Yes / Descending kerbs during locomotion involves the regulation of appropriate foot placement before the kerb-edge and foot clearance over it. It also involves the modulation of gait output to ensure the body-mass is safely and smoothly lowered to the new level. Previous research has shown that vision is used in such adaptive gait tasks for feedforward planning, with vision from the lower visual field (lvf) used for online updating. The present study determined when lvf information is used to control/update locomotion when stepping from a kerb. Methodology/Principal Findings: 12 young adults stepped down a kerb during ongoing gait. Force sensitive resistors (attached to participants' feet) interfaced with an high-speed PDLC 'smart glass' sheet, allowed the lvf to be unpredictably occluded at either heel-contact of the penultimate or final step before the kerb-edge up to contact with the lower level. Analysis focussed on determining changes in foot placement distance before the kerb-edge, clearance over it, and in kinematic measures of the step down. Lvf occlusion from the instant of final step contact had no significant effect on any dependant variable (p>0.09). Occlusion of the lvf from the instant of penultimate step contact had a significant effect on foot clearance and on several kinematic measures, with findings consistent with participants becoming uncertain regarding relative horizontal location of the kerb-edge. Conclusion/Significance: These findings suggest concurrent feedback of the lower limb, kerb-edge, and/or floor area immediately in front/below the kerb is not used when stepping from a kerb during ongoing gait. Instead heel-clearance and pre-landing-kinematic parameters are determined/planned using lvf information acquired in the penultimate step during the approach to the kerb-edge, with information related to foot placement before the kerb-edge being the most salient.

No / Hypoxia in tumours is known to cause resistance to conventional chemotherapeutic drugs. In contrast, little is known about the effects of hypoxia on targeted anti-cancer drugs. This study evaluated the effect of hypoxia on a series of clinically approved tyrosine kinase inhibitors (TKIs). EXPERIMENTAL APPROACH: The effect of hypoxia (0.1% oxygen) on the activity of conventional cytotoxic drugs (5-fluorouracil, doxorubicin and vinblastine), the hypoxia-activated prodrug tirapazamine and 9 TKIs was determined in a panel of cell lines. Where hypoxia had a marked effect on chemosensitivity, Western blot analysis was conducted to determine the effect of hypoxia on target expression and the effect of TKIs on cell signalling response under aerobic and hypoxic conditions. KEY RESULTS: Three patterns of chemosensitivity were observed: resistance under hypoxia, equitoxic activity against hypoxic and aerobic cells, and preferential cytotoxicity to hypoxic cells. Significant hypoxia selectivity (independent of HIF1) was observed in the case of dasatinib and this correlated with the ability of dasatinib to inhibit phosphorylation of Src at tyrosine 530. Sorafenib was significantly less effective under hypoxic conditions but resistance did not correlate with hypoxia-induced changes in Raf/MEK/ERK signalling. CONCLUSIONS AND IMPLICATIONS: Hypoxia influences the activity of TKIs but in contrast to conventional cytotoxic drugs, preferential activity against hypoxic cells can occur. The search for hypoxia-targeted therapies has been long and fruitless and this study suggests that some clinically approved TKIs could preferentially target the hypoxic fraction of some tumour types.

No / The subjective psychological experience of people with moderate to severe dementia living in residential care is insufficiently understood. In the present study we aimed to explore the subjective experience of life with dementia in residential care from the perspective of the person with dementia, and to understand the psychological impact of being in this situation. Design and Methods: This was an exploratory qualitative study. Eighty individuals with dementia who were living in residential care homes engaged in unstructured conversations with a researcher. We subjected the transcripts of the resultant 304 conversations to interpretative phenomenological analysis in order to develop a thematic account. Results: The experience of living with dementia in residential care was fundamentally one of experiencing difficult and distressing emotions relating to loss, isolation, uncertainty, fear, and a sense of worthlessness. Participants generally tried to cope by accepting and making the best of things and affirming their past sense of self and identity, but some also expressed frustration and anger. Implications: Participants were able to describe aspects of their situation and their emotional response to it, grounded in a strong retained sense of self and identity. The participants' experience emphasizes the importance of improving the living situation of elders with dementia in residential care settings.

