A novel cyclosporin a aqueous formulation for dry eye treatment: in vitro and in vivo evaluation.

PURPOSE: The aim of the present study was the in vitro and in vivo evaluation of a novel aqueous formulation based on polymeric micelles for the topical delivery of cyclosporine A for dry eye treatment. METHODS: In vitro experiments were carried out on primary rabbit corneal cells, which were characterized by immunocytochemistry using fluorescein-labeled lectin I/isolectin B4 for the endothelial cells and mouse monoclonal antibody to cytokeratin 3+12 for the epithelial ones. Living cells were incubated for 1 hour or 24 hours with a fluorescently labeled micelle formulation and analyzed by fluorescence microscopy. In vivo evaluations were done by Schirmer test, osmolarity measurement, CyA kinetics in tears, and CyA ocular distribution after topical instillation. A 0.05% CyA micelle formulation was compared to a marketed emulsion (Restasis). RESULTS: The in vitro experiments showed the internalization of micelles in the living cells. The Schirmer test and osmolarity measurements demonstrated that micelles did not alter the ocular surface properties. The evaluation of the tear fluid gave similar CyA kinetics values: AUC = 2339 ± 1032 min*μg/mL and 2321 ± 881.63; Cmax = 478 ± 111 μg/mL and 451 ± 74; half-life = 36 ± 9 min and 28 ± 9 for the micelle formulation and Restasis, respectively. The ocular distribution investigation revealed that the novel formulation delivered 1540 ± 400 ng CyA/g tissue to the cornea. CONCLUSIONS: The micelle formulation delivered active CyA into the cornea without evident negative influence on the ocular surface properties. This formulation could be applied for immune-related ocular surface diseases.

Algebraic decay of velocity fluctuations near a wall

Computer simulations of the dynamics of a colloidal particle suspended in a fluid confined by an interface show that the asymptotic decay of the velocity correlation functions is algebraic. The exponents of the long-time tails depend on the direction of motion of the particle relative to the surface, as well as on the specific nature of the boundary conditions. In particular, we find that for the angular velocity correlation function, the decay in the presence of a slip surface is faster than the one corresponding to a stick one. An intuitive picture is introduced to explain the various long-time tails, and the simulations are compared with theoretical expressions where available.

The use of the SeDeM diagram expert system for the formulation of Captopril SR matrix tablets by direct compression

The SeDeM Diagram Expert System has been used to study excipients, Captopril and designed formulations for their galenic characterization and to ascertain the critical points of the formula affecting product quality to obtain suitable formulations of Captopril Direct Compression SR Matrix Tablets. The application of the Sedem Diagram Expert System enables selecting excipients with in order to optimize the formula in the preformulation and formulation studies. The methodology is based on the implementation of ICH Q8, establishing the design space of the formula with the use of experiment design, using the parameters of the SeDeM Diagram Expert System as system responses.

Accounting system for activity standard costs formulation in ERP environment

Toiminnanohjausjärjestelmän implementointi ja sen mukanaan tuomat muutokset tuotekustannuslaskentaan asettavat haasteita yritykselle. Metallitoimialalla toimivassa yrityksessä on havaittu samat haasteet implementoitaessa SAP R/3 toiminnanohjausjärjestelmää ja sen tuotekustannuslaskentatoiminnallisuutta. SAP R/3 tuotekustannuslogiikka tarvitsee tietoa järjestelmän ulkopuolelta, minkä huomioimatta jättäminen vaikuttaa suoraan laskentatarkkuuteen. Diplomityössä kehitetään sekä standardoitu prosessi että laskentajärjestelmä, joiden avulla pystytään laskemaan tarvittavat niin toimintokustannukset eri teräspalvelukeskuksen kuormituspisteille kuin kustannustenvyörytysarvot. Lasketut arvot muodostavat tarvittavat tekijät SAP R/3 tuotekustannuslaskennan master dataan. Tavoitteena on edesauttaa läpinäkyvän kustannustiedon muodostumista. Diplomityö pohjautuu ns. vesiputousmalliin (SDLC). Ensin tunnistetaan reunaehdot ympäristöstä, jossa tuotekustannuslaskenta toteutetaan. Tämä asettaa joustamattomia komponentteja kehitettävälle laskentajärjestelmälle. Joustavat komponentit sen sijaan antavat vapautta laskentajärjestelmälle. Yhdistämällä joustamattomat ja joustavat komponentit saavutetaan järjestelmä, jolla voidaan täydentää SAP R/3 tuotekustannuslaskennan puutteellisuutta.

