Hypomorphic mutation in the RAG2 gene affects dendritic cell distribution and migration.

In Omenn syndrome, altered dendritic cell distribution and impaired migration represent an additional level of immune dysregulation, contributing to the pathogenesis of autoimmunity. OS is a severe combined immunodeficiency characterized by erythrodermia and protracted diarrhea as a result of infiltration of oligoclonal-activated T cells, caused by hypomorphic mutations in RAGs. The RAG2(R229Q) mouse model fully recapitulates the clinical OS phenotype. We evaluated whether T and B cell defects, together with the abnormal lymphoid structure, could affect DC homeostasis and function. High density of LCs was observed in skin biopsies of Omenn patients and in the derma of RAG2(R229Q) mice, correlating with the presence of erythrodermia. In vivo models of cutaneous skin painting and CHS demonstrated a decreased migration of RAG2(R229Q) DCsin particular, LCsinto draining LNs. Interestingly, at steady state, RAG2(R229Q) mice showed a reduction in DC number in all hematopoietic organs except LNs. Analysis of the MHCII marker revealed a diminished expression also upon the LPS-driven inflammatory condition. Despite the decreased number of peripheral DCs, BM pre-cDCs were present in normal number compared with RAG2(+/+) controls, whereas pDCs and monocytes were reduced significantly. Overall, these results point to a secondary defect in the DC compartment, which contributes to clinical manifestations and autoimmunity in OS

Functionalized metallic 2D transition metal dichalcogenide-based solid-state electrolyte for flexible all-solid-state supercapacitors

Highly efficient and durable flexible solid-state supercapacitors (FSSSCs) are emerging as low-cost devices for portable and wearable electronics due to the elimination of leakage of toxic/corrosive liquid electrolytes and their capability to withstand elevated mechanical stresses. Nevertheless, the spread of FSSSCs requires the development of durable and highly conductive solid-state electrolytes, whose electrochemical characteristics must be competitive with those of traditional liquid electrolytes. Here, we propose an innovative composite solid-state electrolyte prepared by incorporating metallic two-dimensional group-5 transition metal dichalcogenides, namely, liquid-phase exfoliated functionalized niobium disulfide (f-NbS2) nanoflakes, into a sulfonated poly(ether ether ketone) (SPEEK) polymeric matrix. The terminal sulfonate groups in f-NbS2 nanoflakes interact with the sulfonic acid groups of SPEEK by forming a robust hydrogen bonding network. Consequently, the composite solid-state electrolyte is mechanically/dimensionally stable even at a degree of sulfonation of SPEEK as high as 70.2%. At this degree of sulfonation, the mechanical strength is 38.3 MPa, and thanks to an efficient proton transport through the Grotthuss mechanism, the proton conductivity is as high as 94.4 mS cm–1 at room temperature. To elucidate the importance of the interaction between the electrode materials (including active materials and binders) and the solid-state electrolyte, solid-state supercapacitors were produced using SPEEK and poly(vinylidene fluoride) as proton conducting and nonconducting binders, respectively. The use of our solid-state electrolyte in combination with proton-conducting SPEEK binder and carbonaceous electrode materials (mixture of activated carbon, single/few-layer graphene, and carbon black) results in a solid-state supercapacitor with a specific capacitance of 116 F g–1 at 0.02 A g–1, optimal rate capability (76 F g–1 at 10 A g–1), and electrochemical stability during galvanostatic charge/discharge cycling and folding/bending stresses

A database program for enhancing irrigation district management in the Ebro Valley (Spain)

The definitive version is available at: http://www.sciencedirect.com/science/journal/03783774In the last decade irrigation districts in the Ebro Valley of Spain have started to use database applications to enhance their management operations. Such applications often put more emphasis on administrative issues than on water management issues. A new irrigation district management software called “Ador” is presented in this paper. This database application has been designed to overcome limitations identified in an analysis of the software used in the study area. Ador can be used in irrigation districts independently of the type of irrigation system (surface, sprinkler or trickle) and the type of irrigation distribution network (open channel or pressurised). It can even be used in irrigation districts combining different types of irrigation systems and different types of irrigation distribution networks. The software can be used with minimum district information. The goals are to manage detailed information about district water management and to promote better on-farm irrigation practices. Ador is currently used to enhance management of 62 irrigation districts accounting for some 173,000 hectares in the Ebro Valley.National Plan for Research and Development of the Government of Spain (AGL2000-0151-P4-02). FEDER II of the European Union (2FD97-0547-C02). I3P program of the European Union. Oficina del Regante (Government of Aragón, FEOGA funds of the European Union).Peer reviewe

AME position statement on adrenal incidentaloma.