Sammanfattning För att underlätta gränsöverskridande transaktioner ingår stater idag internationella överenskommelser av olika slag. Traktat som de även kallas utgör en del av folkrätten och är reglerade i Wienkonventionen om traktaträtten från 1969. En av de vanligaste formerna av traktat är idag dubbelbeskattningsavtal vilka huvudsakligen syftar till att fördela beskattningsrätt mellan stater för att undvika en dubbelbeskattningssituation. Sveriges dubbelbeskattningsavtal inkorporeras i intern rätt vilket ger uttryck för det dualistiska synsättet.  Inom folkrätten är principen att avtal ska hållas en viktig grundsats som kommer till uttryck i artikel 26 Wienkonventionen. Wienkonventionens artikel 27 stadgar vidare att en part inte kan åberopa sin interna rätt som grund för sin underlåtenhet att fullgöra ett avtal. Likväl väljer vissa stater att ge den interna rätten företräde vid en kollision och detta ses således som ett avtalsbrott, en tax treaty override enligt folkrätten. Att en nationell domstol åsidosätter bestämmelser i ett dubbelbeskattningsavtal har en negativ effekt på det inhemska såväl som det internationella skattesystemet, vilket oundvikligen leder till en osäkerhet för skattskyldiga. HFD meddelade 2008 en dom som utgjorde en treaty override. Domen ledde till många debatter och allt tyder på att det var ett misstag från HFD:s sida. Då HFD endast två år senare meddelade en dom med motsatt utfall uppkommer fråga hur förhållandet mellan dubbelbeskattningsavtal och svensk rätt egentligen ser ut idag samt vilka konsekvenser HFD:s motsägelsefulla domar kan leda till. Risk för att andra nationer kommer avstå från att ingå dubbelbeskattningsavtal med Sverige uppkommer då det föreligger en osäkerhet om Sverige har för avsikt att följa ingångna avtal då stater ingår bilaterala avtal baserat på en tilltro till motpartens ambitioner och vilja att leva upp till sina åtaganden.

A proteína APE1 (do inglêsApurinic/Apyrimidinicendonuclease 1/ Redox Factor-1 - APE1/REF-1) é uma enzima multifuncional, cuja expressão encontra-se frequentemente aumentada em gliomas. Além de apresentar atividade no reparo por excisão de base (BER), o gene APE1 também atua como fator de redução, mantendo fatores de transcrição (FTs) em um estado reduzido ativo. A via BER de reparo do DNA tem sido apontada como um possível fator de resistência a terapias baseadas no uso de agentes alquilantes, tais como temozolomida (TMZ). No presente trabalho, utilizou-se a estratégia de inibição da transcrição do gene APE1 pelo método de RNA interferente(siRNA) e tratamento com a droga TMZ nas células de glioblastoma (GBM), T98G (resistente à TMZ) e U87MG (sensível à TMZ), a fim de verificar a influência do silenciamento do gene APE1 sobre as respostas celulares à droga avaliadas por vários ensaios, bem como os efeitos sobre a expressão transcricional dos genes alvos dos FTs regulados por APE1. O silenciamento de APE1 e o tratamento das células T98G com a TMZ foram eficazes no sentido de reduzir a proliferação e a capacidade clonogênica, além de intervir na progressão do ciclo celular com bloqueio na fase S. Tais efeitos foram acompanhados pelo aumento da indução de danos no DNA e da expressão de H2AX fosforilada (H2AX), o que justifica a queda na sobrevivência celular. O mesmo efeito não foi observado nas células U87MG silenciadas para APE1 e tratadas com a TMZ, havendo o predomínio dos efeitos causados pela TMZ, exceto por uma leve indução de danos no DNA e de H2AX. Adicionalmente, nas células T98G silenciadas e tratadas, verificou-se uma moderada indução de apoptose, que foi observada ao longo dos tempos avaliados (1 a 10 dias), com uma leve indução de caspase-3 (5 dias); nessas células, observou-se também a indução (3,8 vezes) de morte celular autofágica (5 dias). Entretanto, nas células U87MG,a indução de apoptose foi baixa e não houve indução de morte por autofagia, sugerindo outros mecanismos de morte envolvidos na eliminação dessas células em resposta ao tratamento com a TMZ. O silenciamento de APE1 causou uma redução acentuada na invasão das células T98G, de forma similar à observada nas células somente tratadas com a TMZ, sendo que a combinação (silenciamento de APE1 e tratamento com a droga) resultou em um efeito aditivo, enquanto que nas células U87MG a combinação foi eficaz no sentido de reduzir a proporção de células invasivas, fato não observado nas condições isoladas. Os genes COX2 e VEGF, alvos dos FT NFB e HIF-1 (regulados por APE1) foram reprimidos nas células T98G enquanto que o gene VEGF foi induzido nas células U87MG, entretanto, tais