A protocol for precise comparisons of small vessel disease lesions between ex vivo magnetic resonance imaging and histopathology

pp. 310-32La neuroimagen y los estudios clínicos han definido la enfermedad cerebral de los vasos pequeños humanos, pero la fisiopatología sigue siendo relativamente poco comprendida. Para desarrollar terapias eficaces y estrategias preventivas, debemos comprender mejor la heterogeneidad y el desarrollo de la enfermedad de los vasos pequeños a nivel celular.S

Dutch translation and cross-cultural validation of the Adult Social Care Outcomes Toolkit (ASCOT)

Background: The Adult Social Care Outcomes Toolkit was developed to measure outcomes of social care in England. In this study, we translated the four level self-completion version (SCT-4) of the ASCOT for use in the Netherlands and performed a cross-cultural validation. Methods: The ASCOT SCT-4 was translated into Dutch following international guidelines, including two forward and back translations. The resulting version was pilot tested among frail older adults using think-aloud interviews. Furthermore, using a subsample of the Dutch ACT-study, we investigated test-retest reliability and construct validity and compared response distributions with data from a comparable English study. Results: The pilot tests showed that translated items were in general understood as intended, that most items were reliable, and that the response distributions of the Dutch translation and associations with other measures were comparable to the original English version. Based on the results of the pilot tests, some small modifications and a revision of the Dignity items were proposed for the final translation, which were approved by the ASCOT development team. The complete original English version and the final Dutch translation can be obtained after registration on the ASCOT website (http://www.pssru.ac.uk/ascot). Conclusions: This study provides preliminary evidence that the Dutch translation of the ASCOT is valid, reliable and comparable to the original English version. We recommend further research to confirm the validity of the modified Dutch ASCOT translation

Impaired Glymphatic Function and Pulsation Alterations in a Mouse Model of Vascular Cognitive Impairment

ACKNOWLEDGMENTS Schematic diagrams in Figures 2, 8 are created withBiorender.com. FUNDING We gratefully acknowledge the grant support from the Alzheimer’s Society (152 (PG-157); 290 (AS-PG-15b-018); 228 (AS-DTC-2014-017), 314 (AS –PhD-16-006), and Alzheimer’s Research United Kingdom (ART-PG2010-3; ARUK-PG2013- 22; ARUK-PG2016B-6), and The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (G0700704/84698). ML and JB are funded by an Alzheimer’s Society Scotland Doctoral Training Programme and RS Macdonald Trust. ML was also funded by a China Scholarship Council (CSC)/University of Edinburgh scholarship.Peer reviewedPublisher PD

Non-invasive in vivo assessment of 11β-hydroxysteroid dehydrogenase type 1 activity by 19F-Magnetic Resonance Spectroscopy

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) amplifies tissue glucocorticoid levels and is a pharmaceutical target in diabetes and cognitive decline. Clinical translation of inhibitors is hampered by lack of in vivo pharmacodynamic biomarkers. Our goal was to monitor substrates and products of 11β-HSD1 non-invasively in liver via 19Fluorine magnetic resonance spectroscopy (19F-MRS). Interconversion of mono/poly-fluorinated substrate/product pairs was studied in Wistar rats (male, n = 6) and healthy men (n = 3) using 7T and 3T MRI scanners, respectively. Here we show that the in vitro limit of detection, as absolute fluorine content, was 0.625 μmole in blood. Mono-fluorinated steroids, dexamethasone and 11-dehydrodexamethasone, were detected in phantoms but not in vivo in human liver following oral dosing. A non-steroidal polyfluorinated tracer, 2-(phenylsulfonyl)-1-(4-(trifluoromethyl)phenyl)ethanone and its metabolic product were detected in vivo in rat liver after oral administration of the keto-substrate, reading out reductase activity. Administration of a selective 11β-HSD1 inhibitor in vivo in rats altered total liver 19F-MRS signal. We conclude that there is insufficient sensitivity to measure mono-fluorinated tracers in vivo in man with current dosage regimens and clinical scanners. However, since reductase activity was observed in rats using poly-fluorinated tracers, this concept could be pursued for translation to man with further development

Translating international HIV treatment guidelines into local priorities in Indonesia

Objective: International guidelines recommend countries to expand antiretroviral therapy (ART) to all HIV-infected individuals and establish local-level priorities in relation to other treatment, prevention and mitigation interventions through fair processes. However, no practical guidance is provided for such priority-setting processes. Evidence-informed deliberative processes (EDPs) fill this gap and combine stakeholder deliberation to incorporate relevant social values with rational decision-making informed by evidence on these values. This study reports on the first-time implementation and evaluation of an EDP in HIV control, organised to support the AIDS Commission in West Java province, Indonesia, in the development of its strategic plan for 2014–2018. Methods: Under the responsibility of the provincial AIDS Commission, an EDP was implemented to select priority interventions using six steps: (i) situational analysis; (ii) formation of a multistakeholder Consultation Panel; (iii) selection of criteria; (iv) identification and assessment of interventions’ performance; (v) deliberation; and (vi) selection of funding and implementing institutions. An independent researcher conducted in-depth interviews (n = 21) with panel members to evaluate the process. Results: The Consultation Pa

Robust Revascularization in Models of Limb Ischemia Using a Clinically Translatable Human Stem Cell-Derived Endothelial Cell Product

Pluripotent stem cell-derived differentiated endothelial cells offer high potential in regenerative medicine in the cardiovascular system. With the aim of translating the use of a human stem cell-derived endothelial cell product (hESC-ECP) for treatment of critical limb ischemia (CLI) in man, we report a good manufacturing practice (GMP)-compatible protocol and detailed cell tracking and efficacy data in multiple preclinical models. The clinical-grade cell line RC11 was used to generate hESC-ECP, which was identified as mostly endothelial (60% CD31+/CD144+), with the remainder of the subset expressing various pericyte/mesenchymal stem cell markers. Cell tracking using MRI, PET, and qPCR in a murine model of limb ischemia demonstrated that hESC-ECP was detectable up to day 7 following injection. Efficacy in several murine models of limb ischemia (immunocompromised/immunocompetent mice and mice with either type I/II diabetes mellitus) demonstrated significantly increased blood perfusion and capillary density. Overall, we demonstrate a GMP-compatible hESC-ECP that improved ischemic limb perfusion and increased local angiogenesis without engraftment, paving the way for translation of this therapy