Caracterización petrofísica de tres variedades comerciales de areniscas miocenas del valle del Ebro

Miocene sandstones studied were used extensively to build Aragon’s architectural heritage, are still used in modern construction. The quarries presently located on the edge of the Ebro Valley depression. The present paper describes an exhaustive petrophysical study of these materials, which while, of the same age and from the same deposition basin, exhibit different mineralogical and textural characteristics and as a result, different physical and mechanical properties and durability. The petrographic and petrophysical characteristics of these materials were evaluated with tests prescribed in UNE (Spanish), NORMAL and ASTM standards. All the results were subjected to statistical analysis to identify possible textural and compositional nonuniformities in the material that may underlie behavioural changes. The results of the present paper show that their petrophysical characteristics afford these sandstones substantial industrial value as construction materials. Durability was found to be longest in the Alcañiz stone, as a result of the geometry of its pore network.Las areniscas miocenas estudiadas han sido y son ampliamente utilizadas en patrimonio histórico y en obra civil moderna, localizándose las canteras actuales en el borde de la depresión del Ebro. Se ha realizado un exhaustivo estudio de las características petrofísicas de estos materiales, que pese a presentar la misma edad y pertenecer a la misma cuenca sedimentaria presentan características mineralógicas y texturales diferentes que les confieren diferentes propiedades físicas, mecánicas y una diferente durabilidad. Las características petrográficas y petrofísicas se han evaluado mediante la realización de ensayos según las normas UNE, NORMAL y ASTM. Para todos los ensayos se ha realizado un tratamiento estadístico de los resultados para evaluar las posibles inhomogeneidades texturales y composicionales presentes en el material y que pueden originar modificaciones en su comportamiento. Los resultados ponen de manifiesto que estas areniscas presentan un importante valor industrial como materiales de usos constructivos, siendo la arenisca de Alcañiz la que presenta una mayor durabilidad como consecuencia de la configuración de su sistema poroso

Método de análisis para determinar el contenido de humedad adecuado para la obtención de resistencias en fachadas trasventiladas de piedra natural sometidas al agua de lluvia.

El artículo muestra la influencia que tiene la consideración del contenido de humedad en el diseño de las fachadas trasventiladas hechas de piedra natural porosa. Se comprueba cómo este factor influye en la resistencia de las placas y condiciona sus dimensiones. Por ello se propone realizar un análisis más amplio del comportamiento frente al agua, que el propuesto por las normas EN. A través de un ejemplo, se muestra cómo realizar dicho análisis y se dan pautas para elegir un contenido de humedad que represente el grado de absorción que la piedra pueda alcanzar en este tipo de fachadas. Con este contenido, se determinarán las resistencias mecánicas de las placas. El estudio se ha aplicado a tres areniscas de la misma zona del noreste español, obteniendo resultados que demuestran la utilidad del análisis que se propon

Caracterización del sistema poroso y de su influencia en el deterioro por cristalización de sales en calizas y dolomías explotadas en Abanto (Zaragoza, España)

The Abanto natural stone is a rock used in modern constructions and currently quarried as an ornamental rock in Abanto, Zaragoza. The varieties described here are a limestone with depositional texture and a crystalline limestone. In this work we have carried out a detailed study of the mineralogy, texture, hydric behaviour, pore system characteristics, dynamic behaviour and behaviour against the effects of salt crystallisation. After 30 cycles of salts crystallization, the weight loss in these rocks is lower than 0.5%. This low weathering is a consequence of the configuration of their pore system, characterised by a low open porosity and high percentages of microporosity with pore-throat sizes on average of less than a 0.2 µm. The petrographical and physical characteristics, as well as its high resistance against salt crystallisation confer these rocks a high technical quality for their use as building stones in modern construction.La piedra natural de Abanto es un material utilizado en obra civil moderna y explotado como roca Ornamental en Abanto (Zaragoza). Las variedades caracterizadas son una caliza con textura deposicional y una caliza cristalina. En este trabajo se ha realizado un detallado estudio de su mineralogía, textura, características del sistema poroso, comportamiento hídrico, comportamiento dinámico y de su comportamiento frente a la cristalización de sales. La pérdida en peso en estas rocas es inferior al 0,5% tras realizar 30 ciclos de cristalización de sales. Esta baja alterabilidad es consecuencia de la configuración del sistema poroso, caracterizado por presentar una baja porosidad abierta y porcentajes elevados de microporosidad con tamaños de radios de acceso de poro preferentemente inferiores a 0,2 µm. Sus características petrográficas y físicas, así como su elevada resistencia frente a la cristalización de sales, les confieren unas buenas cualidades técnicas para su utilización como materiales de usos constructivos