alterações no padrão de expressão transcricional foram observadas somente em resposta ao tratamento com a TMZ, independentemente do silenciamento de APE1, indicando nenhuma mudança na atividade redox de APE1, possivelmente pela existência de proteínas APE1 remanescentes na célula. Além disso, a expressão proteica de NFBp65(ser563) foi aumentada em ambas as linhagens silenciadas e tratadas com a TMZ, provavelmente devido à inibição da proliferação celular. Em geral, os resultados do presente trabalho demonstraram que a estratégia de inibição do gene APE1 (participante da via BER) mostrou-se potencialmente viável, suportando a contribuição do BER na resistência à TMZ, visto que nas condições testadas, observou-se uma sensibilização das células de GBM, com efeito restrito às células de GBM resistentes (linhagem T98G), sendo pouco eficaz no sentido de sensibilizar as células sensíveis (linhagem U87MG) a esse agente. Assim, há que considerar as características genéticas de cada linhagem de GBM, visto que estas são cruciais para as respostas apresentadas pelas células aos tratamentos empregados. / APE1 (Apurinic/Apyrimidinic endonuclease 1/ Redox Factor-1 - APE1/REF-1) protein is a multifunctional enzyme whose expression is often increased in gliomas. Besides presenting activity in base excision repair (BER), APE1 also acts as a reduction factor, maintaining transcription factors (TFs) in an active reduced state. The BER pathway has been implicated as a possible factor of resistance to therapies based on the use of alkylating agents such as temozolomide (TMZ). In the present study, we have been using a strategy of small interference RNA (siRNA) to down-regulate the APE1 gene under conditions of treatment with TMZ in T98G (resistant to TMZ) and U87MG (sensitive to TMZ), glioblastoma (GBM), in order to determine the effects of APE1 gene silencing on cellular responses to this drug, evaluated by several assays, as well as the effects on the transcriptional expression of target genes of TFs regulated by APE1. APE1 silencing and TMZ treatment was effective to reduce the cell proliferation and clonogenic capacity of T98G cells, in addition to interfering in the cell cycle progression (S-phase arrest). These effects were accompanied by induction of DNA damage and phosphorylation of H2AX (H2AX), which may explain the decrease in cell survival. The same effect was not observed in silenced U87MG and TMZ-treated cells, being observed a predominance of the effects caused by TMZ itself, except for a slight induction of DNA damage and H2AX. Additionally, in silenced T98G and TMZ-treated cells, there was a moderate induction of apoptosis, as observed over time (1 to 10 days), with a slight induction of caspase-3 (on day 5); for those cells, we also observed autophagic induction (3.8 fold) at day 5. However, the induction of apoptosis and autophagy in U87MG cells was very low, suggesting that other mechanisms of cell death might be involved in the elimination of GBM cells under TMZ treatment. APE1 silencing caused a marked reduction on the invasiveness of T98G cells, similarly to that observed in TMZ treated cells, while the combination (APE1 silencing and drug treatment) led to an additive effect. For U87MG, the treatment combination was effective in reducing the proportion of invasive cells, in spite of an absence of any effect produced by each isolated condition tested. Regarding to the expression profile of target genes of TFs regulated by the APE1 redox activity, it was observed that COX2 and VEGF genes, targets of FTs NFB and HIF-1, were down-regulated in T98G while VEGF gene showed induced in U87MG cells; however, such alterations in the transcriptional expression pattern were observed only in response to TMZ treatment, independently of APE1 gene silencing, indicating no change in the APE1 redox activity, possibly due to the presence of APE1 remaining proteins inside cells. In addition, NFBp65(ser563) protein expression was increased in both cell lines (silenced and treated with TMZ), probably due to the reduced cell proliferation rates. In general, the present results show that the strategy of APE1 gene knockdown was potentially viable, supporting the BER contribution of the mechanism of TMZ resistance, since under the conditions tested, there was a sensitization of GBM cells. However, this effect was restricted to the resistant cell line (T98G cells). Thus, it should be considered the genetic characteristics of each GBM cell line, since these are crucial to the cellular responses to the conditions tested in the present work.

