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Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease, with a clear genetic component. While most SLE patients carry rare gene variants in lupus risk genes, little is known about their contribution to disease pathogenesis. Amongst them,SH2B3- a negative regulator of cytokine and growth factor receptor signaling – harbors rare coding variants in over 5% of SLE patients. Here we show that unlike the variant found exclusively in healthy controls, mostSH2B3rare variants found in lupus patients are predominantly hypomorphic alleles. Generation of two mouse lines carrying variants orthologous to those found in patients revealed SH2B3 is important to limit the numbers of immature and transitional B cells. Furthermore, hypomorphic SH2B3 was shown to impair negative selection of immature/transitional self-reactive B cells and accelerate autoimmunity in sensitized mice, at least in part due to increased IL-4R signaling and BAFF-R expression. This work identifies a previously unappreciated role forSH2B3in human B cell tolerance and lupus risk.SummaryZhanget al. reveal a role for hypomorphic SH2B3 in lupus risk. The study shows rare and damaging variants identified in lupus patients enable breach of B cell immune tolerance checkpoints and suggests involvement for dysregulated IL-4R signaling and BAFF-R expression.

This study aims to evaluate a Pacific white shrimp and Nile tilapia integrated system using biofloc technology with or without the addition of the microalgae Scenedesmus obliquus and with or without fish feed supplementation in a two-factor 62-day experiment. The shrimp (2.16 ± 0.01 g) were reared under a density of 400 shrimp m−3 and the fish (1.53 ± 0.12 g) were reared under a density of 522 fish m−3. The microalgae was added to the culture water two times a week. Growth performance, sludge production, and water microbiology were evaluated. Fish feed and the microalgae addition improved fish final biomass in 58% and 14%, respectively (p < 0.05). Fish survival was significantly higher when microalgae was added (93.9 ± 1.8%) compared with the treatments without microalgae addition (86.2 ± 7.6%) (p < 0.05). The yield of the overall system was higher in the treatments with fish feed supplementation (4.2 ± 0.2 kg m−3) compared with no addition (3.9 ± 0.2 kg m−3) (p < 0.05). These results suggest that fish feed supplementation at the rate of 1% of the biomass and microalgae inoculation can improve fish growth performance and system yield, without affecting sludge production and water microbiology. This work is an expansion of a conference paper with the same title.

CONTEXT: Different polymorphisms of the endothelial nitric oxide synthase gene (NOS3) have been related to diabetic kidney disease. OBJECTIVE: To evaluate the association between advanced diabetic chronic kidney disease (ACKD) and the rs1799983 and rs2070744 poymorphisms of NOS3 in a population from the Gran Canaria island. DESIGN: Cross-sectional case-control study. SUBJECTS AND METHODS: Polymorphisms were genotyped in 152 subjects with ACKD secondary to type 2 diabetes [estimated glomerular filtration rate (eGFR)

Myiasis is the invasion of Diptera larvae in live vertebrates tissues. It has been registered in tropical areas, but not in urban animals of North America. Moreover, there is no information about lesions description, laboratory tests, and treatment applied to canines. We report a myiasis located in the dorsum of an overweight male canine. Insect larvae were identified as Lucilia eximia, an opportunistic species that scarcely infest live vertebrates, and with no records in North America animals before. Abnormalities of complete blood count like leukocytosis by neutrophilia and serum biochemical changes like elevations in alanine aminotransferase, aspartate aminotransferase, creatine kinase, globulins and amylase were detected. Because Lucilia is characterized by lower host-specificity and infestation outbreaks occur worldwide, it is imperative to continue increasing the understanding of Lucilia myiasis, its clinical presentation, risk factors, therapy and correct entomological classification. Otherwise, more cases could occur in animals and humans.

