Piperidinium derivatives including spectaline and cassine derivatives, pharmaceutic compositions containing the same and preparation process

Disclosed are compounds of formulae (II) and (III), wherein R1 is other than hydrogen and the remaining substituents are as defined in the specification, processes for their preparation and pharmaceutical compositions containing them. The compounds are capable of inhibiting acetylcholinesterase, and are useful in the treatment of pathologies associated with cholinergic transmission, such as memory related disorders, neurodegenerative disorders such as Alzheimer's Disease, Myasthenia Gravis and intoxication induced by chemical agents.

Nanoparticle preparation process using novel microjet reactor technology for enhancing dissolution rates of poorly water soluble drugs

In this study a novel method MicroJet reactor technology was developed to enable the custom preparation of nanoparticles. rnDanazol/HPMCP HP50 and Gliclazide/Eudragit S100 nanoparticles were used as model systems for the investigation of effects of process parameters and microjet reactor setup on the nanoparticle properties during the microjet reactor construction. rnFollowing the feasibility study of the microjet reactor system, three different nanoparticle formulations were prepared using fenofibrate as model drug. Fenofibrate nanoparticles stabilized with poloxamer 407 (FN), fenofibrate nanoparticles in hydroxypropyl methyl cellulose phthalate (HPMCP) matrix (FHN) and fenofibrate nanoparticles in HPMCP and chitosan matrix (FHCN) were prepared under controlled precipitation using MicroJet reactor technology. Particle sizes of all the nanoparticle formulations were adjusted to 200-250 nm. rnThe changes in the experimental parameters altered the system thermodynamics resulting in the production of nanoparticles between 20-1000 nm (PDI<0.2) with high drug loading efficiencies (96.5% in 20:1 polymer:drug ratio).rnDrug releases from all nanoparticle formulations were fast and complete after 15 minutes both in FaSSIF and FeSSIF medium whereas in mucodhesiveness tests, only FHCN formulation was found to be mucoadhesive. Results of the Caco-2 studies revealed that % dose absorbed values were significantly higher (p<0.01) for FHCN in both cases where FaSSIF and FeSSIF were used as transport buffer.rn

Good manufacturing practice-compliant validation and preparation of BM cells for the therapy of acute myocardial infarction

BACKGROUND: Intracoronary application of BM-derived cells for the treatment of acute myocardial infarction (AMI) is currently being studied intensively. Simultaneously, strict legal requirements surround the production of cells for clinical studies. Thus good manufacturing practice (GMP)-compliant collection and preparation of BM for patients with AMI was established by the Cytonet group. METHODS: As well as fulfillment of standard GMP requirements, including a manufacturing license, validation of the preparation process and the final product was performed. Whole blood (n=6) and BM (n=3) validation samples were processed under GMP conditions by gelafundin or hydroxyethylstarch sedimentation in order to reduce erythrocytes/platelets and volume and to achieve specifications defined in advance. Special attention was paid to the free potassium (<6 mmol/L), some rheologically relevant cellular characteristics (hematocrit <0.45, platelets <450 x 10(6)/mL) and the sterility of the final product. RESULTS: The data were reviewed and GMP compliance was confirmed by the German authorities (Paul-Ehrlich Institute). Forty-five BM cell preparations for clinical use were carried out following the validated methodology and standards. Additionally three selections of CD34+ BM cells for infusion were performed. All specification limits were met. Discussion In conclusion, preparation of BM cells for intracoronary application is feasible under GMP conditions. As the results of sterility testing may not be available at the time of intracoronary application, the highest possible standards to avoid bacterial and other contaminations have to be applied. The increased expense of the GMP-compliant process can be justified by higher safety for patients and better control of the final product.

The preparation of carbon fibres: a study of the physics and chemistry of the preparation of carbon fibres from acrylic precursors

High strength, high modulus carbon fibres are becoming increasingly important as high performance engineering materials. This thesis describes how they may be prepared by heat treatment from filaments spun from polyacrylonitrile and its copolymers. The chemistry of the first stages of heat treatment is very important in controlling the mechanical properties of the carbonised product. A cyclisation reaction has been found to be responsible for the relatively high thermal stability of pyrolysed polyacrylonitrile, but without oxidation the fibres degrade and fuse. An initial oxidation stage is, therefore, essential to the preparation of fibre of high orientation. The cyclised product of pyrolysis is probably a poly 1,4 dihydropiridine and oxidation converts this to aromatic structures, and cyclised structures containing carbonyl and other oxygenated groups. Oxidation is found to assist the carbon fibre preparation process, by producing a product which condenses at an earlier stage of heat treatment, before fusion can occur. Carbon fibre strength and modulus are dependent upon producing a highly oriented crystal structure. While oxidation of the polymer stabilises the fibre so as to prevent disorientation, further large increases in orientation, with a commensurate improvement in strength and modulus, can be obtained by stretching at temperatures above 1,700 °C. This process is analogous to the way fibre orientation is increased by the stretching of the precursor. A lamellar graphite structure can be created in high temperature fibre, by carefully controlling the degree of oxidation. This type of graphite can produce very high values of Young's modulus. More often, however, graphite fibre has a fibrillar fine structure, which is explicable in terms of continuous graphite ribbons. A ribbon model is the most satisfactory representation of the structure of carbon fibre, as it explains the mechanism of the development of long range order and the variation of Young's modulus with crystalline preferred orientation.

