Rapid and sustained B-cell depletion with subcutaneous ofatumumab in relapsing multiple sclerosis: APLIOS, a randomized phase-2 study

Ofatumumab; Multiple sclerosis; PharmacokineticsOfatumumab; Esclerosis múltiple; FarmacocinéticaOfatumumab; Esclerosi múltiple; FarmacocinèticaBackground: Ofatumumab, the first fully human anti-CD20 monoclonal antibody, is approved in several countries for relapsing multiple sclerosis (RMS). Objective: To demonstrate the bioequivalence of ofatumumab administered by an autoinjector versus a pre-filled syringe (PFS) and to explore the effect of ofatumumab on B-cell depletion. Methods: APLIOS (NCT03560739) is a 12-week, open-label, parallel-group, phase-2 study in patients with RMS receiving subcutaneous ofatumumab 20 mg every 4 weeks (q4w) (from Week 4, after initial doses on Days 1, 7, and 14). Patients were randomized 10:10:1:1 to autoinjector or PFS in the abdomen, or autoinjector or PFS in the thigh, respectively. Bioequivalence was determined by area under the curve (AUCτ) and maximum plasma concentration (Cmax) for Weeks 8–12. B-cell depletion and safety/tolerability were assessed. Results: A total of 256 patients contributed to the bioequivalence analyses (autoinjector-abdomen, n = 128; PFS-abdomen, n = 128). Abdominal ofatumumab pharmacokinetic exposure was bioequivalent for autoinjector and PFS (geometric mean AUCτ, 487.7 vs 474.1 h × µg/mL (ratio 1.03); Cmax, 1.409 vs 1.409 µg/mL (ratio 1.00)). B-cell counts (median cells/µL) depleted rapidly in all groups from 214.0 (baseline) to 2.0 (Day 14). Ofatumumab was well tolerated. Conclusion: Ofatumumab 20 mg q4w self-administered subcutaneously via autoinjector is bioequivalent to PFS administration and provides rapid B-cell depletion.The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: the APLIOS trial was funded by Novartis Pharmaceuticals. Novartis Pharmaceuticals supported the development of this manuscript, provided data analyses according to the direction of the authors, and paid for medical writing support

Polylectrolyte- versus membrane-coated electrodes for energy production by Capmix salinity exchange methods

La versión final publicada se puede encontrar en: Journal of Power Sources, 302(20): 387-393 (2016). http://dx.doi.org/10.1016/j.jpowsour.2015.10.076In this paper we analyze the energy and power achievable by means of a re- cently proposed salinity gradient technique for energy production. The method, denominated soft electrode or SE, is based on the potential di erence that can be generated between two porous electrodes coated with cationic and anionic polyelectrolytes. It is related to the Capacitive Donnan Potential (CDP) tech- nique, where the electrical potential variations are mostly related to the Donnan potential, of ion-selective membranes in the case of CDP, and of the polyelec- trolyte coating in SE. It is found that although SE is comparable to CDP in terms of energy production, it presents slower rates of voltage change, and lower achieved power. The separate analysis of the response of positively and neg- atively coated electrodes shows that the latter produces most of the voltage rise and also of the response delay. These results, together with electrokinetic techniques, give an idea on how the two types of polyelectrolytes adsorb on the carbon surface and a ect di erently the di usion layer. It is possible to suggest that the SE technique is a promising one, and it may overcome the drawbacks associated to the use of membranes in CDP.MINECO FIS2013-47666-C3-1-RJunta de Andalucía, PE2012-FQM0694European Union 7th Framework Programme (FP7/2007–2013) under agreement No. 25686

A genetic study of autism in Costa Rica: multiple variables affecting IQ scores observed in a preliminary sample of autistic cases

