An integrated pharmacokinetic and pharmacodynamic study of a new drug of abuse, methylone, a synthetic cathinone sold as 'bath salts'

Material and methods. Methylone was administered to male Sprague-Dawley rats intravenously (10 mg/kg) and orally (15 and 30 mg/kg). Plasma concentrations and metabolites were characterized by LC/MS and LC-MS/MS fragmentation patterns. Locomotor activity was monitored for 180-240 min. Results. Oral administration of methylone induced a dose-dependent increase in locomotor activity in rats. The plasma concentrations after i.v. administration were described by a two-compartment model with distribution and terminal elimination phases of α = 1.95 h− 1 and β = 0.72 h− 1. For oral administration, peak methylone concentrations were achieved between 0.5 and 1 h and fitted to a flip-flop model. Absolute bioavailability was about 80% and the percentage of methylone protein binding was of 30%. A relationship between methylone brain levels and free plasma concentration yielded a ratio of 1.42 ± 0.06, indicating access to the central nervous system. We have identified four Phase I metabolites after oral administration. The major metabolic routes are N-demethylation, aliphatic hydroxylation and O-methylation of a demethylenate intermediate. Discussion. Pharmacokinetic and pharmacodynamic analysis of methylone showed a correlation between plasma concentrations and enhancement of the locomotor activity. A contribution of metabolites in the activity of methylone after oral administration is suggested. Present results will be helpful to understand the time course of the effects of this drug of abuse in humans.

Education and Training in Forensic Intelligence: a New Challenge

From recent calls for positioning forensic scientists within the criminal justice system, but also policing and intelligence missions, this paper emphasizes the need for the development of educational and training programs in the area of forensic intelligence, It is argued that an imbalance exists between perceived and actual understanding of forensic intelligence by police and forensic science managers, and that this imbalance can only be overcome through education. The challenge for forensic intelligence education and training is therefore to devise programs that increase forensic intelligence awareness, firstly for managers to help prevent poor decisions on how to develop information processing. Two recent European courses are presented as examples of education offerings, along with lessons learned and suggested paths forward. It is concluded that the new focus on forensic intelligence could restore a pro-active approach to forensic science, better quantify its efficiency and let it get more involved in investigative and managerial decisions. A new educational challenge is opened to forensic science university programs around the world: to refocus criminal trace analysis on a more holistic security problem solving approach.

An integrated pharmacokinetic and pharmacodynamic study of a new drug of abuse, methylone, a synthetic cathinone sold as 'bath salts'

Material and methods. Methylone was administered to male Sprague-Dawley rats intravenously (10 mg/kg) and orally (15 and 30 mg/kg). Plasma concentrations and metabolites were characterized by LC/MS and LC-MS/MS fragmentation patterns. Locomotor activity was monitored for 180-240 min. Results. Oral administration of methylone induced a dose-dependent increase in locomotor activity in rats. The plasma concentrations after i.v. administration were described by a two-compartment model with distribution and terminal elimination phases of α = 1.95 h− 1 and β = 0.72 h− 1. For oral administration, peak methylone concentrations were achieved between 0.5 and 1 h and fitted to a flip-flop model. Absolute bioavailability was about 80% and the percentage of methylone protein binding was of 30%. A relationship between methylone brain levels and free plasma concentration yielded a ratio of 1.42 ± 0.06, indicating access to the central nervous system. We have identified four Phase I metabolites after oral administration. The major metabolic routes are N-demethylation, aliphatic hydroxylation and O-methylation of a demethylenate intermediate. Discussion. Pharmacokinetic and pharmacodynamic analysis of methylone showed a correlation between plasma concentrations and enhancement of the locomotor activity. A contribution of metabolites in the activity of methylone after oral administration is suggested. Present results will be helpful to understand the time course of the effects of this drug of abuse in humans.