The New Science Intensive Standard of Master Preparation in Sphere of Competitive Intelligence on the Basis of Systemological Knowledge-Oriented Technologies

Methodological, theoretical and technological bases of the new branch standard of Ukraine higher education which regulates preparation process of masters - professionals in the information area and information analysts are considered. The new systemological knowledge-oriented technologies developed in KNURE which considerably surpass foreign analogues are put as the basis of training.

Measurement Of The Hydrodynamic Radius Of Quantum Dots By Fluorescence Correlation Spectroscopy Excluding Blinking.

One of the most important properties of quantum dots (QDs) is their size. Their size will determine optical properties and in a colloidal medium their range of interaction. The most common techniques used to measure QD size are transmission electron microscopy (TEM) and X-ray diffraction. However, these techniques demand the sample to be dried and under a vacuum. This way any hydrodynamic information is excluded and the preparation process may alter even the size of the QDs. Fluorescence correlation spectroscopy (FCS) is an optical technique with single molecule sensitivity capable of extracting the hydrodynamic radius (HR) of the QDs. The main drawback of FCS is the blinking phenomenon that alters the correlation function implicating in a QD apparent size smaller than it really is. In this work, we developed a method to exclude blinking of the FCS and measured the HR of colloidal QDs. We compared our results with TEM images, and the HR obtained by FCS is higher than the radius measured by TEM. We attribute this difference to the cap layer of the QD that cannot be seen in the TEM images.

Basquetebol

Universidade Estadual de Campinas. Faculdade de Educação Física

A new approach to the granulation of beta-cyclodextrin inclusion complexes

Cyclodextrins (CDs) are annular oligosaccharides containing 6-12 glucose unities joined together by alpha-1,4 bonds. They have a conical-truncated shape with a lipophilic cavity in which different molecules can be included resulting in a stable inclusion complex. The cyclodextrins have been widely applied in pharmaceutical technology with the objective of increasing the solubility, stability and bioavailability of drugs in different pharmaceutical dosage forms, such as tablets. In order to obtain beta-CD tablets, liquid dispersions of drug/beta-CD are usually submitted to different drying processes, like spray-drying, freeze-drying or slow evaporation, being this dry material added to a number of excipients. However, such drying processes can generate particulate materials showing problems of flow and compressibility, needing their conversion into granulates by means of wetting with granulation liquid followed by additional drying. In this work, the main objective was to evaluate the preparation of tablets without the need of this additional drying step. For this purpose an aqueous dispersion containing acetaminophen/beta-CD complex and cornstarch was dried using a spouted bed and the obtained granules were compressed in tablets. Acetaminophen was used as model drug due to its low water solubility and the inexpensive and widely available cornstarch was chosen as excipient. Acetaminophen powder was added into a beta-cyclodextrin solution prepared in distilled water at 70 degrees C. Stirring was kept until this dispersion cooled to room temperature. Then cornstarch was added and the resulting dispersion was dried in spouted bed equipment. This material was compressed into tablets using an Erweka Korsh EKO tablet machine. This innovative approach allowed the tablets preparation process to be carried out with fewer steps and represents a technological reliable strategy to produce beta-cyclodextrin inclusion complexes tablets. (C) 2010 Elsevier By. All rights reserved.

Analysis of acute brain slices by electron microscopy: A correlative light-electron microscopy workflow based on Tokuyasu cryo-sectioning.

