Cerebral cortex hyperthyroidism of newborn Mct8-deficient mice transiently suppressed by Lat2 inactivation

Thyroid hormone entry into cells is facilitated by transmembrane transporters. Mutations of the specific thyroid hormone transporter, MCT8 (Monocarboxylate Transporter 8, SLC16A2) cause an X-linked syndrome of profound neurological impairment and altered thyroid function known as the Allan-Herndon-Dudley syndrome. MCT8 deficiency presumably results in failure of thyroid hormone to reach the neural target cells in adequate amounts to sustain normal brain development. However during the perinatal period the absence of Mct8 in mice induces a state of cerebral cortex hyperthyroidism, indicating increased brain access and/or retention of thyroid hormone. The contribution of other transporters to thyroid hormone metabolism and action, especially in the context of MCT8 deficiency is not clear. We have analyzed the role of the heterodimeric aminoacid transporter Lat2 (Slc7a8), in the presence or absence of Mct8, on thyroid hormone concentrations and on expression of thyroid hormone-dependent cerebral cortex genes. To this end we generated Lat2-/-, and Mct8-/yLat2-/- mice, to compare with wild type and Mct8-/y mice during postnatal development. As described previously the single Mct8 KO neonates had a transient increase of 3,5,3′-triiodothyronine concentration and expression of thyroid hormone target genes in the cerebral cortex. Strikingly the absence of Lat2 in the double Mct8Lat2 KO prevented the effect of Mct8 inactivation in newborns. The Lat2 effect was not observed from postnatal day 5 onwards. On postnatal day 21 the Mct8 KO displayed the typical pattern of thyroid hormone concentrations in plasma, decreased cortex 3,5,3′-triiodothyronine concentration and Hr expression, and concomitant Lat2 inactivation produced little to no modifications. As Lat2 is expressed in neurons and in the choroid plexus, the results support a role for Lat2 in the supply of thyroid hormone to the cerebral cortex during early postnatal development

A parallel-group, multicenter randomized, double-blinded, placebo-controlled, phase 2/3, clinical trial to test the efficacy of pyridostigmine bromide at low doses to reduce mortality or invasive mechanical ventilation in adults with severe SARS-CoV-2 infection: the Pyridostigmine In Severe COvid-19 (PISCO) trial protocol

© 2020, The Author(s). Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the causative agent of coronavirus disease 2019 (COVID-19), may lead to severe systemic inflammatory response, pulmonary damage, and even acute respiratory distress syndrome (ARDS). This in turn may result in respiratory failure and in death. Experimentally, acetylcholine (ACh) modulates the acute inflammatory response, a neuro-immune mechanism known as the inflammatory reflex. Recent clinical evidence suggest that electrical and chemical stimulation of the inflammatory reflex may reduce the burden of inflammation in chronic inflammatory diseases. Pyridostigmine (PDG), an ACh-esterase inhibitor (i-ACh-e), increases the half-life of endogenous ACh, therefore mimicking the inflammatory reflex. This clinical trial is aimed at evaluating if add-on of PDG leads to a decrease of invasive mechanical ventilation and death among patients with severe COVID-19. Methods: A parallel-group, multicenter, randomized, double-blinded, placebo-controlled, phase 2/3 clinical trial to test the efficacy of pyridostigmine bromide 60 mg/day P.O. to reduce the need for invasive mechanical ventilation and mortality in hospitalized patients with severe COVID-19. Discussion: This study will provide preliminary evidence of whether or not -by decreasing systemic inflammation- add-on PDG can improve clinical outcomes in patients with severe COVID-19. Trial registration: ClinicalTrials.gov NCT04343963 (registered on April 14, 2020)

Options for agriculture at Marrakech climate talks: messages for SBSTA 45 agriculture negotiators

SBSTA 45 in Marrakech represents a unique opportunity for Parties to decide on the future of agriculture within the UNFCCC. The process of discussions on issues related to agriculture initiated at COP17 in Durban 2011 culminates at COP22 in Marrakech 2016. The explicit reference to food security in the preamble of the Paris Agreement and the Intended Nationally Determined Contributions which prioritize agriculture as a sector for adaptation and mitigation actions, provide a foundation for Parties to develop appropriate frameworks to support actions within the agricultural sector. SBSTA workshops on agriculture in 2015 and 2016 allowed Parties to share experiences, identify priorities, and propose ways of taking action within the agricultural sector and so provide the core knowledge base to work from. As Parties reach a decision on issues related to agriculture at SBSTA 45, a number of options are available. This report presents ten such options that might contribute to a decision, taking into consideration political priorities, implementation arrangements, timelines and level of ambition. Options outlined in this report are not mutually exclusive and can be combined in many different ways

Treballs d'investigació en atenció primària: revisió dels treballs en llengües espanyoles publicats l'any 1986

Revisem 29 treballs elaborats per professionals d'atenció primària i publicats a: Atención Primaria, Medicina Clínica, Gaseta Sanitaria, Revista Clínica Española, Revista Española de Pediatría i Annals de Medicina. La majoria els trobem realitzats per especialistes o residents de Medicina Familiar i Comunitària, amb absència de pediatres. Entre els temes analitzats destaca l'anàlisi de la demanda, hipertensió arterial i vacunacions, que totalitzen quasi el 50% dels treballs. Cal ressaltar un 89% de dissenys descriptius, amb solament dos de tipus analític o experimental. Sobre 6 paràmetres d'adequació metodològica hi hagué un compliment mitjà de 4,38 (DE = 2,23). El 52% dels treballs no tenien tractament estadístic. Creiem que hi ha una extensa variabilitat en la qualitat deis treballs i que és necessari adaptar la temàtica d'interès deis investigadors i adaptar els dissenys a la demostració d'hipòtesis que suposin canvis en la pràctica assistencial

