Protein S deficiency

In 1977, three years after the discovery of the γ-carboxy glutamic acid,[1][1] Richard DiScipio reported on the identification of a new vitamin K-dependent protein which was named protein S.[2][2] Three years later, Frederick Walker reported that bovine protein S functioned as a cofactor t

756 stable amelioration of hemophilia b in dogs by intravenous administration of lentiviral vectors expressing hyper functional factor ix

Lentiviral vectors (LVs) are attractive vehicles for liver-directed gene therapy by virtue of their ability to stably integrate in the genome of target cells and the low prevalence of pre-existing immunity against HIV in humans. Over the past years, we have developed a LV platform that can achieve stable transgene expression in the liver, induce transgene-specific immune tolerance and establish correction of hemophilia in mouse models upon systemic administration. This LV is designed to stringently target transgene expression to hepatocytes through transcriptional and microRNA-mediated regulation. We then investigated the efficacy and safety profile of portal vein administration of LVs expressing canine factor IX (FIX) in a canine model of hemophilia B. We produced large-scale batches of LVs qualified for in vivo administration and treated adult hemophilia B dog by portal vein administration. We observed long-term stable reconstitution of canine FIX activity up to 1% of normal and significant amelioration of the clinical phenotype in 3 treated dogs with 6, 3.5 and 2.5 years of follow up. LV infusion was associated with transient signs of inflammatory response and mild hepatotoxicity, which could be abrogated by pretreatment with anti-inflammatory drugs. There was no detectable long-term toxicity or development of FIX inhibitors. In the perspective of clinical translation and to increase therapeutic efficacy, we next treated two 10-kg hemophilia B dogs by peripheral vein administration of LVs expressing a codon-optimized and hyperfunctional canine FIX at a 5-fold higher dose than those previously administered. Intravenous LV administration was well tolerated with mild and self-limiting elevation of aminotransferases in one dog. In the dog that reached more than 1 year of follow up FIX activity ranged between 4-8% of normal. Treatment of two more dogs at a higher dose is underway. Overall, our studies position LV-mediated liver gene therapy for further pre-clinical development and clinical translation. LVs may thus complement other available vectors to address some of the outstanding challenges posed by liver gene therapy of hemophilia and conceivably other diseases

28. Intravenous Administration of Lentiviral Vectors Expressing Hyperactive Factor IX Converts Severe Into Mild Hemophilia B in a Canine Model

Lentiviral vectors (LVs) are attractive vehicles for liver-directed gene therapy by virtue of their ability to stably integrate in the genome of target cells and the lack of pre-existing immunity against vector components in most humans. Over the past years, we have developed a LV platform that can achieve stable transgene expression in the liver, induce transgene-specific immune tolerance and establish correction of hemophilia in mouse models upon systemic administration. This LV is designed to stringently target transgene expression to hepatocytes through transcriptional and microRNA-mediated regulation. We then investigated the efficacy and safety profile of portal vein administration of LVs expressing wild-type, codon-optimized (c.o.) or c.o. and hyperactive factor IX (FIX) in a canine model of hemophilia B. We produced large-scale batches of LVs qualified for in vivo administration and treated adult hemophilia B dog by portal vein administration. We observed long-term stable reconstitution of canine FIX activity up to 1% of normal and significant amelioration of the clinical phenotype in 3 treated dogs (>9 years cumulative follow up). LV infusion was associated with transient signs of inflammation and mild hepatotoxicity, which could be abrogated by pretreatment with anti-inflammatory drugs. There was no detectable long-term toxicity or development of FIX inhibitors. In the perspective of clinical translation and to increase therapeutic efficacy, we next treated an 11-kg, hemophilia B dog by peripheral vein administration of LVs expressing the c.o. and hyperactive canine FIX at a 5-fold higher dose than those previously administered. At the current follow-up (3 months after gene therapy) FIX activity is 6-9% of normal. Intravenous LV administration, coupled with a 1-day anti-inflammatory and anti-histamine pre-treatment, induced mild and selflimiting leukopenia and elevation of aminotransferases. Treatment of more hemophilia B dogs is underway to confirm and extend these results. Overall, our studies, which suggest comparable efficacy of LV by both portal and peripheral vein administration, position LV-mediated liver gene therapy for further pre-clinical development and clinical translation. LVs may thus complement other available vectors to address some of the outstanding challenges posed by liver gene therapy of hemophilia and conceivably other diseases

