Percepción de los residentes sobre el desarrollo de lamicro región Tierra de Palmares desde la perspectiva del turismo rural integrado

El objetivo de este trabajo es analizar las percepciones de los residentes sobre las variables implicadas en el desarrollo del Turismo Rural Integrado (TRI) así como sus efectos sobre dicho desarrollo. Para ello, se analiza el caso concreto de los residentes de Tierra de Palmares, micro región implicada en un proyecto de desarrollo turístico. Los residentes constituyen uno de los principales actores para que este tipo de turismo pueda desarrollarse de manera exitosa. El análisis descriptivo realizado así como el análisis de Componentes Principales, muestra que los residentes perciben la existencia de las variables clave para alcanzar el tipo de turismo deseado. Así, se comprueba que se percibe la existencia de colaboración entre los agentes implicados y el carácter arraigado, endógeno y complementario de las actividades turísticas desarrolladas, las cuales permiten el empoderamiento de los residentes. Además, los efectos positivos del turismo también se están alcanzando, ya que se percibe la existencia de sostenibilidad económica, sociocultural y medioambiental. Los resultados de las regresiones realizadas muestran que los efectos de todas estas variables sobre el desarrollo del TRI son positivos aunque deben ser analizados con mayor profundidad. Así, se detecta el efecto positivo sobre el TRI de la existencia de redes informativas, del empoderamiento de los residentes, del desarrollo del turismo como complementario a las actividades tradicionales y del uso compartido de recursos con los turistas. Sin embargo, la inclusión de las sostenibilidades en la regresión diluye el efecto ejercido por la complementariedad y el uso compartido. Estos resultados ponen de manifiesto la necesidad de plantear relaciones indirectas entre todas las variables potencialmente determinantes del TRI, las cuales mejorarían la comprensión de su desarrollo. The objective of this work is to analyze the perceptions of residents regarding the variables involved in developing Integrated Rural Tourism (IRT), as well as analyze how those variables affect said development. Therefore, we have analyzed the specific case of the residents of Tierra de Palmares, which is an area involved in a tourism development project. The residents constitute one of the main actors involved in the successful development of this type of tourism. The descriptive analysis performed as well as the Principal Components analysis shows the residents perceive the existence of key variables for reaching the desired type of tourism. Thus, it is verified that there is cooperation between the agents involved and the embedded, endogenous and complementary nature of the tourism activities that are developed, which activities allow empowering the residents. Moreover, it seems that positive effects are being generated by tourism, given that the existence of economic, sociocultural and environmental sustainability is perceived. The results of the regressions performed show that the effects of all these variables on the development of IRT are positive, although they should be analysed more in depth. Thus, the positive effect on IRT of the existence of information networks, the empowerment of residents, the development of tourism as complementary to traditional activities and the sharing of resources with tourists is detected. However, the inclusion of sustainability in the regression dilutes the effect exerted by complementarity and sharing. These results demonstrate the need to establish indirect relationships between all potentially determinant variables of TRI, which would improve the understanding of their development

Effect of AGM and Fetal Liver-Derived Stromal Cell Lines on Globin Expression in Adult Baboon (P. anubis) Bone Marrow-Derived Erythroid Progenitors

This study was performed to investigate the hypothesis that the erythroid micro-environment plays a role in regulation of globin gene expression during adult erythroid differentiation. Adult baboon bone marrow and human cord blood CD34+ progenitors were grown in methylcellulose, liquid media, and in co-culture with stromal cell lines derived from different developmental stages in identical media supporting erythroid differentiation to examine the effect of the micro-environment on globin gene expression. Adult progenitors express high levels of γ-globin in liquid and methylcellulose media but low, physiological levels in stromal cell co-cultures. In contrast, γ-globin expression remained high in cord blood progenitors in stromal cell line co-cultures. Differences in γ-globin gene expression between adult progenitors in stromal cell line co-cultures and liquid media required cell-cell contact and were associated with differences in rate of differentiation and γ-globin promoter DNA methylation. We conclude that γ-globin expression in adult-derived erythroid cells can be influenced by the micro-environment, suggesting new potential targets for HbF induction

