The aim of the present study was to estimate the correlation between Euro NCAP pedestrian rating scores and injury outcome in real-life car to pedestrian crashes, with special focus on long-term disability. The study also surveyed most frequently injured body regions and risk differences for specific elements of pedestrians hit by cars. Another aim was to determine whether Brake Assist systems affect the injury outcome in real-life car to pedestrian crashes and to estimate the effect in injury reduction of a high Euro NCAP ranking score combined with Brake Assist. In the current study, the Euro NCAP pedestrian scoring was compared with the real-life outcome in pedestrian crashes that occurred in Sweden 2003-2010. The real-life crash data was obtained from the data acquisition system STRADA, which combines police records and hospital admission data. The medical data consisted of International Statistical Classification of Diseases and Related Health Problems (ICD) diagnoses and Abbreviated Injury Scale (AIS) scoring. In all approximately 500 pedestrians submitted to hospital were included in the study. Each car model was coded according to Euro NCAP pedestrian scores. In addition, the presence or absence of Brake Assist (BA) was coded for each car involved. Pedestrians were grouped according to associated car scoring. Injury outcomes were analyzed with AIS and, at victim level, with permanent medical impairment. This was done by translating the injury scores for each individual to Risk of Serious Consequences (RSC) at 1, 5 and 10% level of medical disability or more. This indicates the total risk of a medical disability for each victim, given the severity and location of injuries. The mean RSC (mrsc) was then calculated for each pedestrian group and t-tests were conducted to ensure statistically significant differences in mrsc between groups. The results showed a significant reduction of injury severity for pedestrians hit by cars with better pedestrian scoring, although pedestrians hit by cars with a high score (three or four stars) could not be studied, due to lack of cases. The reduction of RSC for pedestrians hit by medium performing (two-star) cars in comparison with pedestrians hit by low performing (one-star) cars was 12, 19 and 28% for 1 ,5 and 10% of medical impairment or more, respectively. These results applied to speed limits up to 90 km/h. In urban areas with speed limits up to 50 km/h the reduction of RSC was 17, 26 and 38% for 1, 5 and 10% of medical impairment or more, respectively. Car to pedestrian crashes was most common at speed limits up to 50 km/h and leg, arm and head were the most frequently injured body regions. RSC for pedestrians hit by cars with Brake Assist was not statistically significant lower than for pedestrians hit by cars without Brake Assist. RSC for pedestrians hit by two-star cars with Brake Assist was 19, 31 and 46% lower for 1, 5 and 10% of medical impairment or more, respectively, compared to pedestrians hit by one-star cars without Brake Assist. A significant correlation between Euro NCAP pedestrian score and injury outcome in real-life car to pedestrian crashes was found. The injury reduction was found to be larger for higher severity and level of permanent medical impairment. Car to pedestrian crashes was most common at lower speed zones. Leg, arm and head were the most frequently injured body regions. Brake Assist had no statistically significant effect measured in RSC on car to pedestrian crashes in this material. A high Euro NCAP scoring combined with Brake Assist was shown to give a high effect in reduction of RSC for pedestrians. / Syftet med denna studie var att uppskatta korrelationen mellan Euro NCAPs testresultat för fotgängarskydd och skadeutfall i verkliga olyckor med