Objective To study the effectiveness and limitations of photodynamic therapy (PDT) as treatment of choice in patients with symptomatic circumscribed choroidal hemangioma. Methods A retrospective study was conducted on 16 patients (13 men and 3 women, with mean age of 54.88 years) with circumscribed choroidal hemangioma, who attended our center and were treated with PDT in the last 7 years. Results All patients had circumscribed choroidal hemangioma, which caused a decrease in visual acuity (VA) secondary to the presence of intraretinal microcystic edema or neurosensory detachment. The mean initial VA was 0.23, and the final mean VA after performing PDT was 0.38 (all the VA were measured in decimal scale). It should be noted that patients needed a mean of 1.69 PDT sessions. Three of the patients needed rescue treatment with trans-pupillary thermotherapy, intravitreal injection of anti-vascular endothelial growth factor (ranibizumab, aflibercept) or a dexamethasone intravitreal implant (Ozurdex ® ). The indication for a change of treatment was the persistence of intraretinal microcystic edema and/or neurosensory detachment (or incomplete resolution) after 3 PDT sessions. As overall results, 62.5% of patients evolved into anatomical and functional (increase in AV or stability) resolution. Conclusions PDT is a straight forward and fast procedure, with a good anatomical and functional response, causing minimal damage to adjacent vessels.

Resumen Objetivo Estudiar la eficacia y las limitaciones de la terapia fotodinamica (TFD) como tratamiento de primera eleccion en pacientes con hemangioma coroideo circunscrito sintomatico. Metodos Se realizo un estudio retrospectivo de 16 pacientes (13 varones y 3 mujeres, con una media de edad de 54,88 anos) con hemangioma coroideo circunscrito visitados en nuestro centro y tratados con TFD en los ultimos 7 anos. Resultados Todos los pacientes presentaban hemangioma coroideo circunscrito, que ocasionaba sintomatologia secundaria a la presencia de edema microquistico intrarretiniano o desprendimiento neurosensorial. La agudeza visual (AV) media inicial del grupo era de 0,23 y la AV media posterior a la realizacion de TFD fue de 0,38 (todas las AV fueron medidas en escala decimal). Cabe destacar que los pacientes necesitaron una media de 1,69 sesiones de TFD. Tres de los pacientes necesitaron un tratamiento de rescate con termoterapia transpupilar, inyeccion intravitrea de antifactor de crecimiento endotelial vascular (ranibizumab, aflibercept) o implante intravitreo de dexametasona (Ozurdex ® ). La indicacion de cambio de tratamiento fue la persistencia de edema microquistico intrarretiniano y/o desprendimiento neurosensorial (o su resolucion incompleta) tras 3 sesiones de TFD. Como resultados generales, destacamos que un 62,5% de los pacientes evoluciono hacia la resolucion anatomica y funcional (incremento de AV o estabilidad). Conclusiones La TFD es un procedimiento dirigido y rapido, con buena respuesta anatomica y funcional, que ocasiona un minimo dano a los vasos adyacentes a la lesion.

OBJECTIVE Experimental evidence suggests that changes in the fetal myocardium result from intrauterine effects of maternal diabetes mellitus and obesity. The aim of this study was to assess fetal cardiac function using two-dimensional speckle-tracking echocardiography to determine the effects of maternal diabetes and obesity on the fetal myocardium. METHODS Comparative cross-sectional evaluation of myocardial function in fetuses of mothers with diabetes mellitus (FDM) or obesity (FO) and normal gestational age-matched control fetuses (FC) was performed using two-dimensional speckle-tracking echocardiography at two centers. RESULTS In total, 178 fetuses (82 FDM, 26 FO and 70 FC) met the enrolment criteria. Mean gestational age at assessment was similar among groups: 25.3 ± 5.1 weeks for FDM, 25.0 ± 4.6 weeks for FO and 25.1 ± 4.9 weeks for FC. Mean maternal body mass index was significantly higher in FDM and FO groups compared with the FC group. Statistically significant differences in fetal cardiac function were detected between FDM and FC for global longitudinal strain (mean ± SD, -21.4 ± 6.5% vs -27.0 ± 5.2%; P