Researching together: Exploring research productivity and collaboration of librarians in ASEAN countries

This study employs bibliometrics to examine the research productivity and patterns of collaboration of librarians in the Association of Southeast Asian Nations (ASEAN) countries. All articles, conference papers, book chapters, and reviews in the LIS field written by librarians from ASEAN countries between 2001 and 2016 indexed by Scopus and Web of Science were extracted. Research publications were analysed in terms of productivity by country and institutions, authorship and collaboration patterns, document types, subject categories and publication year. While many of the librarians had conducted research as a requirement for their bachelor and/or master degree in Library and Information Science (LIS), research writing and knowledge sharing through publishing and paper presentation in conferences were not prevailing research activities. Librarians from Malaysia were the most productive authors in this dataset. Many of the scholarly works were single authored. Therefore, the degree of collaboration between authors was quite low. Likewise, the growth rate of research collaboration cannot be predicted from this data. This study provides recommendations to encourage ASEAN librarians to actively engage in research not just for personal benefits, but also to advance the librarianship as a profession. © 2018, © 2018 Australian Library & Information Association

Oral tetrahydrouridine and decitabine for non-cytotoxic epigenetic gene regulation in sickle cell disease: A randomized phase 1 study

<div><p>Background</p><p>Sickle cell disease (SCD), a congenital hemolytic anemia that exacts terrible global morbidity and mortality, is driven by polymerization of mutated sickle hemoglobin (HbS) in red blood cells (RBCs). Fetal hemoglobin (HbF) interferes with this polymerization, but HbF is epigenetically silenced from infancy onward by DNA methyltransferase 1 (DNMT1).</p><p>Methods and findings</p><p>To pharmacologically re-induce HbF by DNMT1 inhibition, this first-in-human clinical trial (NCT01685515) combined 2 small molecules—decitabine to deplete DNMT1 and tetrahydrouridine (THU) to inhibit cytidine deaminase (CDA), the enzyme that otherwise rapidly deaminates/inactivates decitabine, severely limiting its half-life, tissue distribution, and oral bioavailability. Oral decitabine doses, administered after oral THU 10 mg/kg, were escalated from a very low starting level (0.01, 0.02, 0.04, 0.08, or 0.16 mg/kg) to identify minimal doses active in depleting DNMT1 without cytotoxicity. Patients were SCD adults at risk of early death despite standard-of-care, randomized 3:2 to THU–decitabine versus placebo in 5 cohorts of 5 patients treated 2X/week for 8 weeks, with 4 weeks of follow-up. The primary endpoint was ≥ grade 3 non-hematologic toxicity. This endpoint was not triggered, and adverse events (AEs) were not significantly different in THU-decitabine—versus placebo-treated patients. At the decitabine 0.16 mg/kg dose, plasma concentrations peaked at approximately 50 nM (C_max) and remained elevated for several hours. This dose decreased DNMT1 protein in peripheral blood mononuclear cells by >75% and repetitive element CpG methylation by approximately 10%, and increased HbF by 4%–9% (<i>P</i> < 0.001), doubling fetal hemoglobin-enriched red blood cells (F-cells) up to approximately 80% of total RBCs. Total hemoglobin increased by 1.2–1.9 g/dL (<i>P</i> = 0.01) as reticulocytes simultaneously decreased; that is, better quality and efficiency of HbF-enriched erythropoiesis elevated hemoglobin using fewer reticulocytes. Also indicating better RBC quality, biomarkers of hemolysis, thrombophilia, and inflammation (LDH, bilirubin, D-dimer, C-reactive protein [CRP]) improved. As expected with non-cytotoxic DNMT1-depletion, platelets increased and neutrophils concurrently decreased, but not to an extent requiring treatment holds. As an early phase study, limitations include small patient numbers at each dose level and narrow capacity to evaluate clinical benefits.</p><p>Conclusion</p><p>Administration of oral THU-decitabine to patients with SCD was safe in this study and, by targeting DNMT1, upregulated HbF in RBCs. Further studies should investigate clinical benefits and potential harms not identified to date.</p><p>Trial registration</p><p>ClinicalTrials.gov, <a target="_blank">NCT01685515</a></p></div

Adverse events (AEs).