Predicting long-term disease control in transplant-ineligible patients with multiple myeloma: impact of an MGUS-like signature

Disease control at 5 years would be a desirable endpoint for elderly multiple myeloma (MM) patients, but biomarkers predicting this are not defined. Therefore, to gain further insights in this endpoint, a population of 498 newly diagnosed transplant-ineligible patients enrolled in two Spanish trials (GEM2005MAS65 and GEM2010MAS65), has been analyzed. Among the 435 patients included in this post-hoc study, 18.6% remained alive and progression free after 5 years of treatment initiation. In these patients, overall survival (OS) rate at 10 years was 60.8% as compared with 11.8% for those progressing within the first 5 years. Hemoglobin (Hb) = 12 g/dl (OR 2.74, p = 0.001) and MGUS-like profile (OR 4.18, p = 0.005) were the two baseline variables associated with long-term disease-free survival. Upon including depth of response (and MRD), Hb = 12 g/dl (OR 2.27) and MGUS-like signature (OR 7.48) retained their predictive value along with MRD negativity (OR 5.18). This study shows that despite the use of novel agents, the probability of disease control at 5 years is still restricted to a small fraction (18.6%) of elderly MM patients. Since this endpoint is associated with higher rates of OS, this study provides important information about diagnostic and post-treatment biomarkers helpful in predicting the likelihood of disease control at 5 years

Latin America: the next region for haematopoietic transplant progress

Haematopoietic cell transplant activity in the 28 countries comprising Latin America is poorly defined. We conducted a voluntary survey of members of the Latin American Bone Marrow Transplantation Group regarding transplant activity 2009–2012. Collated responses were compared with data of transplant rates from the Worldwide Network for Blood and Marrow Transplantation for other geographic regions. Several socio-economic variables were analysed to determine correlations with transplant rates. In total, 94 teams from 12 countries reported 11519 transplants including 7033 autotransplants and 4486 allotransplants. Annual activity increased from 2517 transplants in 2009 to 3263 in 2012, a 30% increase. Median transplants rate (transplant per million inhabitants) in 2012 was 64 (autotransplants, median 40; allotransplants, median 24). This rate is substantially lower than that in North America and European regions (482 and 378) but higher than that in the Eastern Mediterranean and Asia Pacific regions (30 and 45). However, the Latin America transplant rate is 5–8-fold lower than that in America and Europe, suggesting a need to increase transplant availability. Transplant team density in Latin America (teams per million population; 1.8) is 3–4-fold lower than that in North America (6.2) or Europe (7.6). Within Latin America, there is substantial diversity in transplant rates by country partially explained by diverse socio-economic variables including per capita gross national income, health expenditure and physician density. These data should help inform future health-care policy in Latin America

Genetic manipulation of LKB1 elicits lethal metastatic prostate cancer

Gene dosage is a key defining factor to understand cancer pathogenesis and progression, which requires the development of experimental models that aid better deconstruction of the disease. Here, we model an aggressive form of prostate cancer and show the unconventional association of LKB1 dosage to prostate tumorigenesis. Whereas loss of Lkbl alone in the murine prostate epithelium was inconsequential for tumorigenesis, its combination with an oncogenic insult, illustrated by Pten heterozygosity, elicited lethal metastatic prostate cancer. Despite the low frequency of LKB1 deletion in patients, this event was significantly enriched in lung metastasis. Modeling the role of LKB1 in cellular systems revealed that the residual activity retained in a reported kinase-dead form, LKB1(K781), was sufficient to hamper tumor aggressiveness and metastatic dissemination. Our data suggest that prostate cells can function normally with low activity of LKB1, whereas its complete absence influences prostate cancer pathogenesis and dissemination

Regional development gaps in Argentina: A multidimensional approach to identify the location of policy priorities

Spatial inequalities within Latin American countries have historically attracted the interest ofacademics, policy-makers, and international agencies. This article aims to provide amultidimensional diagnosis of provincial development gaps in Argentina, in order to identifythe location of policy priorities. Therefore, we built a large database, which covers sevendevelopment dimensions, and applied multivariate analysis techniques to overcome someanalytical limitations of previous studies. Results show the stability of provincial developmentgaps between 2003 and 2013 and some heterogeneity within geographic regions. Instead,cluster analysis offers a better classification of Argentine provinces according to theirdevelopment gaps, which can help the government to prioritize the places wheredevelopment policies are strategic.Fil: Niembro, Andrés Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte; Argentina. Universidad Nacional de Río Negro; ArgentinaFil: Sarmiento, Jesica Isabel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte; Argentina. Universidad Nacional de Río Negro; Argentin

Open access solutions for biodiversity journals : Do not replace one problem with another

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NEXT-CRAB-0: A High Pressure Gaseous Xenon Time Projection Chamber with a Direct VUV Camera Based Readout

The search for neutrinoless double beta decay ($0\nu\beta\beta$) remains one of the most compelling experimental avenues for the discovery in the neutrino sector. Electroluminescent gas-phase time projection chambers are well suited to $0\nu\beta\beta$ searches due to their intrinsically precise energy resolution and topological event identification capabilities. Scalability to ton- and multi-ton masses requires readout of large-area electroluminescent regions with fine spatial resolution, low radiogenic backgrounds, and a scalable data acquisition system. This paper presents a detector prototype that records event topology in an electroluminescent xenon gas TPC via VUV image-intensified cameras. This enables an extendable readout of large tracking planes with commercial devices that reside almost entirely outside of the active medium.Following further development in intermediate scale demonstrators, this technique may represent a novel and enlargeable method for topological event imaging in $0\nu\beta\beta$.Comment: 32 Pages, 22 figure