Adaptive Protocol Stacks for Mobile Devices

Tulevaisuudessa siirrettävät laitteet, kuten matkapuhelimet ja kämmenmikrot, pystyvät muodostamaan verkkoyhteyden käyttäen erilaisia yhteysmenetelmiä eri tilanteissa. Yhteysmenetelmillä on toisistaan poikkeavat viestintäominaisuudet mm. latenssin, kaistanleveyden, virhemäärän yms. suhteen. Langattomille yhteysmenetelmille on myös ominaista tietoliikenneyhteyden ominaisuuksien voimakas muuttuminen ympäristön suhteen. Parhaan suorituskyvyn ja käytettävyyden saavuttamiseksi, on siirrettävän laitteen pystyttävä mukautumaan käytettyyn viestintämenetelmään ja viestintäympäristössä tapahtuviin muutoksiin. Olennainen osa tietoliikenteessä ovat protokollapinot, jotka mahdollistavat tietoliikenneyhteyden järjestelmien välillä tarjoten verkkopalveluita päätelaitteen käyttäjäsovelluksille. Jotta protokollapinot pystyisivät mukautumaan tietyn viestintäympäristön ominaisuuksiin, on protokollapinon käyttäytymistä pystyttävä muuttamaan ajonaikaisesti. Perinteisesti protokollapinot ovat kuitenkin rakennettu muuttumattomiksi niin, että mukautuminen tässä laajuudessa on erittäin vaikeaa toteuttaa, ellei jopa mahdotonta. Tämä diplomityö käsittelee mukautuvien protokollapinojen rakentamista käyttäen komponenttipohjaista ohjelmistokehystä joka mahdollistaa protokollapinojen ajonaikaisen muuttamisen. Toteuttamalla esimerkkijärjestelmän, ja mittaamalla sen suorituskykyä vaihtelevassa tietoliikenneympäristössä, osoitamme, että mukautuvat protokollapinot ovat mahdollisia rakentaa ja ne tarjoavat merkittäviä etuja erityisesti tulevaisuuden siirrettävissä laitteissa.

Training primary care physicians in shared decision making for colorectal cancer screening : Insights from the first statewide colorectal cancer screening program in Switzerland

Background: The State of Vaud has launched the first population-based, organized, colorectal cancer screening program in Switzerland for the population aged 50 to 69. Each primary care physician (PCP) has been invited to participate in an interactive session preparing them to enroll patients in the screening program. We aimed at testing the impact of an interactive seminar for PCPs on their intention to discuss the options of no screening, screening with the fecal-immunological test (FIT) and colonoscopy. We measured attitude, intentions and knowledge through questionnaires filled by PCPs before and after a 2.5 hour-long interactive seminar. The main outcome was the proportion of physicians foreseeing to offer coloscopy vs FIT on an equal basis. Physicians estimated the proportion of their patients prescribed a fecal occult blood test (FOBT) vs coloscopy over the months before the seminar and after the interactive seminar. We used a clinical vignette to test for knowledge about screening indications. The interactive seminar included powerpoint presentations with quizzes and clickers, an 8-minute video presenting a shared decision making (SDM) consultation around CRC screening and distribution of educational materials such as a SDM decision aid and background epidemiological information.

The Total Deviation Index estimated by Tolerance Intervals to evaluate the concordance of measurement devices

Background In an agreement assay, it is of interest to evaluate the degree of agreement between the different methods (devices, instruments or observers) used to measure the same characteristic. We propose in this study a technical simplification for inference about the total deviation index (TDI) estimate to assess agreement between two devices of normally-distributed measurements and describe its utility to evaluate inter- and intra-rater agreement if more than one reading per subject is available for each device. Methods We propose to estimate the TDI by constructing a probability interval of the difference in paired measurements between devices, and thereafter, we derive a tolerance interval (TI) procedure as a natural way to make inferences about probability limit estimates. We also describe how the proposed method can be used to compute bounds of the coverage probability. Results The approach is illustrated in a real case example where the agreement between two instruments, a handle mercury sphygmomanometer device and an OMRON 711 automatic device, is assessed in a sample of 384 subjects where measures of systolic blood pressure were taken twice by each device. A simulation study procedure is implemented to evaluate and compare the accuracy of the approach to two already established methods, showing that the TI approximation produces accurate empirical confidence levels which are reasonably close to the nominal confidence level. Conclusions The method proposed is straightforward since the TDI estimate is derived directly from a probability interval of a normally-distributed variable in its original scale, without further transformations. Thereafter, a natural way of making inferences about this estimate is to derive the appropriate TI. Constructions of TI based on normal populations are implemented in most standard statistical packages, thus making it simpler for any practitioner to implement our proposal to assess agreement.