A game theoretical approach to the algebraic counterpart of the Wagner hierarchy

La hiérarchie de Wagner constitue à ce jour la plus fine classification des langages ω-réguliers. Par ailleurs, l'approche algébrique de la théorie de langages formels montre que ces ensembles ω-réguliers correspondent précisément aux langages reconnaissables par des ω-semigroupes finis pointés. Ce travail s'inscrit dans ce contexte en fournissant une description complète de la contrepartie algébrique de la hiérarchie de Wagner, et ce par le biais de la théorie descriptive des jeux de Wadge. Plus précisément, nous montrons d'abord que le degré de Wagner d'un langage ω-régulier est effectivement un invariant syntaxique. Nous définissons ensuite une relation de réduction entre ω-semigroupes pointés par le biais d'un jeu infini de type Wadge. La collection de ces structures algébriques ordonnée par cette relation apparaît alors comme étant isomorphe à la hiérarchie de Wagner, soit un quasi bon ordre décidable de largeur 2 et de hauteur ω. Nous exposons par la suite une procédure de décidabilité de cette hiérarchie algébrique : on décrit une représentation graphique des ω-semigroupes finis pointés, puis un algorithme sur ces structures graphiques qui calcule le degré de Wagner de n'importe quel élément. Ainsi le degré de Wagner de tout langage ω-régulier peut être calculé de manière effective directement sur son image syntaxique. Nous montrons ensuite comment construire directement et inductivement une structure de n''importe quel degré. Nous terminons par une description détaillée des invariants algébriques qui caractérisent tous les degrés de cette hiérarchie. Abstract The Wagner hierarchy is known so far to be the most refined topological classification of ω-rational languages. Also, the algebraic study of formal languages shows that these ω-rational sets correspond precisely to the languages recognizable by finite pointed ω-semigroups. Within this framework, we provide a construction of the algebraic counterpart of the Wagner hierarchy. We adopt a hierarchical game approach, by translating the Wadge theory from the ω-rational language to the ω-semigroup context. More precisely, we first show that the Wagner degree is indeed a syntactic invariant. We then define a reduction relation on finite pointed ω-semigroups by means of a Wadge-like infinite two-player game. The collection of these algebraic structures ordered by this reduction is then proven to be isomorphic to the Wagner hierarchy, namely a well-founded and decidable partial ordering of width 2 and height $\omega^\omega$. We also describe a decidability procedure of this hierarchy: we introduce a graph representation of finite pointed ω-semigroups allowing to compute their precise Wagner degrees. The Wagner degree of every ω-rational language can therefore be computed directly on its syntactic image. We then show how to build a finite pointed ω-semigroup of any given Wagner degree. We finally describe the algebraic invariants characterizing every Wagner degree of this hierarchy.

Studies on integrating kinematic design method with mechanical systems simulation techniques

