multi-crack tip mixed-mode problems, involving partial crack closure. The crack tip core element was refined and special local crack tip elements were employed to reduce the element density in the neighbourhood of the core region. The work builds upon experience gained by previous research workers and, as part of the general development, the program was modified to incorporate the eight-node isoparametric quadrilateral element. Also. a more flexible solving routine was developed, and provided a very compact method of solving large sets of simultaneous equations, stored in a segmented form. To complement the finite element analysis programs, an automatic mesh generation program has been developed, which enables complex problems. involving fine element detail, to be investigated with a minimum of input data. The scheme has proven to be versati Ie and reasonably easy to implement. Numerous examples are given to demonstrate the accuracy and flexibility of the finite element technique.

Local and systemic delivery of a novel group of inhibitors of transglutaminase enzyme: A potential approach for treating of catheter-related complications and liver fibrosis

The present thesis investigates targeted (locally and systemically) delivery of a novel group of inhibitors of enzyme transglutaminases (TGs). TGs are a widely distributed group of enzymes that catalyse the formation of isopeptide bonds between the y-carboxamide group of protein-bound glutamines and the a-amino group of protein-bound lysines or polyamines. The first group of the novel inhibitors tested were the tluorescently labelled inhibitors of Factor XIIIa (FXIIIa). These small, non-toxic inhibitors have the potential to prevent stabilisation of thrombi by FXIIIa and consequently increase the natural rate of thrombolysis, in addition it reduces staphylococcal colonisation of catheters by inhibiting their FXIIIa¬mediated cross-linking to blood clot proteins on the central venous catheter (CVCs) surface. The aim of this work was to incorporate the FXIIIa inhibitor either within coating of polyurethane (PU) catheters or to integrate it into silicone catheters, so as to reduce the incidence of thrombotic occlusion and associated bacterial infection in CVCs. The initial work focused on the incorporation of FXIIIa inhibitors within polymeric coatings of PU catheters. After defining the key characteristics desired for an effective polymeric-coating, polyvinylpyrrolidone (PVP), poly(lactic-co-glycolic acid) (PLGA) or their combination were studies as polymers of choice for coating of the catheters_ The coating was conducted by dip-coating method in a polymer solution containing the inhibitor. Upon incubation of the inhibitor-and polymer-coated strips in buffer, PVP was dissolved instantly, generating fast and significant drug release, whilst PLGA did not dissolve, yielding a slow and an insufficient amount of drug release. Nevertheless, the drug release profile was enhanced upon employing a blend solution of PVP and PLGA. The second part of the study was to incorporate the FXIIIa inhibitor into a silicone elastomer; results demonstrated that FXIIIa inhibitor can be incorporated and released from silicone by using citric acid (CA) and sodium bicarbonate (SB) as additives and the drug release rate can be controlled by the amount of incorporated additives in the silicone matrix. Furthermore, it was deemed that the inhibitor was still biologically active subsequent to being released from the silicone elastomer strips. Morphological analysis confirmed the formation of channels and cracks inside the specimens upon the addition of CA and SB. Nevertheless, the tensile strength, in addition to Young's modulus of silicone elastomer strips, decreased constantly with an increasing amount of amalgamated CA/ SB in the formulations. According to our results, incorporation of FXIIIa inhibitor into catheters and other medical implant devices could offer new perspectives in preventing bio-material associated infections and thrombosis. The use of tissue transglutaminase (T02) inhibitor for treating of liver fibrosis was also investigated. Liver fibrosis is characterized by increased synthesis and decreased degradation of the extracellular matrix (ECM). Transglutaminase-mediated covalent cross-linking is involved in the stabilization of ECM in human liver fibrosis. Thus, TG2 inhibitors may be used to counteract the decreased degradation of the ECM. The potential of a liposome based drug delivery system for site specific delivery of the fluorescent TG2 inhibitor into the liver was investigated; results indicated that the TG2 inhibitor can be successfully integrated into liposomes and delivered to the liver, therefore demonstrating that liposomes can be employed for site-specific delivery of TG2 inhibitors into the liver and TG2 inhibitor incorporating liposomes could offer a new approach in treating liver fibrosis and its end stage disease cirrhosis.

In vivo measurement of regional variation in anterior scleral resistance to Schiotz indentation

Purpose: Recent studies indicate that ocular and scleral rigidity is pertinent to our understanding of glaucoma, age related macular degeneration and the development and pathogenesis of myopia. The principal method of measuring ocular rigidity is by extrapolation of data from corneal indentation tonometry (Ko) using Friedenwald’s transformation algorithms. Using scleral indentation (Schiotz tonometry) we assess whether regional variations in resistance to indentation occur in vivo across the human anterior globe directly, with reference to the deflection of Schiotz scale readings. Methods: Data were collected from both eyes of 26 normal young adult subjects with a range of refractive error (mean spherical equivalent ± S.D. of -1.77 D ± 3.28 D, range -10.56 to +4.38 D). Schiotz tonometry (5.5 g & 7.5 g) was performed on the cornea and four scleral quadrants; supero-temporal (ST) and -nasal (SN), infero-temporal (IT) and -nasal (IN) approximately 8 mm posterior to the limbus. Results: Values of Ko (mm3)-1 were consistent with those previously reported (mean 0.0101 ± 0.0082, range 0.0019–0.0304). In regards to the sclera, significant differences (p < 0.001) were found across quadrants with indentation readings for both loads between means for the cornea and ST; ST and SN; ST and IT, ST and IN. Mean (±S.D.) scale readings for 5.5 g were: cornea 5.93 ± 1.14, ST 8.05 ± 1.58, IT 7.03 ± 1.86, SN 6.25 ± 1.10, IN 6.02 ± 1.49; and 7.5 g: cornea 9.26 ± 1.27, ST 11.56 ± 1.65, IT 10.31 ± 1.74, SN 9.91 ± 1.20, IN 9.50 ± 1.56. Conclusions: Significant regional variation was found in the resistance of the anterior sclera to indentation produced by the Schiotz tonometer.