A proteína APE1 (do inglêsApurinic/Apyrimidinicendonuclease 1/ Redox Factor-1 - APE1/REF-1) é uma enzima multifuncional, cuja expressão encontra-se frequentemente aumentada em gliomas. Além de apresentar atividade no reparo por excisão de base (BER), o gene APE1 também atua como fator de redução, mantendo fatores de transcrição (FTs) em um estado reduzido ativo. A via BER de reparo do DNA tem sido apontada como um possível fator de resistência a terapias baseadas no uso de agentes alquilantes, tais como temozolomida (TMZ). No presente trabalho, utilizou-se a estratégia de inibição da transcrição do gene APE1 pelo método de RNA interferente(siRNA) e tratamento com a droga TMZ nas células de glioblastoma (GBM), T98G (resistente à TMZ) e U87MG (sensível à TMZ), a fim de verificar a influência do silenciamento do gene APE1 sobre as respostas celulares à droga avaliadas por vários ensaios, bem como os efeitos sobre a expressão transcricional dos genes alvos dos FTs regulados por APE1. O silenciamento de APE1 e o tratamento das células T98G com a TMZ foram eficazes no sentido de reduzir a proliferação e a capacidade clonogênica, além de intervir na progressão do ciclo celular com bloqueio na fase S. Tais efeitos foram acompanhados pelo aumento da indução de danos no DNA e da expressão de H2AX fosforilada (H2AX), o que justifica a queda na sobrevivência celular. O mesmo efeito não foi observado nas células U87MG silenciadas para APE1 e tratadas com a TMZ, havendo o predomínio dos efeitos causados pela TMZ, exceto por uma leve indução de danos no DNA e de H2AX. Adicionalmente, nas células T98G silenciadas e tratadas, verificou-se uma moderada indução de apoptose, que foi observada ao longo dos tempos avaliados (1 a 10 dias), com uma leve indução de caspase-3 (5 dias); nessas células, observou-se também a indução (3,8 vezes) de morte celular autofágica (5 dias). Entretanto, nas células U87MG,a indução de apoptose foi baixa e não houve indução de morte por autofagia, sugerindo outros mecanismos de morte envolvidos na eliminação dessas células em resposta ao tratamento com a TMZ. O silenciamento de APE1 causou uma redução acentuada na invasão das células T98G, de forma similar à observada nas células somente tratadas com a TMZ, sendo que a combinação (silenciamento de APE1 e tratamento com a droga) resultou em um efeito aditivo, enquanto que nas células U87MG a combinação foi eficaz no sentido de reduzir a proporção de células invasivas, fato não observado nas condições isoladas. Os genes COX2 e VEGF, alvos dos FT NFB e HIF-1 (regulados por APE1) foram reprimidos nas células T98G enquanto que o gene VEGF foi induzido nas células U87MG, entretanto, tais alterações no padrão de expressão transcricional foram observadas somente em resposta ao tratamento com a TMZ, independentemente do silenciamento de APE1, indicando nenhuma mudança na atividade redox de APE1, possivelmente pela existência de proteínas APE1 remanescentes na célula. Além disso, a expressão proteica de NFBp65(ser563) foi aumentada em ambas as linhagens silenciadas e tratadas com a TMZ, provavelmente devido à inibição da proliferação celular. Em geral, os resultados do presente trabalho demonstraram que a estratégia de inibição do gene APE1 (participante da via BER) mostrou-se potencialmente viável, suportando a contribuição do BER na resistência à TMZ, visto que nas condições testadas, observou-se uma sensibilização das células de GBM, com efeito restrito às células de GBM resistentes (linhagem T98G), sendo pouco eficaz no sentido de sensibilizar as células sensíveis (linhagem U87MG) a esse agente. Assim, há que considerar as