Prereferral rectal artesunate and referral completion among children with suspected severe malaria in the Democratic Republic of the Congo, Nigeria and Uganda

INTRODUCTION: Children who receive prereferral rectal artesunate (RAS) require urgent referral to a health facility where appropriate treatment for severe malaria can be provided. However, the rapid improvement of a child's condition after RAS administration may influence a caregiver's decision to follow this recommendation. Currently, the evidence on the effect of RAS on referral completion is limited. METHODS: An observational study accompanied the roll-out of RAS in three malaria endemic settings in the Democratic Republic of the Congo (DRC), Nigeria and Uganda. Community health workers and primary health centres enrolled children under 5 years with suspected severe malaria before and after the roll-out of RAS. All children were followed up 28 days after enrolment to assess their treatment-seeking pathways. RESULTS: Referral completion was 67% (1408/2104) in DRC, 48% (287/600) in Nigeria and 58% (2170/3745) in Uganda. In DRC and Uganda, RAS users were less likely to complete referral than RAS non-users in the pre-roll-out phase (adjusted OR (aOR)=0.48, 95% CI 0.30 to 0.77 and aOR=0.72, 95% CI 0.58 to 0.88, respectively). Among children seeking care from a primary health centre in Nigeria, RAS users were less likely to complete referral compared with RAS non-users in the post-roll-out phase (aOR=0.18, 95% CI 0.05 to 0.71). In Uganda, among children who completed referral, RAS users were significantly more likely to complete referral on time than RAS non-users enrolled in the pre-roll-out phase (aOR=1.81, 95% CI 1.17 to 2.79). CONCLUSIONS: The findings of this study raise legitimate concerns that the roll-out of RAS may lead to lower referral completion in children who were administered prereferral RAS. To ensure that community-based programmes are effectively implemented, barriers to referral completion need to be addressed at all levels. Alternative effective treatment options should be provided to children unable to complete referral. TRIAL REGISTRSTION NUMBER: NCT03568344; ClinicalTrials.gov

Community access to rectal artesunate for malaria (CARAMAL): a large-scale observational implementation study in the Democratic Republic of the Congo, Nigeria and Uganda

The key to reducing malaria deaths in highly endemic areas is prompt access to quality case management. Given that many severe cases occur at peripheral level, rectal artesunate (RAS) in the form of suppositories was developed in the 1990s, allowing for rapid initiation of life-saving antimalarial treatment before referral to a health facility with full case management capabilities. One randomized controlled trial published in 2009 showed a protective effect of RAS pre-referral treatment against overall mortality of 26%, but with significant differences according to study sites and length of referral. Two important issues remained unaddressed: (1) whether the mortality impact of RAS observed under controlled trial conditions could be replicated under real-world circumstances; and (2) clear operational guidance for the wide-scale implementation of RAS, including essential health system determinants for optimal impact. From 2018 to 2020, the Community Access to Rectal Artesunate for Malaria (CARAMAL) project was conducted as a large-scale observational implementation study in the Democratic Republic of the Congo (DRC), Nigeria, and Uganda (registered on ClinicalTrials.gov as NCT03568344). CARAMAL aimed to provide high-quality field evidence on the two issues above, in three remote settings with high malaria endemicity. A number of complementary study components were implemented. The core of the CARAMAL study was the Patient Surveillance System (PSS), which allowed tracking of cases of severe febrile illness from first contact at the periphery to a referral health facility, and then on to a Day 28 visit at the home of the patient. Community and provider cross-sectional surveys complemented the PSS. Here we describe in some detail RAS implementation, as well as the key CARAMAL study components and basic implementation experience. This manuscript does not intend to present key study results, but provides an extensive reference document for the companion papers describing the impact, referral process, post-referral treatment and costing of the RAS intervention

Health system readiness and the implementation of rectal artesunate for severe malaria in sub-Saharan Africa: an analysis of real-world costs and constraints