A method for the in-situ determination of the hydraulic conductivity of gravels as used in constructed wetlands for wastewater treatment

A new instrument and method are described that allow the hydraulic conductivities of highly permeable porous materials, such as gravels in constructed wetlands, to be determined in the field. The instrument consists of a Mariotte siphon and a submersible permeameter cell with manometer take-off tubes, to recreate in-situ the constant head permeameter test typically used with excavated samples. It allows permeability to be measured at different depths and positions over the wetland. Repeatability obtained at fixed positions was good (normalised standard deviation of 1–4%), and results obtained for highly homogenous silica sand compared well when the sand was retested in a lab permeameter (0.32 mm.s–1 and 0.31 mm.s–1 respectively). Practical results have a ±30% associated degree of uncertainty because of the mixed effect of natural variation in gravel core profiles, and interstitial clogging disruption during insertion of the tube into the gravel. This error is small, however, compared to the orders of magnitude spatial variations detected. The technique was used to survey the hydraulic conductivity profile of two constructed wetlands in the UK, aged 1 and 15 years respectively. Measured values were high (up to 900 mm.s –1) and varied by three orders of magnitude, reflecting the immaturity of the wetland. Detailed profiling of the younger system suggested the existence of preferential flow paths at a depth of 200 mm, corresponding to the transition between more coarse and less coarse gravel layers (6–12 mm and 3–6 mm respectively), and transverse drift towards the outlet.

Community pharmacy in a commissioning-led NHS:can pharmacy compete effectively?

Introduction – The commissioning of services has been a core responsibility of English Primary Care Trusts (PCTs) since 2002. Primary care organisations (PCOs) in Scotland, Wales and Northern Ireland have also increased their commissioning activities but with, arguably, less fervour than their English counterparts. The commissioning function of English PCTs has been reinforced by the introduction of new contractual frameworks across primary care – for medical services, dentistry and pharmacy. The new pharmaceutical services contract for England and Wales introduced an “enhanced” category of services, the provision of which is dependent on the commissioning decisions of local PCTs. As the NHS, most pertinently in England, continues its transformation from a provider to a commissioner of healthcare, the ability of pharmacy to compete effectively for funding is likely to become increasingly important. Method - After piloting, in August 2006 a self-completion postal questionnaire was sent to a random sample of practising community pharmacists, stratified for country and sex, within Great Britain (n=1998), with a follow-up to non-responders 4 weeks later. Data were analysed using SPSS (v12.0). A final response rate of 51% (n=1023/1998) was achieved. Within the section of the questionnaire relating to service provision, respondents were asked “do you believe that pharmacy will be able to compete effectively with other healthcare providers for access to additional funding to develop services that address a public health need identified by your local Primary Care Organisation (PCO), e.g. PCT/LHB etc.?”. Answers were recorded on a three-point scale; pharmacy “will”, “may”, or “will not” be able to compete effectively for funding. Results - The attitudes of pharmacists showed variation depending on the type of pharmacy they worked in (supermarket, multiple (outlets (n)=200), large chain (200>n>20), small chain (20=n>5), or independent (n=5)) (?2 test with p=0.001). Over a third of survey pharmacists working in small chains and independents (37% (n=21/57) and 33% (n=113/341) respectively) believed that pharmacy would not be able to compete effectively for funding compared to 23% (n=15/65) for supermarket pharmacists, 22% (n=21/97) for pharmacists employed by large chains and just 18% (n=62/353) for pharmacists employed most regularly in multiples. Furthermore, attitudes also varied between the countries of residence of respondents (?2 test with p<0.05). 27% (n=242/893) of pharmacists resident in England and Wales believed that pharmacy would not be able to compete compared to 16% (n=18/116) of pharmacists resident in Scotland. Conclusions – It would appear that community pharmacists believe that the larger pharmacy chains and supermarkets will occupy an advantageous position in terms of attracting finance to develop services. This could have notable implications for service provision across the sector. If corporate pharmacy chains were to monopolise commissioning monies then the proportion of funding available to independents will be diminished; arguably further hastening their demise, as well as stifling the professional development of pharmacists employed within the independent sector. These findings, when combined with the variation observed between UK pharmacists operating under different contractual frameworks, may be a reflection of the divergent policy in the different administrations with developments in England, including the new pharmacy contract, reflecting a market-based approach with Scotland taking a near opposite stance with service integration and a commitment to new public health. However, it should be acknowledged that the questionnaire did not allow for detection of ambiguities in, or misunderstandings of, the survey question and this should be considered as a limitation of the research.