Objective: To assess currently available evidence on adrenal incidentaloma and provide recommendations for clinical practice. Design: A panel of experts (appointed by the Italian Association of Clinical Endocrinologists (AME)) appraised the methodological quality of the relevant studies, summarized their results, and discussed the evidence reports to find consensus. Radiological assessment: Unenhanced computed tomography (CT) is recommended as the initial test with the use of an attenuation value of <= 10 Hounsfield units (HU) to differentiate between adenomas and non-adenomas. For tumors with a higher baseline attenuation value, we suggest considering delayed contrast-enhanced CT studies. Positron emission tomography (PET) or PET/CT should be considered when CT is inconclusive, whereas fine needle aspiration biopsy may be used only in selected cases suspicious of metastases (after biochemical exclusion of pheochromocytoma). Hormonal assessment: Pheochromocytoma and excessive overt cortisol should be ruled out in all patients, whereas primary aldosteronism has to be considered in hypertensive and/or hypokalemic patients. The 1 mg overnight dexamethasone suppression test is the test recommended for screening of subclinical Cushing's syndrome (SCS) with a threshold at 138 nmol/l for considering this condition. A value of 50 nmol/l virtually excludes SCS with an area of uncertainty between 50 and 138 nmol/l. Management: Surgery is recommended for masses with suspicious radiological aspects and masses causing overt catecholamine or steroid excess. Data are insufficient to make firm recommendations for or against surgery in patients with SCS. However, adrenalectomy may be considered when an adequate medical therapy does not reach the treatment goals of associated diseases potentially linked to hypercortisolism

Long-Term Prognosis of Diabetic Patients With Critical Limb Ischemia: A population-based cohort study

OBJECTIVE\u2014 To evaluate the long-term prognosis of critical limb ischemia (CLI) in diabetic patients. RESEARCH DESIGN AND METHODS\u2014 A total of 564 consecutive diabetic patients were hospitalized for CLI from January 1999 to December 2003; 554 were followed until December 2007. RESULTS\u2014 The mean follow-up was 5.93 1.28 years. Peripheral angioplasty (PTA) was performed in 420 (74.5%) and bypass graft (BPG) in 117 (20.6%) patients. Neither PTA nor BPG were possible in 27 (4.9%) patients. Major amputations were performed in 74 (13.4%) patients: 34 (8.2%) in PTA, 24 (21.1%) in BPG, and 16 (59.2%) in a group that received no revascularization. Restenosis occurred in 94 patients, bypass failures in 36 patients, and recurrent ulcers in 71 patients. CLI was observed in the contralateral limb of 225 (39.9%) patients; of these, 15 (6.7%) required major amputations (rate in contralateral compared with initial limb, P 0.007). At total of 276 (49.82%) patients died. The Cox model showed significant hazard ratios (HRs) for mortality with age (1.05 for 1 year [95% CI 1.03\u20131.07]), unfeasible revascularization (3.06 [1.40\u20136.70]), dialysis (3.00 [1.63\u20135.53]), cardiac disease history (1.37 [1.05\u20131.79]), and impaired ejection fraction (1.08 for 1% point [1.05\u20131.09]). CONCLUSIONS\u2014 Diabetic patients with CLI have high risks of amputation and death. In a dedicated diabetic foot center, the major amputation, ulcer recurrence, and major contralateral limb amputation rates were low. Coronary artery disease (CAD) is the leading cause of death, and in patients with CAD history the impaired ejection fraction is the major independent prognostic factor

Efecto del tipo de lactancia sobre la calidad de la canal y de la carne en cabritos