Acute brain slices are slices of brain tissue that are kept vital in vitro for further recordings and analyses. This tool is of major importance in neurobiology and allows the study of brain cells such as microglia, astrocytes, neurons and their inter/intracellular communications via ion channels or transporters. In combination with light/fluorescence microscopies, acute brain slices enable the ex vivo analysis of specific cells or groups of cells inside the slice, e.g. astrocytes. To bridge ex vivo knowledge of a cell with its ultrastructure, we developed a correlative microscopy approach for acute brain slices. The workflow begins with sampling of the tissue and precise trimming of a region of interest, which contains GFP-tagged astrocytes that can be visualised by fluorescence microscopy of ultrathin sections. The astrocytes and their surroundings are then analysed by high resolution scanning transmission electron microscopy (STEM). An important aspect of this workflow is the modification of a commercial cryo-ultramicrotome to observe the fluorescent GFP signal during the trimming process. It ensured that sections contained at least one GFP astrocyte. After cryo-sectioning, a map of the GFP-expressing astrocytes is established and transferred to correlation software installed on a focused ion beam scanning electron microscope equipped with a STEM detector. Next, the areas displaying fluorescence are selected for high resolution STEM imaging. An overview area (e.g. a whole mesh of the grid) is imaged with an automated tiling and stitching process. In the final stitched image, the local organisation of the brain tissue can be surveyed or areas of interest can be magnified to observe fine details, e.g. vesicles or gold labels on specific proteins. The robustness of this workflow is contingent on the quality of sample preparation, based on Tokuyasu's protocol. This method results in a reasonable compromise between preservation of morphology and maintenance of antigenicity. Finally, an important feature of this approach is that the fluorescence of the GFP signal is preserved throughout the entire preparation process until the last step before electron microscopy.

Nanomedicines for active targeting: physico-chemical characterization of paclitaxel-loaded anti-HER2 immunonanoparticles and in vitro functional studies on target cells.

Paclitaxel (Tx)-loaded anti-HER2 immunonanoparticles (NPs-Tx-HER) were prepared by the covalent coupling of humanized monoclonal anti-HER2 antibodies (trastuzumab, Herceptin) to Tx-loaded poly (dl-lactic acid) nanoparticles (NPs-Tx) for the active targeting of tumor cells that overexpress HER2 receptors. The physico-chemical properties of NPs-Tx-HER were compared to unloaded immunonanoparticles (NPs-HER) to assess the influence of the drug on anti-HER2 coupling to the NP surface. The immunoreactivity of sulfo-MBS activated anti-HER2 mAbs and the in vitro efficacy of NPs-Tx-HER were tested on SKOV-3 ovarian cancer cells that overexpress HER2 antigens. Tx-loaded nanoparticles (NPs-Tx) obtained by a salting-out method had a size of 171+/-22 nm (P.I.=0.1) and an encapsulation efficiency of about of 78+/-10%, which corresponded to a drug loading of 7.8+/-0.8% (w/w). NPs-Tx were then thiolated and conjugated to activated anti-HER2 mAbs to obtain immunonanoparticles of 237+/-43 nm (P.I.=0.2). The influence of the activation step on the immunoreactivity of the mAbs was tested on SKOV-3 cells using 125I-radiolabeled mAbs, and the activity of the anti-HER2 mAbs was minimally affected after sulfo-MBS functionalization. Approximately 270 molecules of anti-HER2 mAbs were bound per nanoparticle. NPs-Tx-HER exhibited a zeta potential of 0.2+/-0.1 mV. The physico-chemical properties of the Tx-loaded immunonanoparticles were very similar to unloaded immunonanoparticles, suggesting that the encapsulation of the drug did not influence the coupling of the mAbs to the NPs. No drug loss was observed during the preparation process. DSC analysis showed that encapsulated Tx is in an amorphous or disordered-crystalline phase. These results suggest that Tx is entrapped in the polymeric matrix and not adsorbed to the surface of the NPs. In vitro studies on SKOV-3 ovarian cancer cells demonstrated the greater cytotoxic effect of NPs-Tx-HER compared to other Tx formulations. The results showed that at 1 ng Tx/ml, the viability of cells incubated with drug encapsulated in NP-Tx-HER was lower (77.32+/-5.48%) than the viability of cells incubated in NPs-Tx (97.4+/-12%), immunonanoparticles coated with Mabthera, as irrelevant mAb (NPs-Tx-RIT) (93.8+/-12%) or free drug (92.3+/-9.3%).