Theultimate goal of any research in the mechanism/kinematic/design area may be called predictive design, ie the optimisation of mechanism proportions in the design stage without requiring extensive life and wear testing. This is an ambitious goal and can be realised through development and refinement of numerical (computational) technology in order to facilitate the design analysis and optimisation of complex mechanisms, mechanical components and systems. As a part of the systematic design methodology this thesis concentrates on kinematic synthesis (kinematic design and analysis) methods in the mechanism synthesis process. The main task of kinematic design is to find all possible solutions in the form of structural parameters to accomplish the desired requirements of motion. Main formulations of kinematic design can be broadly divided to exact synthesis and approximate synthesis formulations. The exact synthesis formulation is based in solving n linear or nonlinear equations in n variables and the solutions for the problem areget by adopting closed form classical or modern algebraic solution methods or using numerical solution methods based on the polynomial continuation or homotopy. The approximate synthesis formulations is based on minimising the approximation error by direct optimisation The main drawbacks of exact synthesis formulationare: (ia) limitations of number of design specifications and (iia) failure in handling design constraints- especially inequality constraints. The main drawbacks of approximate synthesis formulations are: (ib) it is difficult to choose a proper initial linkage and (iib) it is hard to find more than one solution. Recentformulations in solving the approximate synthesis problem adopts polynomial continuation providing several solutions, but it can not handle inequality const-raints. Based on the practical design needs the mixed exact-approximate position synthesis with two exact and an unlimited number of approximate positions has also been developed. The solutions space is presented as a ground pivot map but thepole between the exact positions cannot be selected as a ground pivot. In this thesis the exact synthesis problem of planar mechanism is solved by generating all possible solutions for the optimisation process ¿ including solutions in positive dimensional solution sets - within inequality constraints of structural parameters. Through the literature research it is first shown that the algebraic and numerical solution methods ¿ used in the research area of computational kinematics ¿ are capable of solving non-parametric algebraic systems of n equations inn variables and cannot handle the singularities associated with positive-dimensional solution sets. In this thesis the problem of positive-dimensional solutionsets is solved adopting the main principles from mathematical research area of algebraic geometry in solving parametric ( in the mathematical sense that all parameter values are considered ¿ including the degenerate cases ¿ for which the system is solvable ) algebraic systems of n equations and at least n+1 variables.Adopting the developed solution method in solving the dyadic equations in direct polynomial form in two- to three-precision-points it has been algebraically proved and numerically demonstrated that the map of the ground pivots is ambiguousand that the singularities associated with positive-dimensional solution sets can be solved. The positive-dimensional solution sets associated with the poles might contain physically meaningful solutions in the form of optimal defectfree mechanisms. Traditionally the mechanism optimisation of hydraulically driven boommechanisms is done at early state of the design process. This will result in optimal component design rather than optimal system level design. Modern mechanismoptimisation at system level demands integration of kinematic design methods with mechanical system simulation techniques. In this thesis a new kinematic design method for hydraulically driven boom mechanism is developed and integrated in mechanical system simulation techniques. The developed kinematic design method is based on the combinations of two-precision-point formulation and on optimisation ( with mathematical programming techniques or adopting optimisation methods based on probability and statistics ) of substructures using calculated criteria from the system level response of multidegree-of-freedom mechanisms. Eg. by adopting the mixed exact-approximate position synthesis in direct optimisation (using mathematical programming techniques) with two exact positions and an unlimitednumber of approximate positions the drawbacks of (ia)-(iib) has been cancelled.The design principles of the developed method are based on the design-tree -approach of the mechanical systems and the design method ¿ in principle ¿ is capable of capturing the interrelationship between kinematic and dynamic synthesis simultaneously when the developed kinematic design method is integrated with the mechanical system simulation techniques.

Automated formulation of optimisation models for steel beam structures

Over 70% of the total costs of an end product are consequences of decisions that are made during the design process. A search for optimal cross-sections will often have only a marginal effect on the amount of material used if the geometry of a structure is fixed and if the cross-sectional characteristics of its elements are property designed by conventional methods. In recent years, optimalgeometry has become a central area of research in the automated design of structures. It is generally accepted that no single optimisation algorithm is suitable for all engineering design problems. An appropriate algorithm, therefore, mustbe selected individually for each optimisation situation. Modelling is the mosttime consuming phase in the optimisation of steel and metal structures. In thisresearch, the goal was to develop a method and computer program, which reduces the modelling and optimisation time for structural design. The program needed anoptimisation algorithm that is suitable for various engineering design problems. Because Finite Element modelling is commonly used in the design of steel and metal structures, the interaction between a finite element tool and optimisation tool needed a practical solution. The developed method and computer programs were tested with standard optimisation tests and practical design optimisation cases. Three generations of computer programs are developed. The programs combine anoptimisation problem modelling tool and FE-modelling program using three alternate methdos. The modelling and optimisation was demonstrated in the design of a new boom construction and steel structures of flat and ridge roofs. This thesis demonstrates that the most time consuming modelling time is significantly reduced. Modelling errors are reduced and the results are more reliable. A new selection rule for the evolution algorithm, which eliminates the need for constraint weight factors is tested with optimisation cases of the steel structures that include hundreds of constraints. It is seen that the tested algorithm can be used nearly as a black box without parameter settings and penalty factors of the constraints.