BACKGROUND: Rectal artesunate, an efficacious pre-referral treatment for severe malaria in children, was deployed at scale in Uganda, Nigeria, and DR Congo. In addition to distributing rectal artesunate, implementation required additional investments in crucial but neglected components in the care for severe malaria. We examined the real-world costs and constraints to rectal artesunate implementation. METHODS: We collected primary data on baseline health system constraints and subsequent rectal artesunate implementation expenditures. We calculated the equivalent annual cost of rectal artesunate implementation per child younger than 5 years at risk of severe malaria, from a health system perspective, separating neglected routine health system components from incremental costs of rectal artesunate introduction. FINDINGS: The largest baseline constraints were irregular health worker supervisions, inadequate referral facility worker training, and inadequate malaria commodity supplies. Health worker training and behaviour change campaigns were the largest startup costs, while supervision and supply chain management accounted for most annual routine costs. The equivalent annual costs of preparing the health system for managing severe malaria with rectal artesunate were US$2.63,$2.20, and $4.19 per child at risk and$322, $219, and$464 per child treated in Uganda, Nigeria, and DR Congo, respectively. Strengthening the neglected, routine health system components accounted for the majority of these costs at 71.5%, 65.4%, and 76.4% of per-child costs, respectively. Incremental rectal artesunate costs accounted for the minority remainder. INTERPRETATION: Although rectal artesunate has been touted as a cost-effective pre-referral treatment for severe malaria in children, its real-world potential is limited by weak and under-financed health system components. Scaling up rectal artesunate or other interventions relying on community health-care providers only makes sense alongside additional, essential health system investments sustained over the long term. FUNDING: Unitaid. TRANSLATION: For the French translation of the abstract see Supplementary Materials section

Effectiveness of rectal artesunate as pre-referral treatment for severe malaria in children under 5 years of age: a multi-country observational study

BACKGROUND: To prevent child deaths from severe malaria, early parenteral treatment is essential. Yet, in remote rural areas, accessing facilities offering parenteral antimalarials may be difficult. A randomised controlled trial found pre-referral treatment with rectal artesunate (RAS) to reduce deaths and disability in children who arrived at a referral facility with delay. This study examined the effectiveness of pre-referral RAS treatment implemented through routine procedures of established community-based health care systems. METHODS: An observational study accompanied the roll-out of RAS in the Democratic Republic of the Congo (DRC), Nigeria and Uganda. Children <5 years of age presenting to a community-based health provider with a positive malaria test and signs of severe malaria were enrolled and followed up during admission and after 28 days to assess their health status and treatment history. The primary outcome was death; covariates of interest included RAS use, referral completion, and post-referral treatment. RESULTS: Post-roll-out, RAS was administered to 88% of patients in DRC, 52% in Nigeria, and 70% in Uganda. The overall case fatality rate (CFR) was 6.7% (135/2011) in DRC, 11.7% (69/589) in Nigeria, and 0.5% (19/3686) in Uganda; 13.8% (865/6286) of patients were sick on day 28. The CFR was higher after RAS roll-out in Nigeria (16.1 vs. 4.2%) and stable in DRC (6.7 vs. 6.6%) and Uganda (0.7 vs. 0.3%). In DRC and Nigeria, children receiving RAS were more likely to die than those not receiving RAS (aOR=3.06, 95% CI 1.35-6.92 and aOR=2.16, 95% CI 1.11-4.21, respectively). Only in Uganda, RAS users were less likely to be dead or sick at follow-up (aOR=0.60, 95% CI 0.45-0.79). Post-referral parenteral antimalarials plus oral artemisinin-based combination therapy (ACT), a proxy for appropriate post-referral treatment, was protective. However, in referral health facilities, ACT was not consistently administered after parenteral treatment (DRC 68.4%, Nigeria 0%, Uganda 70.9%). CONCLUSIONS: Implemented at scale to the recommended target group, pre-referral RAS had no beneficial effect on child survival in three highly malaria-endemic settings. RAS is unlikely to reduce malaria deaths unless health system issues such as referral and quality of care at all levels are addressed. TRIAL REGISTRATION: The study is registered on ClinicalTrials.gov : NCT03568344

Mutation and deletion analysis of GFRα-1, encoding the co-receptor for the GDNF/RET complex, in human brain tumours

