Multidisciplinary Consideration of Potential Pathophysiologic Mechanisms of Paradoxical Erythema with Topical Brimonidine Therapy.

Rosacea is a chronic inflammatory disease with transient and non-transient redness as key characteristics. Brimonidine is a selective α2-adrenergic receptor (AR) agonist approved for persistent facial erythema of rosacea based on significant efficacy and good safety data. The majority of patients treated with brimonidine report a benefit; however, there have been sporadic reports of worsening erythema after the initial response. A group of dermatologists, receptor physiology, and neuroimmunology scientists met to explore potential mechanisms contributing to side effects as well as differences in efficacy. We propose the following could contribute to erythema after application: (1) local inflammation and perivascular inflammatory cells with abnormally functioning ARs may lead to vasodilatation; (2) abnormal saturation and cells expressing different AR subtypes with varying ligand affinity; (3) barrier dysfunction and increased skin concentrations of brimonidine with increased actions at endothelial and presynaptic receptors, resulting in increased vasodilation; and (4) genetic predisposition and receptor polymorphism(s) leading to different smooth muscle responses. Approximately 80% of patients treated with brimonidine experience a significant improvement without erythema worsening as an adverse event. Attention to optimizing skin barrier function, setting patient expectations, and strategies to minimize potential problems may possibly reduce further the number of patients who experience side effects.FundingGalderma International S.A.S., Paris, France

Syntheses and Properties of Salts of Chromophores with Ferrocenyl Electron Donor Groups and Quaternary Nitrogen Acceptors

A series of five new dipolar cations has been synthesized with ferrocenyl (Fc) electron donor groups connected to N-arylpyridinium, N-methylquinolinium, N-methylbenzothiazolium, or N-methylacridinium acceptors. Together with their known N-methylpyridinium analogue, these chromophores have been characterized as their PF_6^− salts by using various techniques including electronic absorption spectroscopy and cyclic voltammetry. Nine single-crystal X-ray structures have been determined, including two polymorphs of one salt obtained from a single crystallization experiment, and two of these are polar materials. A highly favorable degree of dipolar alignment for bulk NLO effects is observed in one case. Molecular quadratic nonlinear optical (NLO) responses have been determined by using femtosecond hyper-Rayleigh scattering (HRS) at 1300 nm and also via Stark (electroabsorption) spectroscopic studies on the intense π → π^* intraligand and d → π^* metal-to-ligand charge-transfer bands. A broad correlation between the electron acceptor strength and the HRS-derived first hyperpolarizabilities β and the static first hyperpolarizabilities β0 estimated from the Stark data is evident. This is the first time that meaningful (albeit indirectly determined) β_0 data have been reported for Fc compounds, allowing quantitative comparisons with the chromophore in the technologically important material (E)-4′-(dimethylamino)-N-methyl-4-stilbazolium (DAS) tosylate. The observed β_0 values are in several cases similar to that of [DAS]PF_6, and possibly even larger in one instance

The Earth Microbiome Project: Meeting report of the "1 EMP meeting on sample selection and acquisition" at Argonne National Laboratory October 6 2010.

This report details the outcome the first meeting of the Earth Microbiome Project to discuss sample selection and acquisition. The meeting, held at the Argonne National Laboratory on Wednesday October 6(th) 2010, focused on discussion of how to prioritize environmental samples for sequencing and metagenomic analysis as part of the global effort of the EMP to systematically determine the functional and phylogenetic diversity of microbial communities across the world