Reusable Bluetooth Networking Component for Symbian Operating System

Tässä diplomityössä käsitellään eri näkökulmia ohjelmistojen uudelleenkäyttöön sekä esitellään perustiedot langattomiin laitteisiin käytettävästä Symbian-käyttöjärjestelmästä ja langattomasta Bluetooth-teknologiasta. Työn käytännön osuudessa suunniteltiin ja toteutettiin uudelleenkäytettävä Bluetooth-ohjelmistokomponentti Symbiankäyttöjärjestelmälle. Ohjelmistojen uudelleenkäytön edut ovat erittäin selkeitä. Uudelleenkäytettävät ohjelmistokomponentit parantavat ohjelmiston laatua ja suorituskykyä. Ohjelmistotuotteiden tuotekehityssykliä voidaan lyhentää merkittävästi ja kehitystyön kokonaiskustannuksia voidaan alentaa tehokkaalla uudelleenkäyttöohjelmalla. Kuitenkin uudelleenkäytöllä on myös esteitä, esimerkkeinä näistä ovat mm. resurssien puute, koulutus sekä uudelleenkäytön vastaiset asenteet. Bluetooth-teknologia on kypsynyt viimeisen kahden vuoden aikana, kun markkinoille on tullut yhä enemmän Bluetooth-laitteita ja niitä käyttäviä sovelluksia. Kehitetty komponentti tarjoaa perustoiminnallisuudet Bluetooth-yhteyksien muodostamiselle ja datan siirtämiselle laitteiden välillä.

Context-based services for mobile devices

The subject of this master’s thesis was developing a context-based reminder service for mobile devices. Possible sources of context were identified and analyzed. One such source is geographical location obtained via a GPS receiver. These receivers consume a lot of power and techniques and algorithms for reducing power consumptions were proposed and analyzed. The service was implemented as an application on a series 60 mobile phone. The application requirements, user interface and architecture are presented. The end-user experiences are discussed and possible future development and research areas are presented.

Presenting HTML Content Using Mobile Devices

Tämä diplomityö käsittelee HTML-sivujen näyttämistä käytettävästi mobiililla päätelaitteella. Tutkimuskohteena on sivujen käytettävyyden parantaminen mobiilissa internetselaimessa. Diplomityössä esitetään havaittuja käytettävyysongelmia ja pohditaan ratkaisuja näihin selaimessa. Teoriataustaa tarkastellaan useista käytettävyyden näkökulmista, käyttäen apuna tutkimuksia ja teorioita. Tutkimuksiin ja teorioihin perustuen suunnitellaan selaimessa tapahtuvat muutokset, jotka mahdollistaisivat sivujen hyvän käytettävyyden. Tutkimusainestoa kerättiin aikaisimmista käytettävyystutkimuksista, suosituksista sekä tieteellisistä analyyseistä. Tarkastelun kohteena olivat myös nykyisten mobiilien internetselainten käyttämät ratkaisut havaittuihin käytettävyysongelmiin. Työn tuloksena esitetään mobiiliin selaimeen toteutettavat sääntöjoukot, jotka muovaisivat HTML-sivut käytettäväksi päätelaitteelle. Ratkaisuna annetaan ehdotuksia sisällön esittämistavalle ja pohditaan näissä syntyneitä ongelmia. Tulevaisuudessa kun sääntöjoukko on toteutettu selaimeen sillä suoritetaan käytettävyystestaukset.

Positioning Wireless Mobile Terminal Devices

Positioning techniques enable the positioning of mobile transportation vehicles. Location information can be used in transport planning as well as in vehicles. Information can also be transferred between vehicles and transport planning. For example, pickup and delivery information and route instructions can be exchanged wirelessly. In this thesis, techniques suitable for positioning vehicles are studied, as well as techniques enabling wireless connectivity of the vehicles to the transport planning system. A prototype based on one positioning and connectivity technique is implemented. As a result, a system capable of positioning vehicles is created. The vehicles can be located almost in real-time. The accuracy in positioning is sufficient to visualise the locations on a good quality 1:20000 city map.