Dynamic analysis of belt-drives using the absolute nodal coordinate formulation

Belt-drive systems have been and still are the most commonly used power transmission form in various applications of different scale and use. The peculiar features of the dynamics of the belt-drives include highly nonlinear deformation,large rigid body motion, a dynamical contact through a dry friction interface between the belt and pulleys with sticking and slipping zones, cyclic tension of the belt during the operation and creeping of the belt against the pulleys. The life of the belt-drive is critically related on these features, and therefore, amodel which can be used to study the correlations between the initial values and the responses of the belt-drives is a valuable source of information for the development process of the belt-drives. Traditionally, the finite element models of the belt-drives consist of a large number of elements thatmay lead to computational inefficiency. In this research, the beneficial features of the absolute nodal coordinate formulation are utilized in the modeling of the belt-drives in order to fulfill the following requirements for the successful and efficient analysis of the belt-drive systems: the exact modeling of the rigid body inertia during an arbitrary rigid body motion, the consideration of theeffect of the shear deformation, the exact description of the highly nonlinear deformations and a simple and realistic description of the contact. The use of distributed contact forces and high order beam and plate elements based on the absolute nodal coordinate formulation are applied to the modeling of the belt-drives in two- and three-dimensional cases. According to the numerical results, a realistic behavior of the belt-drives can be obtained with a significantly smaller number of elements and degrees of freedom in comparison to the previously published finite element models of belt-drives. The results of theexamples demonstrate the functionality and suitability of the absolute nodal coordinate formulation for the computationally efficient and realistic modeling ofbelt-drives. This study also introduces an approach to avoid the problems related to the use of the continuum mechanics approach in the definition of elastic forces on the absolute nodal coordinate formulation. This approach is applied to a new computationally efficient two-dimensional shear deformable beam element based on the absolute nodal coordinate formulation. The proposed beam element uses a linear displacement field neglecting higher-order terms and a reduced number of nodal coordinates, which leads to fewer degrees of freedom in a finite element.

Database Rights in Safe European Home: The Path to More Rigorous Protection of Information