Glial cell line-derived neurotrophic factor (GDNF) plays a key role in the control of vertebrate neuron survival and differentiation in both the central and peripheral nervous systems. GDNF preferentially binds to GFRα-1 which then interacts with the receptor tyrosine kinase RET. We investigated a panel of 36 independent cases of mainly advanced sporadic brain tumours for the presence of mutations in GDNF and GFRα-1. No mutations were found in the coding region of GDNF. We identified six previously described GFRα-1 polymorphisms, two of which lead to an amino acid change. In 15 of 36 brain tumours, all polymorphic variants appeared to be homozygous. Of these 15 tumours, one also had a rare, apparently homozygous, sequence variant at codon 361. Because of the rarity of the combination of homozygous sequence variants, analysis for hemizygous deletion was pursued in the 15 samples and loss of heterozygosity was found in 11 tumours. Our data suggest that intragenic point mutations of GDNF or GFRα-1 are not a common aetiologic event in brain tumours. However, either deletion of GFRα-1 and/or nearby genes may contribute to the pathogenesis of these tumours

GDNF Selectively Induces Microglial Activation and Neuronal Survival in CA1/CA3 Hippocampal Regions Exposed to NMDA Insult through Ret/ERK Signalling

The glial cell line-derived neurotrophic factor (GDNF) is a potent survival factor for several neuronal populations in different brain regions, including the hippocampus. However, no information is available on the: (1) hippocampal subregions involved in the GDNF-neuroprotective actions upon excitotoxicity, (2) identity of GDNF-responsive hippocampal cells, (3) transduction pathways involved in the GDNF-mediated neuroprotection in the hippocampus. We addressed these questions in organotypic hippocampal slices exposed to GDNF in presence of N-methyl-D-aspartate (NMDA) by immunoblotting, immunohistochemistry, and confocal analysis. In hippocampal slices GDNF acts through the activation of the tyrosine kinase receptor, Ret, without involving the NCAM-mediated pathway. Both Ret and ERK phosphorylation mainly occurred in the CA3 region where the two activated proteins co-localized. GDNF protected in a greater extent CA3 rather than CA1 following NMDA exposure. This neuroprotective effect targeted preferentially neurons, as assessed by NeuN staining. GDNF neuroprotection was associated with a significant increase of Ret phosphorylation in both CA3 and CA1. Interestingly, confocal images revealed that upon NMDA exposure, Ret activation occurred in microglial cells in the CA3 and CA1 following GDNF exposure. Collectively, this study shows that CA3 and CA1 hippocampal regions are highly responsive to GDNF-induced Ret activation and neuroprotection, and suggest that, upon excitotoxicity, such neuroprotection involves a GDNF modulation of microglial cell activity

Cooperation of Mtmr8 with PI3K Regulates Actin Filament Modeling and Muscle Development in Zebrafish

It has been shown that mutations in at least four myotubularin family genes (MTM1, MTMR1, 2 and 13) are causative for human neuromuscular disorders. However, the pathway and regulative mechanism remain unknown.Here, we reported a new role for Mtmr8 in neuromuscular development of zebrafish. Firstly, we cloned and characterized zebrafish Mtmr8, and revealed the expression pattern predominantly in the eye field and somites during early somitogenesis. Using morpholino knockdown, then, we observed that loss-of-function of Mtmr8 led to defects in somitogenesis. Subsequently, the possible underlying mechanism and signal pathway were examined. We first checked the Akt phosphorylation, and observed an increase of Akt phosphorylation in the morphant embryos. Furthermore, we studied the PH/G domain function within Mtmr8. Although the PH/G domain deletion by itself did not result in embryonic defect, addition of PI3K inhibitor LY294002 did give a defective phenotype in the PH/G deletion morphants, indicating that the PH/G domain was essential for Mtmr8's function. Moreover, we investigated the cooperation of Mtmr8 with PI3K in actin filament modeling and muscle development, and found that both Mtmr8-MO1 and Mtmr8-MO2+LY294002 led to the disorganization of the actin cytoskeleton. In addition, we revealed a possible participation of Mtmr8 in the Hedgehog pathway, and cell transplantation experiments showed that Mtmr8 worked in a non-cell autonomous manner in actin modeling.The above data indicate that a conserved functional cooperation of Mtmr8 with PI3K regulates actin filament modeling and muscle development in zebrafish, and reveal a possible participation of Mtmr8 in the Hedgehog pathway. Therefore, this work provides a new clue to study the physiological function of MTM family members