Remote File Access with Wireless Symbian Devices

Erilaisten langattomien päätelaitteiden kuten älypuhelimien ja kommunikaattoreiden määrän lisääntyessä myös kiinnostus liikkuville käyttäjille lisäarvoa tuottavia verkkopalveluita ja -sovelluksia kohtaan kasvaa. Työn tarkoituksena oli tutkia kuinka langattomat Symbianin käyttöjärjestelmää käyttävät laitteet voivat hyödyntää verkkotiedostoja. Työssä arvioitiin eri tiedostojenjakoprotokollien käytettävyyttä langattomissa verkoissa, määriteltiin etätiedostoyhteyden Symbian-alustalle tarjoavan ohjelmiston vaatimukset ja tehtiin alustava suunnitelma ohjelmiston toteuttamiseksi. Läpinäkyvä tiedostojen etäkäyttö vaatii tiedostojenjakoprotokollan toteuttamista sovelluksille yhteisen tiedostosaantimekanismin alle. Tiedostojen etäkäyttö voi perustua eri tiedostojenjakoprotokolliin kuten IP:n päällä toimiviin NFS:ään tai CIFS:ään. Langattomuuden aiheuttamat rajoitukset laitteissa ja tiedonsiirrossa saattavat vähentää sovellutuksen käytettävyyttä ja on huomioitava ohjelmistoa toteutettaessa. Symbian-alusta perustuu asiakas-palvelin arkkitehtuuriin, jossa asiakassovellukset käyttävät tiedostopalveluita yhteisen tiedostopalvelimen kautta. Etätiedostoyhteys on mahdollista toteuttaa liittämällä uusi kirjastomoduuli tiedostopalvelimeen. Protokollan toteuttavan moduulin on muunnettava protokollan viestit tiedostopalvelimelle sopiviksi huolehtien samalla muista samanaikaisista tiedostotapahtumista. Suunniteltu moduulin arkkitehtuuri mahdollistaa eri protokollavaihtoehtojen käyttämisen etätiedostoyhteyden toteuttamiseen.

Dynamic single cell measurements of kinase activity by synthetic kinase activity relocation sensors.

BACKGROUND: Mitogen activated protein kinases (MAPK) play an essential role in integrating extra-cellular signals and intra-cellular cues to allow cells to grow, adapt to stresses, or undergo apoptosis. Budding yeast serves as a powerful system to understand the fundamental regulatory mechanisms that allow these pathways to combine multiple signals and deliver an appropriate response. To fully comprehend the variability and dynamics of these signaling cascades, dynamic and quantitative single cell measurements are required. Microscopy is an ideal technique to obtain these data; however, novel assays have to be developed to measure the activity of these cascades. RESULTS: We have generated fluorescent biosensors that allow the real-time measurement of kinase activity at the single cell level. Here, synthetic MAPK substrates were engineered to undergo nuclear-to-cytoplasmic relocation upon phosphorylation of a nuclear localization sequence. Combination of fluorescence microscopy and automated image analysis allows the quantification of the dynamics of kinase activity in hundreds of single cells. A large heterogeneity in the dynamics of MAPK activity between individual cells was measured. The variability in the mating pathway can be accounted for by differences in cell cycle stage, while, in the cell wall integrity pathway, the response to cell wall stress is independent of cell cycle stage. CONCLUSIONS: These synthetic kinase activity relocation sensors allow the quantification of kinase activity in live single cells. The modularity of the architecture of these reporters will allow their application in many other signaling cascades. These measurements will allow to uncover new dynamic behaviour that previously could not be observed in population level measurements.

A copula-based method for synthetic microarray data generation

In this work, we propose a copula-based method to generate synthetic gene expression data that account for marginal and joint probability distributions features captured from real data. Our method allows us to implant significant genes in the synthetic dataset in a controlled manner, giving the possibility of testing new detection algorithms under more realistic environments.

Consensus recommendations on training and competing in the heat.

Exercising in the heat induces thermoregulatory and other physiological strain that can lead to impairments in endurance exercise capacity. The purpose of this consensus statement is to provide up-to-date recommendations to optimise performance during sporting activities undertaken in hot ambient conditions. The most important intervention one can adopt to reduce physiological strain and optimise performance is to heat acclimatise. Heat acclimatisation should comprise repeated exercise-heat exposures over 1-2 weeks. In addition, athletes should initiate competition and training in a euhydrated state and minimise dehydration during exercise. Following the development of commercial cooling systems (eg, cooling-vest), athletes can implement cooling strategies to facilitate heat loss or increase heat storage capacity before training or competing in the heat. Moreover, event organisers should plan for large shaded areas, along with cooling and rehydration facilities, and schedule events in accordance with minimising the health risks of athletes, especially in mass participation events and during the first hot days of the year. Following the recent examples of the 2008 Olympics and the 2014 FIFA World Cup, sport governing bodies should consider allowing additional (or longer) recovery periods between and during events, for hydration and body cooling opportunities, when competitions are held in the heat.