1. Introduction "The one that has compiled ... a database, the collection, securing the validity or presentation of which has required an essential investment, has the sole right to control the content over the whole work or over either a qualitatively or quantitatively substantial part of the work both by means of reproduction and by making them available to the public", Finnish Copyright Act, section 49.1 These are the laconic words that implemented the much-awaited and hotly debated European Community Directive on the legal protection of databases,2 the EDD, into Finnish Copyright legislation in 1998. Now in the year 2005, after more than half a decade of the domestic implementation it is yet uncertain as to the proper meaning and construction of the convoluted qualitative criteria the current legislation employs as a prerequisite for the database protection both in Finland and within the European Union. Further, this opaque Pan-European instrument has the potential of bringing about a number of far-reaching economic and cultural ramifications, which have remained largely uncharted or unobserved. Thus the task of understanding this particular and currently peculiarly European new intellectual property regime is twofold: first, to understand the mechanics and functioning of the EDD and second, to realise the potential and risks inherent in the new legislation in economic, cultural and societal dimensions. 2. Subject-matter of the study: basic issues The first part of the task mentioned above is straightforward: questions such as what is meant by the key concepts triggering the functioning of the EDD such as presentation of independent information, what constitutes an essential investment in acquiring data and when the reproduction of a given database reaches either qualitatively or quantitatively the threshold of substantiality before the right-holder of a database can avail himself of the remedies provided by the statutory framework remain unclear and call for a careful analysis. As for second task, it is already obvious that the practical importance of the legal protection providedby the database right is in the rapid increase. The accelerating transformationof information into digital form is an existing fact, not merely a reflection of a shape of things to come in the future. To take a simple example, the digitisation of a map, traditionally in paper format and protected by copyright, can provide the consumer a markedly easier and faster access to the wanted material and the price can be, depending on the current state of the marketplace, cheaper than that of the traditional form or even free by means of public lending libraries providing access to the information online. This also renders it possible for authors and publishers to make available and sell their products to markedly larger, international markets while the production and distribution costs can be kept at minimum due to the new electronic production, marketing and distributionmechanisms to mention a few. The troublesome side is for authors and publishers the vastly enhanced potential for illegal copying by electronic means, producing numerous virtually identical copies at speed. The fear of illegal copying canlead to stark technical protection that in turn can dampen down the demand for information goods and services and furthermore, efficiently hamper the right of access to the materials available lawfully in electronic form and thus weaken the possibility of access to information, education and the cultural heritage of anation or nations, a condition precedent for a functioning democracy. 3. Particular issues in Digital Economy and Information Networks All what is said above applies a fortiori to the databases. As a result of the ubiquity of the Internet and the pending breakthrough of Mobile Internet, peer-to-peer Networks, Localand Wide Local Area Networks, a rapidly increasing amount of information not protected by traditional copyright, such as various lists, catalogues and tables,3previously protected partially by the old section 49 of the Finnish Copyright act are available free or for consideration in the Internet, and by the same token importantly, numerous databases are collected in order to enable the marketing, tendering and selling products and services in above mentioned networks. Databases and the information embedded therein constitutes a pivotal element in virtually any commercial operation including product and service development, scientific research and education. A poignant but not instantaneously an obvious example of this is a database consisting of physical coordinates of a certain selected group of customers for marketing purposes through cellular phones, laptops and several handheld or vehicle-based devices connected online. These practical needs call for answer to a plethora of questions already outlined above: Has thecollection and securing the validity of this information required an essential input? What qualifies as a quantitatively or qualitatively significant investment? According to the Directive, the database comprises works, information and other independent materials, which are arranged in systematic or methodical way andare individually accessible by electronic or other means. Under what circumstances then, are the materials regarded as arranged in systematic or methodical way? Only when the protected elements of a database are established, the question concerning the scope of protection becomes acute. In digital context, the traditional notions of reproduction and making available to the public of digital materials seem to fit ill or lead into interpretations that are at variance with analogous domain as regards the lawful and illegal uses of information. This may well interfere with or rework the way in which the commercial and other operators have to establish themselves and function in the existing value networks of information products and services. 4. International sphere After the expiry of the implementation period for the European Community Directive on legal protection of databases, the goals of the Directive must have been consolidated into the domestic legislations of the current twenty-five Member States within the European Union. On one hand, these fundamental questions readily imply that the problemsrelated to correct construction of the Directive underlying the domestic legislation transpire the national boundaries. On the other hand, the disputes arisingon account of the implementation and interpretation of the Directive on the European level attract significance domestically. Consequently, the guidelines on correct interpretation of the Directive importing the practical, business-oriented solutions may well have application on European level. This underlines the exigency for a thorough analysis on the implications of the meaning and potential scope of Database protection in Finland and the European Union. This position hasto be contrasted with the larger, international sphere, which in early 2005 does differ markedly from European Union stance, directly having a negative effect on international trade particularly in digital content. A particular case in point is the USA, a database producer primus inter pares, not at least yet having aSui Generis database regime or its kin, while both the political and academic discourse on the matter abounds. 5. The objectives of the study The above mentioned background with its several open issues calls for the detailed study of thefollowing questions: -What is a database-at-law and when is a database protected by intellectual property rights, particularly by the European database regime?What is the international situation? -How is a database protected and what is its relation with other intellectual property regimes, particularly in the Digital context? -The opportunities and threats provided by current protection to creators, users and the society as a whole, including the commercial and cultural implications? -The difficult question on relation of the Database protection and protection of factual information as such. 6. Dsiposition The Study, in purporting to analyse and cast light on the questions above, is divided into three mainparts. The first part has the purpose of introducing the political and rationalbackground and subsequent legislative evolution path of the European database protection, reflected against the international backdrop on the issue. An introduction to databases, originally a vehicle of modern computing and information andcommunication technology, is also incorporated. The second part sets out the chosen and existing two-tier model of the database protection, reviewing both itscopyright and Sui Generis right facets in detail together with the emergent application of the machinery in real-life societal and particularly commercial context. Furthermore, a general outline of copyright, relevant in context of copyright databases is provided. For purposes of further comparison, a chapter on the precursor of Sui Generi, database right, the Nordic catalogue rule also ensues. The third and final part analyses the positive and negative impact of the database protection system and attempts to scrutinize the implications further in the future with some caveats and tentative recommendations, in particular as regards the convoluted issue concerning the IPR protection of information per se, a new tenet in the domain of copyright and related rights.