características genéticas de cada linhagem de GBM, visto que estas são cruciais para as respostas apresentadas pelas células aos tratamentos empregados. / APE1 (Apurinic/Apyrimidinic endonuclease 1/ Redox Factor-1 - APE1/REF-1) protein is a multifunctional enzyme whose expression is often increased in gliomas. Besides presenting activity in base excision repair (BER), APE1 also acts as a reduction factor, maintaining transcription factors (TFs) in an active reduced state. The BER pathway has been implicated as a possible factor of resistance to therapies based on the use of alkylating agents such as temozolomide (TMZ). In the present study, we have been using a strategy of small interference RNA (siRNA) to down-regulate the APE1 gene under conditions of treatment with TMZ in T98G (resistant to TMZ) and U87MG (sensitive to TMZ), glioblastoma (GBM), in order to determine the effects of APE1 gene silencing on cellular responses to this drug, evaluated by several assays, as well as the effects on the transcriptional expression of target genes of TFs regulated by APE1. APE1 silencing and TMZ treatment was effective to reduce the cell proliferation and clonogenic capacity of T98G cells, in addition to interfering in the cell cycle progression (S-phase arrest). These effects were accompanied by induction of DNA damage and phosphorylation of H2AX (H2AX), which may explain the decrease in cell survival. The same effect was not observed in silenced U87MG and TMZ-treated cells, being observed a predominance of the effects caused by TMZ itself, except for a slight induction of DNA damage and H2AX. Additionally, in silenced T98G and TMZ-treated cells, there was a moderate induction of apoptosis, as observed over time (1 to 10 days), with a slight induction of caspase-3 (on day 5); for those cells, we also observed autophagic induction (3.8 fold) at day 5. However, the induction of apoptosis and autophagy in U87MG cells was very low, suggesting that other mechanisms of cell death might be involved in the elimination of GBM cells under TMZ treatment. APE1 silencing caused a marked reduction on the invasiveness of T98G cells, similarly to that observed in TMZ treated cells, while the combination (APE1 silencing and drug treatment) led to an additive effect. For U87MG, the treatment combination was effective in reducing the proportion of invasive cells, in spite of an absence of any effect produced by each isolated condition tested. Regarding to the expression profile of target genes of TFs regulated by the APE1 redox activity, it was observed that COX2 and VEGF genes, targets of FTs NFB and HIF-1, were down-regulated in T98G while VEGF gene showed induced in U87MG cells; however, such alterations in the transcriptional expression pattern were observed only in response to TMZ treatment, independently of APE1 gene silencing, indicating no change in the APE1 redox activity, possibly due to the presence of APE1 remaining proteins inside cells. In addition, NFBp65(ser563) protein expression was increased in both cell lines (silenced and treated with TMZ), probably due to the reduced cell proliferation rates. In general, the present results show that the strategy of APE1 gene knockdown was potentially viable, supporting the BER contribution of the mechanism of TMZ resistance, since under the conditions tested, there was a sensitization of GBM cells. However, this effect was restricted to the resistant cell line (T98G cells). Thus, it should be considered the genetic characteristics of each GBM cell line, since these are crucial to the cellular responses to the conditions tested in the present work.