<p><b>(A)</b> AEs with possible relatedness to the study drug (AEs other than “unrelated”) per judgement of the treating clinical teams. <b>(B)</b> All grade 3 AEs occurring in study drug—and placebo-treated patients. These grade 3 AEs were sickle cell complications judged to be unrelated to the study drug by the treating clinical teams. <b>(C)</b> Statistical comparison of grade 3 AEs between placebo and decitabine dose-level patients. R function poisson.test(), an exact test, was used. Abbreviation: ED/Hosp, emergency department/hospital.</p

Pharmacokinetics (PK) and pharmacodynamics (PD) of oral tetrahydrouridine (THU)-decitabine.

<p><b>(A)</b> Decitabine PK. Samples for PK analysis were obtained in 12 of the 15 patients who received the study drug. Times are listed in hours after administration of oral decitabine. Data points are measured values and curves are fits using the R package PKLMfit. The inset shows a close-up of hours 0–4. Decitabine was quantified by a validated liquid chromatography tandem mass spectrometry (LCMS/MS) method. <b>(B)</b> DNMT1 protein levels in peripheral blood mononuclear cells (PBMC) measured by flow cytometry in cohorts 4 and 5 (decitabine 0.08 mg/kb and 0.16 mg/kg, respectively) and in all placebo-treated patients. Analyses were blinded to treatment assignment. Shown are means of 2 independent measurements. <b>(C)</b> Methylation of long interspersed nuclear elements (LINE-1) repetitive element CpGs (3 individual CpGs) in PBMC in cohorts 4 and 5 placebo and drug-treated patients. Analyses were blinded to treatment assignment. Measurements were made by pyrosequencing. Shown are means of 2 independent measurements.</p

Blood counts and other parameters in cohort 4 (decitabine 0.08 mg/kg) and 5 (decitabine 0.16 mg/kg) tetrahydrouridine (THU)-decitabine–treated patients.

<p><b>(A)</b> Total hemoglobin. <b>(B)</b> Statistical analysis of the rates of change in total hemoglobin (Hbg) with increasing doses of decitabine (0 = placebo); <i>P</i> value determined by linear regression. <b>(C)</b> Absolute reticulocyte counts (ARC). <b>(D, E)</b> LDH and total bilirubin. These are biomarkers of hemolysis. <b>(F)</b> D-dimer. A biomarker of coagulation activation. <b>(G)</b> C-reactive protein (CRP). A biomarker of inflammation. <b>(H)</b> Platelets. <b>(I)</b> Absolute neutrophil counts (ANC).</p

Fetal hemoglobin (HbF) induction in cohort 4 and 5 patients.

<p><b>(A)</b> HbF percentage (HbF%) over time in cohorts 4 and 5 (decitabine 0.08 mg/kg and 0.16 mg/kg, respectively) patients. <b>(B)</b> Statistical analysis of the rates of change in HbF% with increasing doses of decitabine (0 = placebo); <i>P</i> value determined by linear regression. <b>(C)</b> Change in HbF% from pretreatment to week 8 or 10. <b>(D)</b> Absolute HbF levels. <b>(E)</b> Proportion of red blood cells (RBCs) expressing high levels of HbF (F-cells) in cohort 4 and 5 patients. <b>(F)</b> Raw F-cell flow cytometry data for cohort 5 tetrahydrouridine (THU)-decitabine—and placebo-treated patients. Abbreviation: FS, forward scatter.</p