A mathematical study of fuzzy logic; an algebraic approach

Fuzzy set theory and Fuzzy logic is studied from a mathematical point of view. The main goal is to investigatecommon mathematical structures in various fuzzy logical inference systems and to establish a general mathematical basis for fuzzy logic when considered as multi-valued logic. The study is composed of six distinct publications. The first paper deals with Mattila'sLPC+Ch Calculus. THis fuzzy inference system is an attempt to introduce linguistic objects to mathematical logic without defining these objects mathematically.LPC+Ch Calculus is analyzed from algebraic point of view and it is demonstratedthat suitable factorization of the set of well formed formulae (in fact, Lindenbaum algebra) leads to a structure called ET-algebra and introduced in the beginning of the paper. On its basis, all the theorems presented by Mattila and many others can be proved in a simple way which is demonstrated in the Lemmas 1 and 2and Propositions 1-3. The conclusion critically discusses some other issues of LPC+Ch Calculus, specially that no formal semantics for it is given.In the second paper the characterization of solvability of the relational equation RoX=T, where R, X, T are fuzzy relations, X the unknown one, and o the minimum-induced composition by Sanchez, is extended to compositions induced by more general products in the general value lattice. Moreover, the procedure also applies to systemsof equations. In the third publication common features in various fuzzy logicalsystems are investigated. It turns out that adjoint couples and residuated lattices are very often present, though not always explicitly expressed. Some minor new results are also proved.The fourth study concerns Novak's paper, in which Novak introduced first-order fuzzy logic and proved, among other things, the semantico-syntactical completeness of this logic. He also demonstrated that the algebra of his logic is a generalized residuated lattice. In proving that the examination of Novak's logic can be reduced to the examination of locally finite MV-algebras.In the fifth paper a multi-valued sentential logic with values of truth in an injective MV-algebra is introduced and the axiomatizability of this logic is proved. The paper developes some ideas of Goguen and generalizes the results of Pavelka on the unit interval. Our proof for the completeness is purely algebraic. A corollary of the Completeness Theorem is that fuzzy logic on the unit interval is semantically complete if, and only if the algebra of the valuesof truth is a complete MV-algebra. The Compactness Theorem holds in our well-defined fuzzy sentential logic, while the Deduction Theorem and the Finiteness Theorem do not. Because of its generality and good-behaviour, MV-valued logic can be regarded as a mathematical basis of fuzzy reasoning. The last paper is a continuation of the fifth study. The semantics and syntax of fuzzy predicate logic with values of truth in ana injective MV-algerba are introduced, and a list of universally valid sentences is established. The system is proved to be semanticallycomplete. This proof is based on an idea utilizing some elementary properties of injective MV-algebras and MV-homomorphisms, and is purely algebraic.