Developing customer-based e-solutions

Logistiikkapalveluiden markkinat ovat viime vuosina muuttuneet. Kilpailtu toimiala ja asiakasvaatimusten muuttuminen ovat pakottaneet yritykset pyrkimään entistä tehokkaampaan jakeluketjuun. Työn tarkoituksena oli tutkia sähköisten asiakasliittymien toimivuutta asiakkaan näkökulmasta Euro Express tuotannossa ja prosessissa. Tarkoituksena oli selvittää eri sidosryhmien vaatimukset prosessille huomioiden sähköisen liiketoiminnan tuomat edut ja ominaispiirteet. Tavoitteena oli kuvata olemassa oleva prosessi ja tutkia prosessin rajapinnat –asiakas, tuotanto ja ulkoiset sidosryhmät. Tutkielmassa sähköisten ratkaisujen ominaispiirteet on käyty läpi ja tulevaisuuden kehitysnäkökulmista keskusteltu. Kehittyneiden tietoteknisten ratkaisujen avulla jatkuva prosessien uudistaminen (Business Process Reengineering) on mahdollista. Yleisesti epäolennaisuudet asiakasrajapinnassa, informaation kulussa ja yhteyksissä eri järjestelmien välillä aiheuttavat ongelmia sähköisten ratkaisujen toteuttamisessa. Tulevaisuudessa logistiikka yritykset ottavat entistä enemmän käyttöönsä uudenaikaisia teknologisia ratkaisuja tilaukseen, tuotantoon ja asiakaspalveluun. Näiden uudenlaisten ratkaisujen kehittämisestä on hyötyä sekä käyttäjälle että tarjoajalle, mutta ne ovat myös pakollisia palveluntarjoajalle kehittyäkseen markkinoilla. Tulevaisuudessa kilpailun tiivistyessä ja asiakkaiden vaatimusten kasvaessa on kiinnitettävä entistä suurempaa huomiota koko prosessiketjun toimivuuteen. Uudet teknologiset ratkaisut ja niiden käyttäminen tehokkaasti tuovat yrityksille kilpailuetuja, joita ei muuten olisi saavutettavissa.

WorldSkills - ammattitaitovalmennus osana kone- ja metallialan kilpailukykyä

Nykyaikain ammattitaitovalmennus alkaa olla verrattavissa huippu-urheiluun ja sen sisältämiin valmennusprosesseihin. Tämän tutkimuksen tavoitteena oli kartoittaa ne prosessit, joita käyttämällä ammattitaitovalmennettava saadaan tiedollisesti ja taidollisesti mandollisimman hyvin valmennettua WorldSkills-tason kilpailuihin. Valittuja prosesseja soveltaen ohjeistetaan CAD-suunnittelun valmennus ja kokonaisvaltainen valmistautuminen kilpailuihin. Hyvänä taustapohjana on tutkimuksen tekijän omakohtainen osallistuminen Taitaja-2007 kilpailun järjestämiseen lajivastaavana CAD-suunnittelussa. Tutkimuksessa tehtiin myös kartoitus kilpailutoiminnan vaikuttavuudesta ja sen mandollisista vaikutuksista kone- ja metallialan koulutukseen hakeutuvien nuorten määriin. Tutkimuksen pääkohteina olivat Taitaja-kilpailujen järjestäjinä toimineet paikkakunnat ja koulutuksenjärjestäjät peräkkäisiltä vuosilta eli Turku, Tampere ja Joensuu. Tämän lisäksi Helsingissä järjestetty WorldSkills-2005 kilpailu aiheutti positiivisia vaikutuksia koko ammattitaitovalmennuksen kenttään ja sen esille nostamiseen ammatillisessa koulutuksessa. Näitä tietoja ja prosesseja voidaan käyttää hyväksi ammattitaitovalmennuksen kanssa toimivien oppilaitoksien, työpaikkojen ja valmentajien sekä muiden asiasta kiinnostuneiden tahojen jatkossa tehtävään valmennukseen liittyvään kehitystyöhön.

Influência do agente precipitante na preparação do óxido de nióbio (V) hidratado pelo método da precipitação em solução homogênea

This work reports the preparation, characterization and study of the ion exchange behavior of hydrous niobium oxide prepared by a homogeneous precipitation method. The precipitating agent was obtained in aqueous solution by thermal decomposition of urea or ammonium carbonate. The compounds were chemically and physically characterized by X-ray diffractometry, thermal analysis (TG/DTG), surface area measurements and ion exchange behavior with sodium. The materials prepared with ammonium carbonate presented a higher degree of crystallinity and better ion exchange capacity with sodium than materials prepared with urea. In the homogeneous precipitation method, materials were obtained with specific surface area of 123 - 224 m² g-1. A variation of the preparation process produced hydrous niobium oxide with a different degree of hydration and specific surface area. This provided materials with different physico-chemical properties.