Introduction L’avenement de l’immunotherapie est associe a la survenue d’evenements pancreatiques immuno-induits. L’elevation asymptomatique de la lipase est a distinguer de celle temoignant d’une authentique pancreatite, le plus souvent aigue (PA), pouvant conduire a l’arret du traitement. La PA est definie par la presence d’au moins deux criteres parmi les trois suivants : douleur abdominale evocatrice, augmentation de la lipase serique > 3 N, image radiologique. L’incidence rapportee de la pancreatite sous immunotherapie est inferieure a 1 %. Elle survient le plus souvent au 4–5e cycle et s’associe a d’autres manifestations auto-immunes. Une elevation de la lipase serique precede le plus souvent la PA radiologique. L’objectif de notre travail est de decrire les pancreatites rapportees sous immunotherapie en verifiant leur realite, l’imputabilite du traitement et leur severite, afin d’etablir un bilan standardise a realiser devant toute pancreatite sous immunotherapie, pour guider le choix de poursuivre ou non le traitement. Materiel et methodes Il s’agit d’un travail retrospectif mene dans deux hopitaux parisiens, l’hopital Saint-Louis et l’hopital Bichat. La population actuelle de l’etude, dont le recrutement est toujours en cours, est constituee de 5 patients. Resultats L’âge median des patients ayant eu une pancreatite sous immunotherapie etait de 65 ans (extremes : 34–80 ans). Parmi eux, 4 patients etaient suivis pour un melanome metastatique et un patient pour un adenocarcinome pulmonaire metastatique. Il s’agissait de trois hommes et deux femmes. Deux patients etaient traites par ipilimimab et nivolumab, deux autres par pembrolizumab seul et un dernier par nivolumab en monotherapie. Les causes biliaire, alcoolique et medicamenteuse ont ete ecartees chez tous les patients. Tous les patients sauf un ont eu une augmentation asymptomatique de la lipase avant la survenue de la pancreatite. Toutes les elevations de lipase etaient de grade 2 selon la classification CTCAE 5.0. Le chiffre de lipasemie semble plus eleve en cas de pancreatite affirmee que d’elevation asymptomatique. La chronologie des pancreatites etait variee : survenue au cycle 3 pour deux d’entre elles, 4, 6 et 55 respectivement. Il faut souligner, 3 des 5 PA etaient asymptomatiques, ne remplissant que le critere biologique et radiologique. Aucune des cinq PA n’etait grave, notamment sans collection ou necrose glandulaire. Une recidive de PA est survenue chez un seul des 5 patients dans un delai de 6 semaines apres l’arret du traitement par immunotherapie. Tous les patients sauf un etaient en reponse tumorale selon RECIST 1.1 au moment de la PA. Conclusion Les PA sous immunotherapie etaient dans cette serie souvent precedees d’une augmentation asymptomatique de la lipase et aucune d’entre elles n’etait grave. Il est a noter qu’il n’y a, au sein de cette serie, qu’un seul cas de reintroduction de l’immunotherapie sans recidive de pancreatite a ce jour.

Metallocarboxypeptidases (MCPs) of the M14 family are Zn 2+ -dependent exoproteases present in almost every tissue or fluid in mammals. These enzymes perform a large variety of physiological functions and are involved in several pathologies, such as pancreatic diseases, inflammation, fibrinolysis, and cancer. Here, we describe the synthesis and functional/structural characterization of a series of reversible tight-binding phosphinic pseudopeptide inhibitors that show high specificity and potency toward these proteases. Characterization of their inhibitory potential against a large variety of MCPs, combined with high-resolution crystal structures of three selected candidates in complex with human carboxypeptidase A (CPA)1, allowed to decipher the structural determinants governing selectivity for type-A of the M14A MCP family. Further, the phosphinic pseudopeptide framework was exploited to generate an optical probe selectively targeting human CPAs. The phosphinic pseudopeptides presented here constitute the first example of chemical probes useful to selectively report on type-A MCPs activity in complex media. © 2019 American Chemical Society.

Summary The seismic processing technique known as “Diffraction Imaging” has demonstrated to be an interesting method in order to map geological sub surface discontinuities, in special those high frequency features related to such as discontinuities. They have been study in the prestack time as well as in the prestack depth domain by several authors. Detection of geobodies (channel system) is important when developing continental type sandstone reservoirs. Understanding the location and orientation of such as features is important for optimal well placement and field delineation. Seismic diffraction can be used for imaging not only systems of natural fractures but also for mapping wedge limits caused by channels. Diffracted waves are created when an incident wavefield encounters small size objects or even discontinuities such as faults, sharp curvature geoforms or wedges. The diffractive portion of this wavefield can be extracted from its total in order to produce images that contain information regarding subsurface scattered energy due to discontinuities. This is the first time that this technique is applied in the company in order to characterise and improve the delineation of channel systems.