Identifying the Role of Final Consumption in Structural Path Analysis: An Application to Water Uses

The complexity of the connexions within an economic system can only be reliably reflected in academic research if powerful methods are used. Researchers have used Structural Path Analysis (SPA) to capture not only the linkages within the production system but also the propagation of the effects into different channels of impacts. However, the SPA literature has restricted itself to showing the relations among sectors of production, while the connections between these sectors and final consumption have attracted little attention. In order to consider the complete set of channels involved, in this paper we propose a structural path method that endogenously incorporates not only sectors of production but also the final consumption of the economy. The empirical application comprises water usages, and analyses the dissemination of exogenous impacts into various channels of water consumption. The results show that the responsibility for water stress is imputed to different sectors and depends on the hypothesis used for the role played by final consumption in the model. This highlights the importance of consumers’ decisions in the determination of ecological impacts. Keywords: Input-Output Analysis, Structural Path Analysis, Final Consumption, Water uses.

The potential impact of new effervescent alendronate formulation on compliance and persistence in osteoporosis treatment.

Osteoporotic fractures are a public health problem and their incidence and subsequent economic and social costs are expected to rise in the next future. Different drugs have been developed to reduce osteoporosis and the risk of osteoporotic fractures, and among them, antiresorptive agents, and in particular oral alendronate, are the most widely utilized. However, one of the most common problems with antiresorptive drugs is poor adherence to treatment, which is associated with a high fracture incidence and with an increase in hospitalization costs. One of the main reasons of poor adherence to these treatments is the occurrence of adverse events, mainly at gastrointestinal (GI) level, including dyspepsia, dysphagia, and esophageal ulcers. In light of these considerations the aim of this paper is to perform a literature review to show the pathophysiologic bases of GI alendronate-induced adverse events and how new bisphosphonate formulations like effervescent alendronate can improve compliance and persistence to treatment and decrease the fracture rate incidence in osteoporotic patients.

Dendrochronological study of the avalanche path Canal del Roc Roig: first results of the ALUDEX Project in the Pyrenees

Historical data about ancient avalanches are scarce in the Pyrenees. Dendrochronology can provide new data about past avalanches and their return period, but up to now little research has been carried out with this purpose. The Aludex project aims to obtain information about the frequency and extent of extreme avalanches, using a dendrochronological and a nivo-meteorological approach. In this paper, we present the results of a dendrochronological study of the Canal del Roc Roig avalanche path which was affected by two extreme avalanches in February 1996. This first dendrochronological study has permitted us to assess the tree-ring signals due to avalanche events in 53 out of 132 dated trees. The trees presented a variety of responses to the 1996 avalanche events. It is shown that the type of tree-ring signal depends on tree age. The methodology has proved successful in detecting the 1996 and 1972 documented avalanche events, and provided outstanding evidence of undocumented past events such as one in 1930.

Synthesis of triheptanoin and formulation as a solid diet for rodents

Triheptanoin-enriched diets have been successfully used in the experimental treatment of various metabolic disorders. Maximal therapeutic effect is achieved in the context of a ketogenic diet where triheptanoin oil provides 30-40% of the daily caloric intake. However, pre-clinical studies using triheptanoin-rich diets are hindered by the difficulty of administering to laboratory animals as a solid foodstuff. In the present study, we successfully synthesized triheptanoin to the highest standards of purity from glycerol and heptanoic acid, using sulfonated charcoal as a catalyst. Triheptanoin oil was then formulated as a solid, stable and palatable preparation using a ketogenic base and a combination of four commercially available formulation agents: hydrophilic fumed silica, hydrophobic fumed silica, microcrystalline cellulose, and talc. Diet compliance and safety was tested on C57Bl/6 mice over a 15-week period, comparing overall status and body weight change. Practical applications: This work provides a complete description of (i) an efficient and cost-effective synthesis of triheptanoin and (ii) its formulation as a solid, stable, and palatable ketogenic diet (triheptanoin-rich; 39% of the caloric intake) for rodents. Triheptanoin-rich diets will be helpful on pre-clinical experiments testing the therapeutic efficacy of triheptanoin in different rodent models of human diseases. In addition, using the same solidification procedure, other oils could be incorporated into rodent ketogenic diet to study their dosage and long-term effects on mammal health and development. This approach could be extremely valuable as ketogenic diet is widely used clinically for epilepsy treatment.