BACKGROUND: Autism is a heritable developmental disorder of communication and socialization that has not been well studied in Hispanic populations. Therefore, we are collecting and evaluating all possible cases of autism from a population isolate in the Central Valley of Costa Rica (CVCR) for a clinical and genetic study. METHODS: We are assessing all subjects and parents, as appropriate, using the newly translated Spanish versions of the Autism Diagnostic Interview-Revised (ADI-R) and the Autism Diagnostic Observation Schedule (ADOS) as well as tests of intelligence and adaptive behavior. Detailed obstetric and family medical/psychiatric histories are taken. All cases are tested for Fragile X and will be extensively evaluated for cytogenetic abnormalities. RESULTS: To date we have obtained clinical evaluations on over 76 cases of possible autism referred to our study and report data for the initial 35 complete cases. The mean age of the probands is 6.7 years, and 31 of the 35 cases are male. Twenty-one of the cases have IQs <50 and only 6 cases have IQs ≥ 70. Over half of the mothers had complications during pregnancy and/or delivery. No cases have tested positively for Fragile X or PKU. Chromosomal G-banding is not yet complete for all cases. CONCLUSION: Diagnostic data gathered on cases of autism in the CVCR using Spanish versions of the ADI-R and ADOS look similar to that generated by studies of English-speaking cases. However, only 17% of our cases have IQs within the normal range, compared to the figure of 25% seen in most studies. This result reflects an ascertainment bias in that only severe cases of autism come to treatment in the CVCR because there are no government-sponsored support programs or early intervention programs providing an incentive to diagnose autism. The severity of mental retardation seen in most of our cases may also be exaggerated by the lack of early intervention programs and the use of IQ tests without Costa Rican norms. Still, we must formally train healthcare providers and teachers to recognize and refer autistic cases with normal or near normal IQs that are not seen in treatment

MODELAMIENTO TERMOCINEMÁTICO 3D DE LA HISTORIA DE EXHUMACIÓN DEL SECTOR DE GUAYABETAL, KM 58 VÍA BOGOTÁ – VILLAVICENCIO: RELACIONES ENTRE CLIMA, RELIEVE Y TECTÓNICA

Las interacciones -clima-tectónica pueden dar lugar a cambios topográficos significativos tanto por aumentos en la elevación como por el incremento de pendientes. Estos cambios, en conjunción con la acción de la gravedad suscitan a su vez diferencias en la energía potencial de materiales geológicos (rocas, agua, etc.) desencadenando procesos geomórficos importantes tales como la erosión por agua, tanto laminar como concentrada, y los movimientos en masa En la vía Bogotá-Villavicencio en el kilómetro 58 del municipio de Guayabetal, se han presentado numerosos fenómenos de remoción en masa. La presente investigación explora como operan las interacciones entre el clima y la tectónica como procesos controladores del relieve actual a corto y largo plazo sobre la zona de estudio. Con esta finalidad se compilaron edades termocronológicas existentes en la zona, y se generó un modelo directo termocinemático 3D para estimar los pulsos y las tasas de exhumación. Los resultados de este último sugieren 3 pulsos de exhumación: el primero entre 40 Ma - 25 Ma a una tasa de exhumación de 0,5 km/Ma, seguido de un pulso entre 25 Ma - 15 Ma con una tasa de 0,1 km/Ma, y finalmente, desde 15 Ma al presente tasas de ~2 km/Ma. Adicionalmente, datos de precipitación fueron utilizados para estimar atributos primarios y secundarios del terreno, mientras que los datos de sismicidad instrumental fueron empleados para calcular la deformación sísmica, energía sísmica y levantamiento vertical por deformación sísmica. Las distintas variables fueron comparadas estadísticamente. Se concluye que el paisaje actual de la zona no es afectado uniformemente por la tectónica y las precipitaciones. En el noroccidente del área existen bajas tasas de erosión y actividad tectónica, así la evolución del paisaje es más pasiva, y el relieve es controlado por el patrón de precipitaciones. En contraste, hacia el suroriente específicamente entre macizo de Quetame y el piedemonte llanero, el relieve es controlado por la tectónica presente en el área. El efecto antrópico con las modificaciones al paisaje introducidas por la creación de una vía nacional, aunque es importante no fue analizado en la presente investigación