Maximising microprocessor reliability through game theory and heuristics

PhD ThesisEmbedded Systems are becoming ever more pervasive in our society, with most routine daily tasks now involving their use in some form and the market predicted to be worth USD 220 billion, a rise of 300%, by 2018. Consumers expect more functionality with each design iteration, but for no detriment in perceived performance. These devices can range from simple low-cost chips to expensive and complex systems and are a major cost driver in the equipment design phase. For more than 35 years, designers have kept pace with Moore's Law, but as device size approaches the atomic limit, layouts are becoming so complicated that current scheduling techniques are also reaching their limit, meaning that more resource must be reserved to manage and deliver reliable operation. With the advent of many-core systems and further sources of unpredictability such as changeable power supplies and energy harvesting, this reservation of capability may become so large that systems will not be operating at their peak efficiency. These complex systems can be controlled through many techniques, with jobs scheduled either online prior to execution beginning or online at each time or event change. Increased processing power and job types means that current online scheduling methods that employ exhaustive search techniques will not be suitable to define schedules for such enigmatic task lists and that new techniques using statistic-based methods must be investigated to preserve Quality of Service. A new paradigm of scheduling through complex heuristics is one way to administer these next levels of processor effectively and allow the use of more simple devices in complex systems; thus reducing unit cost while retaining reliability a key goal identified by the International Technology Roadmap for Semi-conductors for Embedded Systems in Critical Environments. These changes would be beneficial in terms of cost reduction and system exibility within the next generation of device. This thesis investigates the use of heuristics and statistical methods in the operation of real-time systems, with the feasibility of Game Theory and Statistical Process Control for the successful supervision of high-load and critical jobs investigated. Heuristics are identified as an effective method of controlling complex real-time issues, with two-person non-cooperative games delivering Nash-optimal solutions where these exist. The simplified algorithms for creating and solving Game Theory events allow for its use within small embedded RISC devices and an increase in reliability for systems operating at the apex of their limits. Within this Thesis, Heuristic and Game Theoretic algorithms for a variety of real-time scenarios are postulated, investigated, refined and tested against existing schedule types; initially through MATLAB simulation before testing on an ARM Cortex M3 architecture functioning as a simplified automotive Electronic Control Unit.Doctoral Teaching Account from the EPSRC

Suppression of Epithelial to Mesenchymal Transitioning (EMT) Enhances Ex Vivo Reprogramming of Human Exocrine Pancreatic Tissue towards Functional Insulin Producing β-Like Cells

Because of the lack of tissue available for islet transplantation, new sources of β-cells have been sought for the treatment of type 1 diabetes. The aim of this study was to determine whether the human exocrine-enriched fraction from the islet isolation procedure could be reprogrammed to provide additional islet tissue for transplantation. The exocrine-enriched cells rapidly dedifferentiated in culture and grew as a mesenchymal monolayer. Genetic lineage tracing confirmed that these mesenchymal cells arose, in part, through a process of epithelial-to-mesenchymal transitioning (EMT). A protocol was developed whereby transduction of these mesenchymal cells with adenoviruses containing Pdx1, Ngn3, MafA, and Pax4 generated a population of cells that were enriched in glucagon-secreting α-like cells. Transdifferentiation or reprogramming toward insulin-secreting β-cells was enhanced, however, when using unpassaged cells in combination with inhibition of EMT by inclusion of Rho-associated kinase (ROCK) and transforming growth factor-β1 inhibitors. Resultant cells were able to secrete insulin in response to glucose and on transplantation were able to normalize blood glucose levels in streptozotocin diabetic NOD/SCID mice. In conclusion, reprogramming of human exocrine-enriched tissue can be best achieved using fresh material under conditions whereby EMT is inhibited, rather than allowing the culture to expand as a mesenchymal monolayer

Finite element modelling of healthy and osteoporotic bone

On a macro-structural level, the bones of the human skeleton is comprised mainly of trabecular (spongy) and cortical bone (dense). Trabecular bone typically occurs at the end points of long bones and has a structure described as a network of plates and rods. Cortical bone forms the hard outer shell and comprised mainly of osteons called Haversian systems. Bone is a composite material consisting mainly of an organic collagenous matrix ad carbonated apatite crystals. The structure of bone material is hierarchically organised and the inhomogeneous nature of bone material results in anisotropic mechanical properties. Bone adapts to its loading history and undergoes hypertrophy as result of increased loading and atrophy when loading is significantly reduced or completely removed. Osteoporosis is a disease of the bone which is characterised by loss of bone material and hence weakening of the bone. As a result of this, osteoporotic bone is more likely to fracture as a result of everyday loading. In this study three-dimensional finite element models of the shaft of the tibia were developed using the ABAQUS (Simula) finite element modelling programme. Models were developed to represent three symptoms of osteoporosis - bone thinning, low density and increased porosity. The models were subjected to compressive and torsional loading, and the stress distribution in response to these loads was analysed to gain an understanding of what areas of the tibia are at greatest risk of fracture and under what loading conditions. A risk of fracture for each of the elements was calculated and the maximum risk of fracture in each model gave an indication of fracture likelihood. This study found that osteoporotic bone showed increased stress and risk of fracture in both compression and torsion. However, torsion of bone with increased porosity was the only combination that produced results that indicate the occurrence of fracture. The aim is for the bone models developed in this study to be used clinically to reduce fracture occurrence in patients with osteoporotic bone loss.On a macro-structural level, the bones of the human skeleton is comprised mainly of trabecular (spongy) and cortical bone (dense). Trabecular bone typically occurs at the end points of long bones and has a structure described as a network of plates and rods. Cortical bone forms the hard outer shell and comprised mainly of osteons called Haversian systems. Bone is a composite material consisting mainly of an organic collagenous matrix ad carbonated apatite crystals. The structure of bone material is hierarchically organised and the inhomogeneous nature of bone material results in anisotropic mechanical properties. Bone adapts to its loading history and undergoes hypertrophy as result of increased loading and atrophy when loading is significantly reduced or completely removed. Osteoporosis is a disease of the bone which is characterised by loss of bone material and hence weakening of the bone. As a result of this, osteoporotic bone is more likely to fracture as a result of everyday loading. In this study three-dimensional finite element models of the shaft of the tibia were developed using the ABAQUS (Simula) finite element modelling programme. Models were developed to represent three symptoms of osteoporosis - bone thinning, low density and increased porosity. The models were subjected to compressive and torsional loading, and the stress distribution in response to these loads was analysed to gain an understanding of what areas of the tibia are at greatest risk of fracture and under what loading conditions. A risk of fracture for each of the elements was calculated and the maximum risk of fracture in each model gave an indication of fracture likelihood. This study found that osteoporotic bone showed increased stress and risk of fracture in both compression and torsion. However, torsion of bone with increased porosity was the only combination that produced results that indicate the occurrence of fracture. The aim is for the bone models developed in this study to be used clinically to reduce fracture occurrence in patients with osteoporotic bone loss