Myocardial structural and functional abnormalities are known to occur in fetuses of mothers with diabetes mellitus (FMDM). The main aim of this investigation was to explore the cardiovascular circulatory patterns in FMDM using a validated lumped computational model of the cardiovascular system. This was a multi-institutional study involving FMDM compared to fetuses of maternal controls (FC). Fetal echocardiographic Doppler data from left and right ventricular outflow tracts, aortic isthmus, middle cerebral and umbilical arteries were fitted into a validated fetal circulation computational model to estimate patient-specific placental and vascular properties. Non-parametric comparisons were made between resistances, compliances and flows in the brain and placenta in FMDM and FC. The funders had no role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. This study was partly supported by Ministerio de Economia y Competitividad (TIN2014-52923-R); Instituto de Salud Carlos III (PI11/01709, PI12/00801, PI14/00226, PI15/00263; PI15/00130) integrados en el Plan Nacional de I + D + I y cofinanciados por el ISCIII-Subdirección General de Evaluación y el Fondo Europeo de Desarrollo Regional (FEDER) “Otra manera de hacer Europa”; the EU-FP7 for research, technological development and demonstration under grant agreement VP2HF (no611823); The Cerebra Foundation for the Brain Injured Child (Carmarthen, UK); AGAUR 2014 SGR grant nº 928; additionally the research leading to these results has received funding from “la Caixa” Foundation. P.G.C. was supported by the Programa de Ayudas Predoctorales de Formación en investigación en Salud (FI12/00362) from the Instituto Carlos III, Spain. B.V.A. was supported by Programa de Ayudas Postdoctorales from Agència de Gestió d'Ajuts Universitaris i de Recerca [grant number: 2013FI_B 00667].

The aim of this study was to determine the effects of obesity on myocardial mechanics and ventriculo-arterial coupling (V-A) in children.Strain parameters, stroke volume, arterial elastance, left ventricular (LV) elastance and V-A were compared after adjusting for age and hypertension and after multivariate sub-group analysis between patients with and without obesity.Among 123 retrospectively enrolled subjects, 6-21 years age, 79.7% males, 52% were obese. Median (range) Body Mass Index Z score was +2.35 (1.67-4.43) for obese and +0.68 (-2.48-1.63) for non-obese. Subjects with obesity had higher LV mass indexedObesity causes alterations in myocardial mechanics with preserved V-A in children. These findings may aid intervention in preventing the long-term cadiovascular effects of obesity.

Filiació URV: SIInclòs a la memòria: SI Salou, which is one of the many highly specialized tourist resorts located on the Spanish Mediterranean coast, is a hundred kilometres south of Barcelona. Within its narrow boundaries of 1.481 ha, Salou hosts 7.4 million overnight stays per year and is home to 52 hotels. A ratio which ranks Salou amongst the tenth most visited municipalities in Spain [1]. Distance from Salou's historical town centre, the area of Carles Buigas Avenue (CB) emerges as being the heart of the municipality's tourism and leisure industry. Salou developed, as did so many other Spanish coastal touristic locations, during the sixties and seventies as a consequence of the increasing demand for sun and beach destinations amongst the European and Spanish middle classes. Unfortunately, the "ageing" of this built up area clamours for close attention today. The visible physical degradation of the property is becoming a cause for concern and preoccupation amongst the main property owners and investors: public administration, hotel managers, shopkeepers and neighbours. Hotels emerge as the key problem within the set physical boundaries of this study. They occupy approximately 50% of the total land surface, 28 out of a total of 52 hotels within the town being concentrated in that area. This accumulation of hotels also breaks the particularity of the predominance of second residences which is so customary along the Spanish Coast. This paper delves into the data and proposals obtained from analysing the public space of the CB area. Similarly, as a consequence of the previous analysis, a set of proposals for intervention are also presented. The proposals are conceived to be developed within different time scales, in response to political and social willingness and econo