Sukupolvenvaihdoksen toteuttaminen henkilöyhtiössä

Tutkielma on kvalitatiivinen tutkimus, jossa pääpaino perustuu kirjallisuus- ja oikeustapaustutkimukseen. Tutkielman tavoitteena on selvittää henkilöyhtiön sukupolvenvaihdoksen toteuttamisen vaihtoehdot sekä henkilöyhtiön yhtiöosuuksien luovutuksena että yhtiömuodon muutoksella, jolloin henkilöyhtiö muutetaan ensin osakeyhtiöksi ja sen jälkeen osakeyhtiö voi jakautua. Perheyrityksen sukupolvenvaihdoksen ja siihen liittyvien veroseuraamusten optimointi edellyttää suunnitelmallista prosessia, missä otetaan huomioon eri toteutusvaihtoehtojen verotuksellinen kohtelu sekä luopujien että jatkajien kannalta. Perheen sisällä tapahtuvat sukupolvenvaihdokset tapahtuvat useimmiten lahjana tai lahjanluonteisena kauppana, jolloin perintö- ja lahjaverotus on tarpeen ottaa huomioon jo suunnitteluvaiheessa. Yritysvarallisuuden arvostaminen perintö- ja lahjaverotuksessa sekä sukupolvenvaihdoksen yhteydessä saatavat verohuojennukset ja niiden huomioon ottaminen ovat tärkeitä tekijöitä. Tutkielman case- yrityksessä luopujien ja jatkajien tarpeet huomioiden yhtiömuodon muutos ja jakautuminen voitiin todeta kannattavimmaksi vaihtoehdoksi.

Sotilaspolitiikka Kremlin Olympoksella. Venäjän sotilasreformin diskursiivinen rakentuminen venäläisessä sanomalehdistössä 2008–2012

Tutkimus käsittelee venäläisessä sanomalehdistössä esiintyvää keskustelua Venäjän sotilasreformista. Tutkimuksessa haluttiin selvittää, millaisia diskursseja keskustelussa käytetään sotilasreformin oikeuttamiseksi ja miten ne toimivat vallankäytön välineenä. Tutkimus on monitieteinen. Se antaa vastauksia kielitieteellisessä kehyksessä kielen ja diskurssin roolista päätöksenteossa, yhteiskuntatieteellisessä kehyksessä venäläisestä mediasta ja päätöksentekojärjestelmästä sekä sotatieteellisessä kehyksessä asevoimien kehityksestä ja sotilaspolitiikasta. Tutkimuksen primääriaineisto muodostuu 220 artikkelista, jotka kerättiin yhdeksästä venäläisestä sanomalehdestä vuosien 2008–2012 ajalta. Venäjän johtohenkilöt ja heitä tukevat sanomalehdet oikeuttivat sotilasreformia julkisessa keskustelussa ensisijaisesti viiden syyn avulla: uhkien lisääntymisellä, sodan kuvan muutoksella, asevoimien kalustollisella ja toiminnallisella jälkeenjääneisyydellä, henkilöstön osaamisen alhaisella tasolla ja tarpeella toiminnan järkeistykseen. Sotilasreformin päätöksiä oikeutettiin vetoamalla niiden huolelliseen suunnitteluun, henkilöstön asialliseen kohteluun ja taloudellisten asioiden vakauteen. Sanomalehdistössä esiintyi paljon toisistaan poikkeavia näkemyksiä kehitykseen tarvittavasta suunnasta. Suurin osa kritisoivista diskursseista keskittyi kritisoimaan reformin toteutusta, ei sen olemassaoloa. Kritiikki keskittyi tiedotuksen ja demokraattisen päätöksenteon puutteeseen sekä epäilyksiin reformin valmisteluprosessista. Venäjän asevoimia ja sotilaspolitiikkaa koskevaa uutisointia on ongelmallista tarkastella ilman diskurssikäytäntöjen huomiointia. Venäjän johdon ja sen legitimiteettiä vahvistavien sanomalehtien diskursiivisen vallankäytön tavoitteena on saada Venäjä näyttämään todellisuutta vahvemmalta ja yhtenäisemmältä. Vaikka venäläinen media ja siinä etenkin televisio ei ole vapaata, sanomalehdistö on verrattain hyvä tiedonlähde. Sen varsin monipuolinen omistajuus tutkimusaineiston rajauksen aikana mahdollisti erilaisten näkökulmien esillepääsyn. Analyyttisimmin sotilasreformista uutisoivat ne sanomalehdet, jotka eivät nähneet länsimaita Venäjän uhkana ja representoivat diskursseissaan liberalistisia arvoja kuten avoimuutta ja demokratiaa. Sanomalehdistön vaatimaton rooli venäläisessä mediakentässä heikentää kuitenkin sen vaikuttavuutta yleiseen mielipiteeseen. Sanomalehtien diskurssikäytäntöjen analysointi ideologioiden ja vallankäytön kautta voi tarjota mahdollisuuksia parantaa venäläisen valtionjohdon päätösten ennustettavuutta.