fotgängare och personbilar, med särskilt fokus på skador som ger medicinsk invaliditet. I studien kartlades även de mest frekvent skadade kroppsregionerna och riskskillnader för särskilda faktorer för fotgängare påkörda av personbilar. Studien syftar dessutom till att undersöka bromsassistanssystems påverkan av skadeutfallet för fotgängare i verkliga olyckor med personbil och att uppskatta den skadereducerande effekten av en hög Euro NCAP-poäng kombinerat med en bromsassistansutrustning. I denna studie var Euro NCAPs fotgängarskyddspoäng jämförd mot skadeutfallet i verkliga olyckor som skett i Sverige 2003-2010. Data från verkliga olyckor inhämtades från databasen STRADA (Swedish Traffic Accident Data Acquisition) som kombinerar polis- och sjukvårdsrapporterad data. De medicinska data innehåller diagnoser av typen ICD (International Statistical Classification of Diseases and Related Health Problems) och värden för AIS (Abbreviated Injury Scale). I helhet var omkring 500 fotgängare inkluderade i studien. Varje enskild personbilmodell kodades enligt Euro NCAPs fotgängarskyddspoäng. Dessutom kodades förekomst eller avsaknad av bromsassistansutrustning för varje enskild personbil inkluderad i studien. Fotgängarna grupperades enligt påkörande personbils fotgängarskyddspoäng. Skadeutfallet analyserades med AIS, på individnivå och med medicinsk invaliditet. Detta gjordes genom översättning av skadeutfall för varje fotgängare till risk för allvarliga konsekvenser (RSC, Risk of Serious Consequences) på 1, 5 och 10 % medicinsk invaliditet eller mer. Detta påvisar den totala risken för medicinsk invaliditet med hänsyn till skadegrad och -lokalisering. Medelvärdet av RSC (mrsc) beräknades sedan för varje fotgängargrupp och t-test utfördes för att säkerställa statistiskt signifikanta skillnader mellan gruppernas mrsc. Resultaten visade en signifikant skadereduktion för fotgängare påkörda av personbilar med en högre fotgängarskyddspoäng, trots att fotgängarolyckor med personbilar som har hög poäng (stjärnbetyg tre och fyra) inte kunde studeras på grund av fåtaligt antal olycksfall. Reduktionen av RCS för fotgängare påkörda av medelpresterande (stjärnbetyg två) personbilar i jämförelse med fotgängare påkörda av lågpresterande (stjärnbetyg ett) personbilar var 12, 19 och 28 % för 1, 5 respektive 10 % medicinsk invaliditet eller mer. Dessa resultat gäller olyckor på vägar med hastighetsgräns upp till 90 km/h. I stadsmiljö med hastighetsgräns upp till 50 km/h var reduktionen av RSC 17, 26 och 38 % för 1, 5 respektive 10 % medicinsk invaliditet eller mer. Fotgängarolyckor med personbil var vanligast på vägar med hastighetsgräns upp till 50 km/h och ben, arm och huvud var de mest frekvent skadade kroppsregionerna. RSC för fotgängare påkörda av personbilar utrustade med bromsassistans var inte statistiskt signifikant lägre än för fotgängare påkörda av personbilar utan bromsassistansutrustning. RSC för fotgängare påkörda av tvåstjärniga personbilar utrustade med bromsassistans var 19, 31 och 46 % lägre för 1, 5 respektive 10 % medicinsk invaliditet eller mer jämfört med fotgängare påkörda av enstjärniga personbilar utan bromsassistansutrustning. En signifikant korrelation mellan Euro NCAPs fotgängarpoäng och skadeutfall i verkliga fotgängarolyckor med personbil påträffades. Skadereduktionen visade sig vara högre för högre skadegrad och nivå av medicinsk invaliditet. Det var vanligare att personbilar kör på fotgängare på vägar med lägre hastighetsgräns. Ben, arm och huvud var de mest frekvent skadade kroppsregionerna. Bromsassistans hade inte en statistiskt signifikant effekt mätt i RSC för fotgängarolyckor i detta material. En hög Euro NCAP poäng kombinerat med bromsassistansutrustning visade sig ge en hög effekt av att reducera fotgängares RSC.