Within the framework of the ASTRID project, core design studies are being conducted by the CEA with support from AREVA and EDF. The pre-conceptual design studies are being conducted in accordance with the GEN IV reactor objectives, particularly in terms of improving safety. This involves limiting the consequences of 1) a hypothetical control rod withdrawal accident (by minimizing the core reactivity loss during the irradiation cycle), and 2) an hypothetical loss-of-flow accident (by reducing the sodium void worth). Two types of cores are being studied for the ASTRID project. The first is based on a ‘large pin/small spacing wire’ concept derived from the SFR V2b, while the other is based on an innovative CFV design. A distinctive feature of the CFV core is its negative sodium void worth. In 2011, the evaluation of a preliminary version (v1) of this CFV core for ASTRID underlined its potential capacity to improve the prevention of severe accidents. An improved version of the ASTRID CFV core (v2) was proposed in 2012 to comply with all the control rod withdrawal criteria, while increasing safety margins for all unprotected-loss-of-flow (ULOF) transients and improving the general design. This paper describes the CFV v2 design options and reports on the progress of the studies at the end of pre-conceptual design phase 1 concerning: - Core performance, - Intrinsic behavior during unprotected transients, - Simulation of severe accident scenarios, - Qualification requirements. The paper also specifies the open options for the materials, sub-assemblies, absorbers, and core monitoring that will continue to be studied during the conceptual design phase.

L’hemorragie diverticulaire est la cause la plus frequente d’hemorragie digestive basse et est en cause dans 35 % des cas. Elle touche le plus souvent la personne âgee. Elle cesse spontanement dans la majorite des cas (90 %), mais peut etre severe et necessiter le recours a un traitement specifique et des transfusions. Les hemorragies diverticulaires peuvent engager le pronostic vital avec une mortalite pouvant atteindre 5 % des cas. La coloscopie precoce est un examen de choix pour le diagnostic et le traitement des hemorragies diverticulaires. Une recidive hemorragique s’observe jusque dans 25% des cas a quatre ans. Les facteurs de risque de recidive sont a ce jour mal connus. Le traitement des hemorragies diverticulaires n’est pas clairement codifie, le traitement endoscopique fait appel aux injections de serum adrenaline, a la pose de clips ou a la ligature endoscopique. L’embolisation supra-selective est une alternative efficace en cas d’impossibilite ou d’echec du traitement endoscopique. Une colectomie d’hemostase est rarement necessaire et ne doit se discuter qu’en cas d’hemorragie non controlee par les traitements endoscopiques et/ou radiologiques et apres avoir au mieux localise le siege du saignement.

Chronic intestinal pseudo-obstruction (CIPO) is a rare but life-threatening disease characterized by severe intestinal dysmotility. Histopathologic studies in CIPO patients have identified several different mechanisms that appear to be involved in the dysmotility, including defects in neurons, smooth muscle, or interstitial cells of Cajal. Currently there are few mouse models of the various forms of CIPO. We generated a mouse with a point mutation in the RNA recognition motif of the Nup35 gene, which encodes a component of the nuclear pore complex. Nup35 mutants developed a severe megacolon and exhibited a reduced lifespan. Histopathologic examination revealed a degenerative myopathy that developed after birth and specifically affected smooth muscle in the colon; smooth muscle in the small bowel and the bladder were not affected. Furthermore, no defects were found in enteric neurons or interstitial cells of Cajal. Nup35 mice are likely to be a valuable model for the subtype of CIPO characterized by degenerative myopathy. Our study also raises the possibility that Nup35 polymorphisms could contribute to some cases of CIPO.

To study the effectiveness and limitations of photodynamic therapy (PDT) as treatment of choice in patients with symptomatic circumscribed choroidal haemangioma.A retrospective study was conducted on 16 patients (13 men and 3 women, with mean age of 54.88 years) with circumscribed choroidal haemangioma, who attended our centre and were treated with PDT in the last 7 years.All patients had circumscribed choroidal haemangioma, which caused a decrease in visual acuity (VA) secondary to the presence of intraretinal microcystic oedema or neurosensory detachment. The mean initial VA was 0.23, and the final mean VA after performing PDT was 0.38 (all the VA were measured in decimal scale). It should be noted that patients needed a mean of 1.69 PDT sessions. Three of the patients needed rescue treatment with trans-pupillary thermotherapy, intravitreal injection of anti-vascular endothelial growth factor (ranibizumab, aflibercept) or a dexamethasone intravitreal implant (OzurdexPDT is a straight forward and fast procedure, with a good anatomical and functional response, causing minimal damage to adjacent vessels.