Experimental phonetic study of the timing of voicing in English obstruents

The treatment given to the timing of voicing in three areas of phonetic research -- phonetic taxonomy, speech production modelling, and speech synthesis -- Is considered in the light of an acoustic study of the timing of voicing in British English obstruents. In each case, it is found to be deficient. The underlying cause is the difficulty in applying a rigid segmental approach to an aspect of speech production characterised by important inter-articulator asynchronies, coupled to the limited quantitative data available concerning the systematic properties of the timing of voicing in languages. It is argued that the categories and labels used to describe the timing of voicing In obstruents are Inadequate for fulfilling the descriptive goals of phonetic theory. One possible alternative descriptive strategy is proposed, based on incorporating aspects of the parametric organisation of speech into the descriptive framework. Within the domain of speech production modelling, no satisfactory account has been given of fine-grained variability of the timing of voicing not capable of explanation in terms of general properties of motor programming and utterance execution. The experimental results support claims In the literature that the phonetic control of an utterance may be somewhat less abstract than has been suggestdd in some previous reports. A schematic outline is given, of one way in which the timing of voicing could be controlled in speech production. The success of a speech synthesis-by-rule system depends to a great extent on a comprehensive encoding of the systematic phonetic characteristics of the target language. Only limited success has been achieved in the past thirty years. A set of rules is proposed for generating more naturalistic patterns of voicing in obstruents, reflecting those observed in the experimental component of this study. Consideration Is given to strategies for evaluating the effect of fine-grained phonetic rules In speech synthesis

Apportionment of primary and secondary organic aerosols in Southern California during the 2005 Study of Organic Aerosols in Riverside (SOAR-1)

Ambient sampling was conducted in Riverside, California during the 2005 Study of Organic Aerosols in Riverside to characterize the composition and sources of organic aerosol using a variety of state-of-the-art instrumentation and source apportionment techniques. The secondary organic aerosol (SOA) mass is estimated by elemental carbon and carbon monoxide tracer methods, water soluble organic carbon content, chemical mass balance of organic molecular markers, and positive matrix factorization of high-resolution aerosol mass spectrometer data. Estimates obtained from each of these methods indicate that the organic fraction in ambient aerosol is overwhelmingly secondary in nature during a period of several weeks with moderate ozone concentrations and that SOA is the single largest component of PM1 aerosol in Riverside. Average SOA/OA contributions of 70−90% were observed during midday periods, whereas minimum SOA contributions of ~45% were observed during peak morning traffic periods. These results are contrary to previous estimates of SOA throughout the Los Angeles Basin which reported that, other than during severe photochemical smog episodes, SOA was lower than primary OA. Possible reasons for these differences are discussed

Helping patients in Uganda overcome weight gain and obesity using motivational interviewing

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Necessary fictions: indigenous claims and the humanity of rights

Indigenous right insistently challenges the surpassing arrogations of sovereign right. In so doing, it affirms dimensions of being-together denied or stunted in sovereign modes of political formation. This force of Indigenous right is amplified here through legal and literary instantiations. These, in turn, uncover the continuously created and fictional quality of rights, revealing them to be necessary fictions