The polo-like kinase 1 (PLK1) inhibitor NMS-P937 is effective in a new model of disseminated primary CD56+ acute monoblastic leukaemia

CD56 is expressed in 15–20% of acute myeloid leukaemias (AML) and is associated with extramedullary diffusion, multidrug resistance and poor prognosis. We describe the establishment and characterisation of a novel disseminated model of AML (AML-NS8), generated by injection into mice of leukaemic blasts freshly isolated from a patient with an aggressive CD56+ monoblastic AML (M5a). The model reproduced typical manifestations of this leukaemia, including presence of extramedullary masses and central nervous system involvement, and the original phenotype, karyotype and genotype of leukaemic cells were retained in vivo. Recently Polo-Like Kinase 1 (PLK1) has emerged as a new candidate drug target in AML. We therefore tested our PLK1 inhibitor NMS-P937 in this model either in the engraftment or in the established disease settings. Both schedules showed good efficacy compared to standard therapies, with a significant increase in median survival time (MST) expecially in the established disease setting (MST = 28, 36, 62 days for vehicle, cytarabine and NMS-P937, respectively). Importantly, we could also demonstrate that NMS-P937 induced specific biomarker modulation in extramedullary tissues. This new in vivo model of CD56+ AML that recapitulates the human tumour lends support for the therapeutic use of PLK1 inhibitors in AML

Resistance to autosomal dominant Alzheimer's disease in an APOE3 Christchurch homozygote: a case report.

We identified a PSEN1 (presenilin 1) mutation carrier from the world's largest autosomal dominant Alzheimer's disease kindred, who did not develop mild cognitive impairment until her seventies, three decades after the expected age of clinical onset. The individual had two copies of the APOE3 Christchurch (R136S) mutation, unusually high brain amyloid levels and limited tau and neurodegenerative measurements. Our findings have implications for the role of APOE in the pathogenesis, treatment and prevention of Alzheimer's disease

Materials selection for optimum energy production by double layer expansion methods

NOTICE: this is the author’s version of a work that was accepted for publication in Journal of Power Sources. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Journal of Power Sources (2014) DOI:http://dx.doi.org/10.1016/j.jpowsour.2013.12.125The capacitive mixing procedure for energy extraction based on Double Layer Expansion (CDLE) belongs to the group of so-called CAPMIX techniques, which aim at obtaining energy from the salinity difference between fresh and sea waters. Specifically, the CDLE technique takes advantage of the voltage rise that occurs when sea water is exchanged for river water in a pair of porous electrodes which jointly behave as an electrical double layer supercapacitor. In this article, we deal with some experimental aspects that are key for optimizing the extracted energy, and have not been analyzed yet with sufficient detail. This investigation will help in evaluating those parameters which we need to be fixed in a future CDLE device. These include the charging potential, the durations of the different cycle steps, the load resistance used, and the porosity and hydrophilicity of the carbon.Departamento de Física Aplicada, Universidad de GranadaThe research leading to these results received funding from the European Union 7th Framework Programme (FP7/2007-2013) under agreement No. 256868. Further financial support from Junta de Andalucía (Spain), project PE-2008-FQM3993 is also gratefully acknowledged