Mieloma Múltiplo é a segunda doença com maior prevalência nas doenças malignidades hematológica, incurável com média de sobrevivência de 3-5 anos. MM é uma malignidade das células do plasma caracterizada pela destruição e reabsorção óssea e supressão da formação do osso. A quimiocina SDF-1 (CXCL12) e seu receptor CXCR4 têm um importante papel direcional na migração, homing das células do plasma em mieloma múltiplo e mobilização das células de MM para fora da medula óssea. A talidomida tem sido usada com êxito no tratamento de pacientes com mieloma múltiplo. Neste estudo verificamos o efeito da talidomida na expressão da quimiocina SDF-1 e seu receptor CXCR4 em pacientes com mieloma múltiplo e em linhagem de células de mieloma múltiplo humano (RPMI-8226) tratados e sem tratamento de talidomida. Nossos resultamos mostraram uma expressão heterogênea na expressão da quimiocina SDF-1 e seu receptor CXCR4 nos pacientes com mieloma múltiplo estudado (n= 79). Entretanto, pacientes com mieloma múltiplo tratados com talidomida mostraram uma baixa expressão da quimiocina SDF-1 e seu receptor CXC4 quando comparados com pacientes recém diagnosticados para mieloma múltiplo e pacientes com mieloma múltiplo tratados com outros medicamentos. Nossos resultados sugerem que o tratamento com talidomida induz uma baixa regulação na expressão no ligante SDF-1 e seu receptor CXCR4 em pacientes com mieloma múltiplo / Multiple Myeloma (MM) is a second most prevalent hematological malignancy and remains incurable with a median survival of 3-5 years. MM is a plasma cell malignancy characterized by devastating bone destruction due to the enhanced bone resorption and suppressed bone formation. The chemokine stromal-derived factor-1 (SDF-1) and its receptor CXCR4 play an important role in directional migration, homing of plasma cells in multiple myeloma (MM) and mobilization of MM cells out of the bone marrow. The drug thalidomide has been successfully used in the treatment of patients with MM. In this study, we assessed the effect of thalidomide on SDF-1 and CXCR4 expression in MM patients and human myeloma-derived cell line, RPMI 8226 treated with or without thalidomide. A heterogeneous expression pattern of chemokines SDF-1 and CXCR4 receptor were observed for all MM patients studied. However, patients treated with thalidomide showed a significantly decrease in expression of SDF-1 and CXCR4 as compared to newly diagnosed MM patients and MM patients treated with other drugs. RPMI 8226 cell line treated with 10, 20 and 100µM thalidomide also demonstrated decrease in SDF-1 and CXCR4 expression as compared with cell control (RPMI-8226 without thalidomide). Ours results indicate that thalidomide therapy induces down-regulation of CXCR4 and its ligand SDF-1 in multiple myeloma

Mieloma Múltiplo é a segunda doença com maior prevalência nas doenças malignidades hematológica, incurável com média de sobrevivência de 3-5 anos. MM é uma malignidade das células do plasma caracterizada pela destruição e reabsorção óssea e supressão da formação do osso. A quimiocina SDF-1 (CXCL12) e seu receptor CXCR4 têm um importante papel direcional na migração, homing das células do plasma em mieloma múltiplo e mobilização das células de MM para fora da medula óssea. A talidomida tem sido usada com êxito no tratamento de pacientes com mieloma múltiplo. Neste estudo verificamos o efeito da talidomida na expressão da quimiocina SDF-1 e seu receptor CXCR4 em pacientes com mieloma múltiplo e em linhagem de células de mieloma múltiplo humano (RPMI-8226) tratados e sem tratamento de talidomida. Nossos resultamos mostraram uma expressão heterogênea na expressão da quimiocina SDF-1 e seu receptor CXCR4 nos pacientes com mieloma múltiplo estudado (n= 79). Entretanto, pacientes com mieloma múltiplo tratados com talidomida mostraram uma baixa expressão da quimiocina SDF-1 e seu receptor CXC4 quando comparados com pacientes recém diagnosticados para mieloma múltiplo e pacientes com mieloma múltiplo tratados com outros medicamentos. Nossos resultados sugerem que o tratamento com talidomida induz uma baixa regulação na expressão no ligante SDF-1 e seu receptor CXCR4 em pacientes com mieloma múltiplo / Multiple Myeloma (MM) is a second most prevalent hematological malignancy and remains incurable with a median survival of 3-5 years. MM is a plasma cell malignancy characterized by devastating bone destruction due to the enhanced bone resorption and suppressed bone formation. The chemokine stromal-derived factor-1 (SDF-1) and its receptor CXCR4 play an important role in directional migration, homing of plasma cells in multiple myeloma (MM) and mobilization of MM cells out of the