Paleopatología del sacro en cazadores recolectores de Patagonia Austral

El sacro es importante para la estabilidad corporal, la fijación de las extremidades inferiores y la protección de los órganos pélvicos. Este hueso puede verse afectado por patologías de índole congénito, degenerativo o multifactorial. El objetivo del presente estudio es analizar lesiones sacrales en una muestra bien preservada de cazadores-recolectores de Patagonia Austral y la posible influencia de los factores temporo-espaciales y el estilo de vida, con especial atención al momento de contacto nativo-europeo. Se analizaron 56 sacros adultos de ambos sexos fechados en un amplio rango cronológico (5.200 años AP - s. XX), siguiendo la metodología propuesta por Campo (2003, 2015). Las patologías analizadas mostraron que los individuos originarios que habitaron espacios misionales presentaron mayores niveles de prevalencia que sujetos pre-contacto y post-contacto fuera de la misión, excepto en el caso de los nódulos de Schmörl. Los efectos de la edad y el sexo mostraron un patrón similar al observado en otras poblaciones. Se apreció una alta prevalencia de espondilolisis, similar a la observada en Inuits. Debido a la carencia de una metodología estandarizada en la clasificación de la Espina Bífida Oculta -SBO-, este trabajo propone el uso de la propuesta por Kumar y Tubbs (2011).Sacrum is important for body stability, lowerlimbs attachment and pelvic organs protection. This bone could be affected bycongenital, degenerative or multifactorial pathologies. The aim of thepresent study is to analyse sacral lesions in a sample well preserved remainsfrom Southern Patagonian hunter-gatherers and the possible influences oftemporal-spatial and lifestyle variables, with special attention to theNative-European contact effect. Pathological signs from 56 adult sacral bonesfrom both sexes and comprising a wide chronology range (5200 years BP- 20thcentury), were analyzed following the methodology proposed by Campo (2003,2015). Pathologies analysed showed that native individualswho lived at missionary places presented higher lesion prevalence thanpre-contact and post-contact out of mission samples, except for Schmörl nodes. Ageand sex effect showed similar patterns with respect to other populations. Highprevalence of spondylolysis was observed, similarly to Inuit samples.Fil: D'angelo del Campo, Manuel Domingo. Universidad Autónoma de Madrid; EspañaFil: Medialdea, Laura. Universidad Autónoma de Madrid; EspañaFil: García Laborde, Pamela. Universidad Nacional del Centro de la Provincia de Buenos Aires; ArgentinaFil: Salemme, Monica Cira. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Austral de Investigaciones Científicas; ArgentinaFil: Santiago, Fernando Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Austral de Investigaciones Científicas; ArgentinaFil: Campo Martín, Manuel. Universidad Autónoma de Madrid; EspañaFil: González Martín, Armando. Universidad Autónoma de Madrid; EspañaFil: Guichón, Ricardo Anibal. Universidad Nacional del Centro de la Provincia de Buenos Aires; Argentin

Possible environment influence in spine segmentation anomalies

Segmentation anomalies of the spine transformations are relatively common in humans, mainly in adjacent regions. Its aetiology is multifactorial, a combination of genetic, environmental, and epigenetic interaction. A sample of 50 adult individuals of both sexes from two different sites and chronologies of the current Argentine territory was examined. This work proposes a new approach to analyse segmentation anomalies, considering the taphonomic characteristics of the spine, together with the most common occasional contour shifts of such anomalies. Likewise, a bibliographic review was conducted to compile the knowledge achieved to date on this topic. The results showed different patterns of expression of segmentation anomalies among the analysed samples, with the lumbosacral transformations being the most prevalent. The similarities and disparities observed between Southern Patagonian samples and Inuit populations suggest that cold, as an environmental factor, could play an important role in the phenotypic plasticity of human populations. Similarly, hypoxia could influence the sample from Pukará de Tilcara. Due to the scarce existing methodological standardization for addressing segmentation anomalies, a systematization of the methods used to analyse segmentation anomalies is recommended; our approach is a proposal for this purpose.Fil: D'angelo del Campo, Manuel Domingo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Autónoma de Madrid. Facultad de Ciencias. Departamento de Biología; España. Universidad Nacional del Centro de la Pcia.de Bs.as.. Unidad de Enseñanza Universitaria Quequen.; ArgentinaFil: Pastor, Sara. Universidad Autónoma de Madrid. Facultad de Ciencias. Departamento de Biología; EspañaFil: Medialdea, Laura. Universidad Autónoma de Madrid. Facultad de Ciencias. Departamento de Biología; EspañaFil: Caballero Grijalba, Mónica. Universidad Autónoma de Madrid. Facultad de Ciencias. Departamento de Biología; EspañaFil: Garcia Laborde, Pamela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Sociales. Grupo de Estudios Interdisciplinarios sobre Poblaciones Humanas de Patagonia Austral; ArgentinaFil: Salemme, Monica Cira. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Austral de Investigaciones Científicas; ArgentinaFil: Campo Martín, Manuel. Universidad Autónoma de Madrid. Facultad de Ciencias. Departamento de Biología; EspañaFil: González Martín, Armando. Universidad Autónoma de Madrid. Facultad de Ciencias. Departamento de Biología; EspañaFil: Seldes, Verónica. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Filosofía y Letras. Instituto de Ciencias Antropológicas. Sección Antropología Biológica; ArgentinaFil: Guichon, Ricardo Anibal. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional del Centro de la Pcia.de Bs.as.. Unidad de Enseñanza Universitaria Quequen.; Argentin