NIVEL DE CONOCIMIENTOS DEL DIABÉTICO SOBRE SU AUTO CUIDADO

INTRODUCTION The diabetes treatment is complex. Its results depend, to a great extent, on the level of comprehension, skill and motivation that the user face up to the therapeutic requirements. OBJETIVE To identify the knowledge level that the diabetic user has about his/her autocare. MATERIAL AND METHODS A descriptive survey was carried out in 94 diabetic inpatients in the services of Internal Medicine and Surgery of the General Regional Hospital No. 1 of Culiacán, Sinaloa. Diabetics of 20 years old and older with more of 72 hours of hospitalization in internal medicine and surgery were included in the survey. A questionnaire providing socio-demographic aspects such as age, gender, education, knowledge level of the diabetic user about his/her autocare dealing aspects like exercise, diet, feet care and pharmacological treatment was used. RESULTS More than half (56%) of the studied population is men, with an average age of 60 years old with a standard deviation of +- 12.36. The knowledge level about his/her autocare was insufficient in 79%. CONCLUSIONS The diabetic users have insufficient knowledge about their autocare. The aspects they know more about are the exercise and the diet, while they know little about the feet care and pharmacological treatment.INTRODUCCIÓN El tratamiento de la diabetes es complejo y sus resultados dependen, en gran medida del nivel de comprensión, destreza y motivación con que el usuario afronta las exigencias terapéuticas. OBJETIVO Identificar el nivel de conocimiento que el usuario diabético tiene sobre su autocuidado. MATERIAL Y MÉTODOS Se realizó una encuesta descriptiva a 94 diabéticos hospitalizados en los servicios de medicina interna y cirugía del Hospital General Regional No. 1 de Culiacán Sinaloa. Se incluyeron diabéticos de 20 y más años de edad, con más de 72 horas de hospitalización en el servicio. Se utilizó un cuestionario que contempló aspectos sociodemográficos como son edad, sexo, escolaridad, nivel de conocimiento del usuario diabético sobre su autocuidado, contemplando aspectos como ejercicio, alimentación, cuidado de los pies y tratamiento farmacológico. RESULTADO De la población estudiada se encontró que el 56% son del sexo masculino, con un promedio de 60 años de edad con una desviación estándar de + - 12.36. Nivel de conocimiento del diabético sobre su auto cuidado fue insuficiente en un 79 %. CONCLUSIONES Los usuarios diabéticos tienen conocimientos insuficientes sobre su autocuidado. Los aspectos sobre los que más conoce son el ejercicio y la alimentación, no así el cuidado de sus pies y lo relacionado al tratamiento farmacológico

Effect of Solution Composition on the Energy Production by Capacitive Mixing in Membrane-Electrode Assembly

The final edited version of the paper can be found at: http://pubs.acs.org/articlesonrequest/AOR-c9UMxSzGY3eiU5SENNgT The complete citation is: Ahualli, S.; et al. Effect of Solution Composition on the Energy Production by Capacitive Mixing in Membrane-Electrode Assembly. Journal of Physical Chemistry, 118(29): 15590-15599 (2014). DOI:10.1021/jp504461mOpen access in the Journal on May 26, 2015In this work we consider the extent to which the presence of multi-valent ions in solution modifies the equilibrium and dynamics of the energy production in a capacitive cell built with ion-exchange membranes in contact with high surface area electrodes. The cell potential in open circuit (OCV) is controlled by the difference between both membrane potentials, simulated as constant volume charge regions. A theoretical model is elaborated for steady state OCV, first in the case of monovalent solutions, as a reference. This is compared to the results in multi-ionic systems, containing divalent cations in concentrations similar to those in real sea water. It is found that the OCV is reduced by about 25 % (as compared to the results in pure NaCl solutions) due to the presence of the divalent ions, even in low concentrations. Interestingly, this can be related to the “uphill” transport of such ions against their concentration gradients. On the contrary, their effect on the dynamics of the cell potential is negligible in the case of highly charged membranes. The comparison between model predictions and experimental results shows a very satisfactory agreement, and gives clues for the practical application of these recently introduced energy production methods.The research leading to these results received funding from the European Union 7th Framework Programme (FP7/2007-2013) under agreement No. 256868. Further financial support from Junta de Andalucia, Spain (PE2012-FQM 694) is also acknowledged. One of us, M.M.F., received financial support throughan FPU grant from the Universityof Granada