Offentlig upphandling har stor betydelse i Sverige och inom området är det viktigt med priskonkurrens både för upphandlande myndigheter och leverantörer. Priskonkurrens medför att myndigheter sparar skattemedel och leverantörer ges möjlighet att konkurrera om kontrakt. Det är även viktigt att motverka osunda anbud i upphandlingar eftersom myndigheters trovärdighet och konkurrensen i branscher kan skadas om upphandlande myndigheter tilldelar kontrakt till leverantörer som lämnat osunda anbud. Sådana anbud kan exempelvis vara anbud från leverantörer som inte följer lagstiftning. Osunda anbud har försökts stävjas genom att upphandlande myndigheter styr leverantörers anbudspriser, vilket dock kan försämra priskonkurrensen mellan leverantörer. Syftet med uppsatsen är att fastställa hur myndigheter får styra leverantörers anbudspriser med golvpriser, takpriser och fasta priser. Därtill syftar uppsatsen till att fastställa om myndigheter bör tillåtas att styra anbudspriser för att motverka osunda anbud.  I uppsatsen framkommer att det inte går att ange exakt hur anbudspriser får styras även fast det kommit två domar från Högsta förvaltningsdomstolen avseende golvpriser och takpriser. Golvpriser med en bestämd nedre gräns torde dock alltid vara otillåtna. Takpriser med en bestämd övre gräns synes ofta vara tillåtna, men inte alltid. Huruvida golvpriser och takpriser som har en relativ utformning, innebärande att kraven avser förhållandet mellan olika poster i samma anbud, är tillåtna beror på hur kraven och upphandlingarna utformas. Det som är av avgörande betydelse vid bedömningen av om golvpriser och takpriser är tillåtna är huruvida kraven åsidosätter likabehandlingsprincipen genom att hindra priskonkurrensen mellan leverantörer. Vad som nu anförts gäller både när golvpriser och takpriser används som obligatoriska krav och när de används i utvärderingsmodeller. Golvpriser som endast uppställs som en rekommendation har en annan karaktär och synes generellt sett vara tillåtet, men i vissa fall kan användandet av en sådan rekommendation strida mot de allmänna principerna.  Att använda fasta priser och låta leverantörer endast konkurrera om kvalitet tillåts när det finns nationella bestämmelser om fastställande av priser. Huruvida fasta priser får användas i andra fall är dock inte helt klart, men troligtvis får inte fasta priser användas om inte nationella bestämmelser finns. Det finns skäl som talar både för och emot att myndigheter bör tillåtas att styra anbudspriser. Att inte tillåta styrning av anbudspriser synes dock utifrån ett rättsekonomiskt perspektiv medföra lägst kostnader, vilket kan tala för att myndigheter inte bör få styra anbudspriser. Med beaktande av att flera sätt att styra anbudspriser på är otillåtet och att tillåtligheten i hög grad avgörs i det enskilda fallet bör upphandlande myndigheter vara återhållsamma med att styra leverantörers anbudspriser.

No description available.

Lake sediments can play an important role in understanding and reconstructing temporal characteristics of the geomagnetic field, as they potentially offer near continuous high-resolution archives of magnetic information extending throughout the Holocene. To date lake sediment geomagnetic data has typically been excluded from British archaeomagnetic secular variation curves (SVC) due to uncertainties with the acquisition of magnetisation by lake sediments. This paper presents the argument that, with regards to British datasets, the real problem lies with poor chronological control and sets out to illustrate that with British archaeomagnetic data some progress has been made. The results indicate that it is not currently possible to resolve secular variation on a time scale of ¿100 years from published British lake sediment data but more success has been made with data from archaeological sediments. This level of detail has been considered necessary for the incorporation of lake sediment data into the British archaeomagnetic dataset, as the ability to resolve short-term geomagnetic changes is critical for the integration of any dataset into the British SVC. As the latter is predominantly employed to date archaeological architecture and artefacts requires that it has the ability to resolve changes over timescales relevant to human lifetimes. Using currently available data this retrospective critique confirms that, in archaeological sediments, depositional and thermoremanent magnetisation can record the same direction over the same time interval.

BACKGROUND: Various human and animal studies suggest that peak alcohol exposure during a binge episode, rather than total alcohol exposure, may determine fetal development. Research about the impact of binge drinking on birth outcomes is sparse and inconclusive. Data from the Born in Bradford cohort study were used to explore the impact of binge drinking on birth outcomes. METHODS: Interview-administered questionnaire data about the lifestyle and social characteristics of 10 851 pregnancies were linked to maternity and birth data. The impact of self-reported binge drinking (5 units: 40 g of pure alcohol) on two birth outcomes (small for gestational age (SGA) and preterm birth (<37 weeks)) was assessed using multivariate logistic regression models, while adjusting for confounders. RESULTS: The percentage of women classified as binge drinkers fell from 24.5% before pregnancy to 9% during the first trimester and 3.1% during the second trimester. There was a significant association between SGA birth and binge drinking (all categories combined; OR 1.68, 95% CI 1.15 to 2.47, p=0.01). No association was observed between moderate drinking and either birth outcome, or between binge drinking and preterm birth. CONCLUSIONS: Binge drinking during the second trimester of pregnancy was associated with an increased risk of SGA birth. No association was found between any level of alcohol consumption and premature birth. This work supports previous research showing no association between SGA and low-alcohol exposure but adds to evidence of a dose-response relationship with significant risks observed at binge drinking levels.