Educational Impact on Apixaban Adherence in Atrial Fibrillation (the AEGEAN STUDY): A Randomized Clinical Trial

IntroductionAdherence to non-vitamin-K oral anticoagulants (NOACs) may be lower than to vitamin K antagonists because NOACs do not require routine monitoring.ObjectiveWe assessed the impact of an educational program on adherence and persistence with apixaban in patients with non-valvular atrial fibrillation (NVAF).MethodsPatients with NVAF eligible for NOACs with one or more stroke risk factor (prior stroke/transient ischemic attack, age ≥ 75 years, hypertension, diabetes, or symptomatic heart failure) were randomized (1:1) to standard of care (SOC) or SOC with additional educational (information booklet, reminder tools, virtual clinic access). The primary outcome was adherence to apixaban (2.5 or 5 mg twice daily) at 24 weeks. Patients receiving the educational program were re-randomized (1:1) to continue the program for 24 further weeks or to switch to secondary SOC. Implementation adherence and persistence were reassessed at 48 weeks.ResultsIn total, 1162 patients were randomized (SOC, 583; educational program, 579). Mean implementation adherence ± standard deviation (SD) at 24 weeks was 91.6% ± 17.1 for SOC and 91.9% ± 16.1 for the educational program arm; results did not differ significantly between groups at any time-point. At 48 weeks, implementation adherence was 90.4% ± 18.0, 90.1% ± 18.6, and 89.3% ± 18.1 for continued educational program, SOC, and secondary SOC, respectively; and corresponding persistence was 86.1% (95% confidence interval [CI] 81.3-89.7), 85.2% (95% CI 81.5-88.2), and 87.8% (95% CI 83.4-91.1). Serious adverse events were similar across groups.ConclusionHigh implementation adherence and persistence with apixaban were observed in patients with NVAF receiving apixaban. The educational program did not show additional benefits.Clinical trial registrationThis study is registered at ClinicalTrials.gov [NCT01884350]

Base de Información Bioantropológica de Patagonia Austral (B.I.B.P.A)

The human skeletal remains of Southern Patagonia are scattered throughout numerous European and American institutions. Currently there are more than 1150 individuals in those institutions. Information about the remains and the peer-reviewed published bioanthropological information about each of them have been compiled in the Base de Información Bioantropológica de Patagonia Austral (Southern Patagonian Bioanthropological Information Base). This platform is conceived as a tool that seeks to facilitate and streamline the work of the community of bioanthropologists and other scientists. The database is public and open source, and it is available to both the scientific community and the wider public. It will be updated periodically, with the information that the community generates and makes available to its peers by meansof the various formats that scientists employ to publish their scientific work.Los restos óseos humanos de Patagonia Austral se encuentran dispersos en numerosas instituciones europeas y americanas. Actualmente se contabilizan más de 1150 individuos. Esos sujetos y la información de orden bioantropológica publicada acerca de cada uno de ellos ha sido compilada en la Base de Información Bioantropológica de Patagonia Austral. Esta plataforma se concibe como una herramienta que busca facilitar y agilizar la labor de la comunidad de antropólogos biólogos y afines, de la región. Es de carácter público y código abierto, y se encuentra a disposición tanto de la comunidad científica como de la sociedad. Se actualizará de manera periódica, con la información que la comunidad genere y ponga a disposición de sus pares a través de los diversos formatos que los científicos tienen para difundir su labor científica