En el trabajo se han tomado 40 cabritos pertenecientes a las razas autóctonas Florida Sevillana y Payoya, 20 animales de lactancia natural y 20 de lactancia artificial con el objeto de comparar los parámetros de la calidad de la canal y de la carne. Los resultados nos muestran que aunque existen diferencias en el algunas medidas de la canal, el resto de los parámetros estudiados no presentaron diferencias significativas entre los dos tipos de lactancia.Diputación de BadajozJunta de Extremadur

B lymphocytes limit senescence-driven fibrosis resolution and favor hepatocarcinogenesis in mouse liver injury

Hepatocellular carcinoma (HCC) is a frequent neoplasia and a leading cause of inflammation-related cancer mortality. Despite that most HCCs arise from persistent inflammatory conditions, pathways linking chronic inflammation to cancer development are still incompletely elucidated. We dissected the role of adaptive immunity in the Mdr2 knockout (Mdr2\u2013/\u2013) mouse, a model of inflammation-associated cancer, in which ablation of adaptive immunity has been induced genetically (Rag2\u2013/\u2013Mdr2\u2013/\u2013 and \u3bcMt-Mdr2\u2013/\u2013 mice) or with in vivo treatments using lymphocyte-specific depleting antibodies (anti-CD20 or anti-CD4/CD8). We found that activated B and T lymphocytes, secreting fibrogenic tumor necrosis factor alpha (TNF\u3b1) and other proinflammatory cytokines, infiltrated liver of the Mdr2\u2013/\u2013 mice during chronic fibrosing cholangitis. Lymphocyte ablation, in the Rag2\u2013/\u2013Mdr2\u2013/\u2013 and \u3bcMt-Mdr2\u2013/\u2013 mice, strongly suppressed hepatic stellate cell (HSC) activation and extracellular matrix deposition, enhancing HSC transition to cellular senescence. Moreover, lack of lymphocytes changed the intrahepatic metabolic/oxidative state, resulting in skewed macrophage polarization toward an anti-inflammatory M2 phenotype. Remarkably, hepatocarcinogenesis was significantly suppressed in the Rag2\u2013/\u2013Mdr2\u2013/\u2013 mice, correlating with reduced TNF\u3b1/NF-\u3baB (nuclear factor kappa B) pathway activation. Ablation of CD20+ B cells, but not of CD4+/CD8+ T cells, in Mdr2\u2013/\u2013 mice, promoted senescence-mediated fibrosis resolution and inhibited the protumorigenic TNF\u3b1/NF-\u3baB pathway. Interestingly, presence of infiltrating B cells correlated with increased tumor aggressiveness and reduced disease-free survival in human HCC. Conclusion: Adaptive immunity sustains liver fibrosis (LF) and favors HCC growth in chronic injury, by modulating innate components of inflammation and limiting the extent of HSC senescence. Therapies designed for B-cell targeting may be an effective strategy in LF. (Hepatology 2018;67:1970-1985)

Proteome Investigation of Rat Lungs subjected to Ex Vivo Perfusion (EVLP)

Ex vivo lung perfusion (EVLP) is an emerging procedure that allows organ preservation, assessment and reconditioning, increasing the number of marginal donor lungs for transplantation. However, physiological and airflow measurements are unable to unveil the molecular mechanisms responsible of EVLP beneficial effects on lung graft and monitor the proper course of the treatment. Thus, it is urgent to find specific biomarkers that possess these requirements but also accurate and reliable techniques that identify them. The purpose of this study is to give an overview on the potentiality of shotgun proteomic platforms in characterizing the status and the evolution of metabolic pathways during EVLP in order to find new potential EVLP-related biomarkers. A nanoLC-MS/MS system was applied to the proteome analysis of lung tissues from an optimized rat model in three experimental groups: native, pre- and post-EVLP. Technical and biological repeatability were evaluated and, together with clustering analysis, underlined the good quality of data produced. In-house software and bioinformatics tools allowed the label-free extraction of differentially expressed proteins among the three examined conditions and the network visualization of the pathways mainly involved. These promising findings encourage further proteomic investigations of the molecular mechanisms behind EVLP procedure