Preclinical carotid atherosclerosis in patients with latent autoimmune diabetes in adults (LADA), type 2 diabetes and classical type 1 diabetes

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.This project was funded by Grants Nos. PI12/00183 and PI15/00625, both included in Plan Nacional de I + D + I, and co-financed by Instituto de Salud Carlos III, Subdireccion General de Evaluacion, Ministry of Economy and Competitiveness, and Fondo Europeo de Desarrollo Regional (FEDER). CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM) is an initiative from Instituto de Salud Carlos III, Spain

The DAC system and associations with multiple myeloma

Despite the clear progress achieved in recent years in the treatment of MM, most patients eventually relapse and therefore novel therapeutic options are still necessary for these patients. In this regard, several drugs that target specific mechanisms of the tumor cells are currently being explored in the preclinical and clinical setting. This manuscripts offers a review of the rationale and current status of the antimyeloma activity of one of the most relevant examples of these targeted drugs: deacetylase inhibitors (DACi). Several studies have demonstrated the prooncogenic activity of deacetylases (DACs) through the targeting not only of histones but also of non histone proteins relevant to tumor progression, such as p53, E2F family members, Bcl-6, Hsp90, HIF-1α or Nur77. This fact together with the DACs overexpression present in several tumors, has prompted the development of some DACi with potential antitumor effect. This situation is also evident in the case of MM as two mechanisms of DACi, the inhibition of the epigenetic inactivation of p53 and the blockade of the unfolded protein response, through the inhibition of the aggressome formation (by targeting DAC6) and the inactivation of the chaperone system (by acetylating HSP-90), provides the rationale for the exploration of the potential antimyeloma activity of these compounds. Several DACi with different chemical structure and different selectivity for targeting the DAC families have been tested in MM. Their preclinical activity in monotherapy has been quite exciting and has been described to be mediated by various mechanisms: the induction of apoptosis and cell cycle arrest mainly by the upregulation of p21; the interferece with the interaction between plasma cells and the microenvironment, by reducing the expression and signalling of several cytokines or by inhibiting angiogenesis. Finally they also have a role in protecting murine models from myeloma bone disease. Neverteless, the clinical activity in monotherapy of these drugs in relapsed/refractory MM patients has been very modest. This has prompted the development of combinations such as the one with bortezomib or lenalidomide and dexamethasone, which have already been taken into the clinics with positive preliminary results

Exploring consensus on how to measure smoking cessation. A Delphi study

Background Different criteria regarding outcome measures in smoking research are used, which can lead to confusion about study results. Consensus in outcome criteria may enhance the comparability of future studies. This study aims (1) to provide an overview of tobacco researchers’ considered preferences regarding outcome criteria in randomized controlled smoking cessation trials, and (2) to identify the extent to which researchers can reach consensus on the importance of these outcome criteria. Methods A three-round online Delphi study was conducted among smoking cessation experts. In the first round, the most important smoking cessation outcome measures were collected by means of open-ended questions, which were categorized around self-reported and biochemical validation measures. Experts (n = 17) were asked to name the outcome measures (as well as their assessment method and ideal follow-up period) that they thought were important when assessing smoking-related outcomes. In the second (n = 48) and third rounds (n = 37), a list of outcome measures—identified in the first round—was presented to experts. Asking them to rate the importance of each measure on a seven-point scale. Results Experts reached consensus on several items. For self-reports, experts agreed that prolonged abstinence (6 or/and 12 months), point prevalence abstinence (7 days), continuous abstinence (6 months), and the number of cigarettes smoked (7 days) are important outcome measures. Experts reached consensus that biochemical validation methods should not always be used. The preferred biochemical validation methods were carbon monoxide (expired air) and cotinine (saliva). Preferred follow-ups included 6 and/or 12 months, with or without intermediate measurements. Conclusions Findings suggest only partial compliance with the Russell standard and that more outcome measures may be important (including seven-day point-prevalence abstinence, number of cigarettes smoked, and cotinine when using biochemical validation). This study showed where there is and is not consensus, reflecting the need to develop a more comprehensive standard. For these purposes we provided suggestions for the Russell 2.0 standard

The Atlantic Ocean at the last glacial maximum: 2. Reconstructing the current systems with a global ocean model

We use a global ocean general circulation model (OGCM) with low vertical diffusion and isopycnal mixing to simulate the circulation in the Atlantic Ocean at present-day and the Last Glacial Maximum (LGM). The OGCM includes d18O as a passive tracer. Regarding the LGM sea-surface boundary conditions, the temperature is based on the GLAMAP reconstruction, the salinity is estimated from the available d18O data, and the wind-stress is derived from the output of an atmospheric general circulation model. Our focus is on changes in the upper-ocean hydrology, the large-scale horizontal circulation and the d18O distribution. In a series of LGM experiments with a step-wise increase of the sea-surface salinity anomaly in the Weddell Sea, the ventilated thermocline was colder than today by 2 3°C in the North Atlantic Ocean and, in the experiment with the largest anomaly (1.0 beyond the global anomaly), by 4-5°C in the South Atlantic Ocean; furthermore it was generally shallower. As the meridional density gradient grew, the Antarctic Circumpolar Current strengthened and its northern boundary approached Cape of Good Hope. At the same time the southward penetration of the Agulhas Current was reduced, and less thermocline-to-intermediate water slipped from the Indian Ocean along the southern rim of the African continent into the South Atlantic Ocean; the 'Agulhas leakage' was diminished by up to 60% with respect to its modern value, such that the cold water route became the dominant path for North Atlantic Deep Water (NADW) renewal. It can be speculated that the simulated intensification of the Benguela Current and the enhancement of NADW upwelling in the Southern Ocean might reduce the import of silicate into the Benguela System, which could possibly resolve the 'Walvis Opal Paradox'. Although d18Ow was restored to the same surface values and could only reflect changes in advection and diffusion, the resulting d18Oc distribution came close to reconstructions based on fossil shells of benthic foraminifera

Confronting or Complementing? A Case Study on NGO-State Relations from Kerala, India

Contains fulltext : 90089.pdf (publisher's version ) (Closed access)NGOs have, of late, found some of their traditional domains, such as provision of micro-credit and participatory development, coinciding with or being taken away by the state. How do they position themselves and retain relevance vis-a-vis the state in the changed scenario? Tracing the trajectory of interventions of a local NGO in Kerala, India, this article shows that NGOs exhibit ‘multiple identities’— selective collaboration, gap-filling and posing alternatives—in the process of engagement with the state. The ‘strategizing’ of such identities may hold the key to their relevance vis-a-vis the state