bone marrow. The drug thalidomide has been successfully used in the treatment of patients with MM. In this study, we assessed the effect of thalidomide on SDF-1 and CXCR4 expression in MM patients and human myeloma-derived cell line, RPMI 8226 treated with or without thalidomide. A heterogeneous expression pattern of chemokines SDF-1 and CXCR4 receptor were observed for all MM patients studied. However, patients treated with thalidomide showed a significantly decrease in expression of SDF-1 and CXCR4 as compared to newly diagnosed MM patients and MM patients treated with other drugs. RPMI 8226 cell line treated with 10, 20 and 100µM thalidomide also demonstrated decrease in SDF-1 and CXCR4 expression as compared with cell control (RPMI-8226 without thalidomide). Ours results indicate that thalidomide therapy induces down-regulation of CXCR4 and its ligand SDF-1 in multiple myeloma

The nasal mucosa provides a non-invasive route for drug administration to the systemic circulation and potentially directly to the CNS. Nanoparticles made from biodegradable polymers, including PLGA, are of great interest for use in drug delivery systems due to their relative safety and ease of surface modification. Owing to their small size, nanoparticles may provide enhanced targeting and transport through the nasal mucosa. An improved understanding of the mechanisms and pathways of nanoparticle transfer across the nasal mucosa is needed to design effective new nasal delivery systems. This study focuses on the preparation of PLGA nanoparticles in various diameters and with varying surface characteristics followed by the in vitro investigation of the mechanisms of endocytosis and exocytosis of PLGA nanoparticles in the nasal mucosa. PLGA nanoparticles (60 nm or 125 nm) containing the lipophilic fluorescent dye, Nile Red, were prepared using a surfactant-free nanoprecipitation method. In one investigation, the inherent negative surface charge of 60 nm PLGA nanoparticles was modified to a positive charge using a 5th generation polyamidoamine dendrimer (PAMAM) during preparation of nanoparticles. In addition, 60 nm PLGA nanoparticle surfaces were coated by adding 5 % (w/v) bovine serum albumin (BSA) to the nanoparticle dispersion and allowing protein adsorption on the particle surface. Nile Red-loaded PLGA nanoparticles were transported into the epithelial layer and reached the sub-mucosal connective tissues, yet only < 5% of the PLGA nanoparticle load was transferred into the nasal mucosa. Total uptake was size dependent, where the uptake of 60 nm unmodified PLGA nanoparticles was significantly higher than uptake of 125 nm nanoparticles. The amount of Nile Red measured in the tissues after expose to the 125 nm nanoparticles was double the amount from the 60 nm nanoparticles due to differences in the carrying capabilities of the 60 and 125 nm PLGA nanoparticles. Modification of the nanoparticle surface with PAMAM or BSA decreased the uptake of 60 nm PLGA nanoparticles into the nasal mucosa. Endocytic mechanisms involved in the uptake of PLGA nanoparticles were studied using chemical inhibitors. Nanoparticle uptake in the nasal respiratory mucosa involved energy-dependent processes utilizing multiple known mechanisms, including clathrin-mediated endocytosis and macropinocytosis. In the olfactory mucosa, significant energy-independent nanoparticle uptake was also observed. In order to investigate how nanoparticles exit epithelial cells for further distribution to distant tissues, the exocytosis of 60 nm Nile Red-loaded PLGA nanoparticles was evaluated using three different epithelial cell line models, RPMI-2650 (nasal), Calu-3 (lung) and MDCK-II wild type (kidney) cells. Following a 30 min exposure to a 60 nm PLGA nanoparticles dispersion, nanoparticle exocytosis into a protein-free medium was evaluated for additional 30 or 60 min. Only a limited number of NP (~ 20 % of the endocytosed NP) underwent exocytosis into the medium after 60 min, while the majority of the internalized nanoparticles remained within the cells. The measurable transfer of PLGA nanoparticles into the nasal mucosal tissues indicates that they may be useful drug carriers for nasal administration. However, the limited exocytosis of 60 nm NP and the resulting potential for intracellular accumulation may raise toxicity concerns and result in potential cellular injury. While PLGA nanoparticles provide promising drug delivery systems for nasal administration, only with careful design of the nanoparticles, including their size and surface characteristics, will efficient and effective, safe drug delivery be accomplished.

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