Chronic Intestinal Pseudo-Obstruction (CIPO) is a rare, but life-threatening, disease characterized by severe intestinal dysmotility. Histopathological studies of CIPO patients have identified several different mechanisms that appear to be responsible for the dysmotility, including defects in neurons, smooth muscle or interstitial cells of Cajal. Currently there are few mouse models of the various forms of CIPO. We generated a mouse with a point mutation in the RNA Recognition Motif of the Nup35 gene, which encodes a component of the nuclear pore complex. Nup35 mutants developed a severe megacolon and exhibited reduced lifespan. Histopathological examination revealed a degenerative myopathy that developed after birth and specifically affected smooth muscle in the colon; smooth muscle in the small bowel and the bladder were not affected. Furthermore, no defects were found in enteric neurons or interstitial cells of Cajal. Nup35 mice are likely to be a valuable model for the sub-type of CIPO characterized by degenerative myopathy. Our study also raises the possibility that Nup35 polymorphisms could contribute to some cases of CIPO.

A total of sixty Bulgarian Murrah buffalo cows were observed of their activities prior, during and after milking to determine the relation of milk yield and time of milking on the temperament and milk let-down characteristics of the animals. The cows were classified into two groups based on their milk yield, namely: Group 1 (G1) for animals with average daily milk yield of 5 kg and above and Group 2 (G2) for animals with a daily milk yield of less than 5 kg. All the cows were milked twice a day, one in the morning and one in the afternoon using milking machine. Results of the study showed that the temperament of the cows prior to milking, during milking, and after milking were not affected by their milk yield capacity. The time of milking also showed no significant effect on the temperament of cows prior and after milking. However, the animals milked in the afternoon were significantly (P

In this paper we study best local quasi-rational approximation and best local approximation from finite dimensional subspaces of vectorial functions of several variables. Our approach extends and unifies several problems concerning best local multi-point approximation in different norms.

Background: Obesity (OB) and hypertension (HTN) are risk factors for early cardiovascular disease (CVD). The aim of this study was to determine the effect of OB and HTN on myocardial mechanics in children using speckle-tracking echocardiography (STE). Methods: Echocardiograms (echo) and ambulatory blood pressure monitors were performed in children referred for HTN from 2009 to 2014. Traditional echo Doppler indices, mass and volume parameters, 24-hr systolic blood pressures (24SBP) and 24-hr diastolic BP indices were obtained. Post-processing was performed on the 2D gray scale images of LV in apical 4-chamber and parasternal short axis mid-papillary views to obtain strain indices (Image Arena, Tomtec). Associations of obesity and BP to the myocardial indices were explored independently using Spearman correlation coefficient. Results: Among 107 patients, 6 - 21 yrs age, 79.4% were males; 42% OB and 53% were hypertensive. Mean Z scores for BMI were 1.5 ± 1.1 and SBP were 1.5 ± 1.2. Mean LV mass (LVM, 2D area-length) was 131 + 42.8 gms, LVMI 2.7 was 40.7 + 9.6 gms, LVM/volume ratio was 0.94 + 0.17. Mean mitral septal E/e’ was 8.3 + 2.1, lateral E/e’ was 5.9 + 1.5 and mitral E/A ratio was 1.8 + 0.4. The mean global longitudinal strain (GLS) was – 17.7 + 3.6, global circumferential strain (GCS) was -20.4 + 3.8, average radial strain (ARS) was 22 + 11.9, average longitudinal strain rate (ALSR) was -1.0 + 0.35 and average circumferential strain rate (ACSR) was -1.5 + 0.5 for all patients. BMI Z scores positively correlated with LVM (r=0.38, p2.7 (r=0.5, Conclusions: Obesity causes adverse cardiac remodeling in obese children. This may provide insights into mechanisms of long-term CV effects of obesity. Myocardial effects of HTN were not apparent, possibly due to heterogeneity of the study group and low power.