Chemical Bonding, 10Dq Parameter and Superexchange in the Model Compound KNiF3.

The cubic field splitting parameter, 10Dq, plays a central role in the ligand field theory on insulating transition metal compounds. Experimental data obtained in the last 50 years prove that 10Dq is highly dependent on changes of the metal-ligand distance, R, induced by chemical or applied pressures. Despite this fact has important consequences on optical and magnetic properties of such compounds, its actual origin is still controversial. Seeking to clarify that crucial issue, this work is focused on KNiF3, a reference system among insulating transition metal compounds. By means of first principles calculations we show that, contrary to what is usually thought, the R-dependence of 10Dq arises neither from the crystal field contribution nor from the covalent admixture of 3d(Ni) with valence 2p(F) orbitals. Indeed, we prove that it is mainly due to the residual covalency with deep 2s(F) orbitals, highly sensitive to R variations. As a salient feature the present calculations show that the 3d-2pσ and 3d-2pπ admixtures raise practically equal the energy of antibonding eg and t2g orbitals of NiF6 4- units in KNiF3 thus leading to a null contribution to 10Dq. This conclusion is not significantly altered when considering the change of covalency on passing from the ground state 3A2(t2g 6eg 2) to the excited state 3T2(t2g 5eg 3). The different influence of chemical bonding on the superexchange constant, J, and 10Dq is also discussed in a second step. It is pointed out that the strong dependence of J upon R can hardly be explained through the behavior of the 3d-2pσ covalency derived for a single NiF6 4- unit. For the sake of clarity, the meaning of 10Dq is also briefly analyzed.

Characterization of gene expression in the kidney of renal tubular cell-specific NFAT5 knockout mice.

Nuclear factor of activated T cells 5 (NFAT5; also called TonEBP/OREBP) is a transcription factor that is activated by hypertonicity and induces osmoprotective genes to protect cells against hypertonic conditions. In the kidney, renal tubular NFAT5 is known to be involved in the urine concentration mechanism. Previous studies have suggested that NFAT5 modulates the immune system and exerts various effects on organ damage, depending on organ and disease states. Pathophysiological roles of NFAT5 in renal tubular cells, however, still remain obscure. We conducted comprehensive analysis by performing transcription start site (TSS) sequencing on the kidney of inducible and renal tubular cell-specific NFAT5 knockout (KO) mice. Mice were subjected to unilateral ureteral obstruction to examine the relevance of renal tubular NFAT5 in renal fibrosis. TSS sequencing analysis identified 722 downregulated TSSs and 1,360 upregulated TSSs, which were differentially regulated ≤-1.0 and ≥1.0 in log2 fold, respectively. Those TSSs were annotated to 532 downregulated genes and 944 upregulated genes, respectively. Motif analysis showed that sequences that possibly bind to NFAT5 were enriched in TSSs of downregulated genes. Gene Ontology analysis with the upregulated genes suggested disorder of innate and adaptive immune systems in the kidney. Unilateral ureteral obstruction significantly exacerbated renal fibrosis in the renal medulla in KO mice compared with wild-type mice, accompanied by enhanced activation of immune responses. In conclusion, NFAT5 in renal tubules could have pathophysiological roles in renal fibrosis through modulating innate and adaptive immune systems in the kidney.NEW & NOTEWORTHY TSS-Seq analysis of the kidney from renal tubular cell-specific NFAT5 KO mice uncovered novel genes that are possibly regulated by NFAT5 in the kidney under physiological conditions. The study further implied disorders of innate and adaptive immune systems in NFAT5 KO mice, thereby exacerbating renal fibrosis at pathological states. Our results may implicate the involvement of renal tubular NFAT5 in the progression of renal fibrosis. Further studies would be worthwhile for the development of novel therapy to treat chronic kidney disease.

Propuesta para mejorar la formación en profesionalismo y en competencias transversales en los estudios de medicina de las universidades de Cataluña / Proposal to improve training in professionalism and transversal competences in medical studies at the universities of Catalonia

Introducción: En un grupo de trabajo de la Administración de la Generalitat de Cataluña y de los decanos de las facultades con estudios de Medicina de las universidades catalanas se creó una comisión para elaborar una propuesta para fomentar la formación en profesionalismo, en humanidades y en competencias transversales de los graduados en Medicina. Desarrollo: Dicha comisión, compuesta por docentes de todas las facultades, elaboró un documento con tres objetivos específicos: a) mostrar el estado real de dicha formación en los currículos; b) proponer actividades docentes concretas para mejorar dicha formación, considerando las buenas prácticas que se están realizando en las universidades; y c) sugerir criterios y métodos de evaluación de la formación en profesionalismo o de competencias transversales y, también, evaluar competencias específicas que pueden favorecer el desarrollo de las competencias genéricas. Conclusiones: Se espera que las sugerencias presentadas puedan servir para aumentar la formación en valores profesionales, en humanidades y en competencias transversales de los futuros profesionales de la medicina, con el objetivo final de mejorar la salud de la población.(AU)

Introduction: In a working group of the Administration of the regional government of Catalonia and the deans of the faculties with medical studies of the Catalan universities, a commission was created to prepare a document to promote training in professionalism and transversal competences of graduates in Medicine. Development: This commission, made up of teachers from all the faculties, prepared a document with three specific objectives: a) show the real state of said training in the curricula; b) propose specific teaching activities to improve said training, considering those good practices that are being carried out in universities; and c) suggest criteria and methods of evaluation of training in professionalism or of transversal competences and, also, evaluate specific competences that can improve the development of generic competences. Conclusions: It is hoped that the suggestions presented can serve to increase training in professional values, in the humanities and in transversal competences of future medical professionals with the ultimate goal of improving the health of the population.(AU)

Red Shift in Optical Excitations on Layered Copper Perovskites under Pressure: Role of the Orthorhombic Instability.

The red shift under pressure in optical transitions of layered compounds with CuCl6 4- units is explored through first-principles calculations and the analysis of available experimental data. The results on Cu2+ -doped (C2 H5 NH3 )2 CdCl4 , that is taken as a guide, show the existence of a highly anisotropic response to pressure related to a structural instability, driven by a negative force constant, that leads to an orthorhombic geometry of CuCl6 4- units but with a hole displaying a dominant 3z2 -r2 character (z being the direction perpendicular to the layer plane). As a result of such an instability, a pressure of only 3 GPa reduces by 0.21 Šthe longest Cu2+ -Cl- distance, lying in the layer plane, while leaving unmodified the two other metal-ligand distances. Owing to this fact, it is shown that the lowest d-d transition would experience a red shift of 0.34 eV while the first allowed charge transfer transition is also found to be red shifted but only by 0.11 eV that reasonably concurs with the experimental value. The parallel study on Jahn-Teller systems CdCl2 :Cu2+ and NaCl:Cu2+ involving tetragonal elongated CuCl6 4- units shows that the reduction of the long axis by a pressure of 3 GPa is three times smaller than that for the layered (C2 H5 NH3 )2 CdCl4 :Cu2+ compound. Accordingly, the optical transitions of such systems, which involve a positive force constant, are much less sensitive to pressure than in layered compounds. The origin of the red shift under pressure undergone by the lowest d-d and charge transfer transitions of (C2 H5 NH3 )2 CdCl4 :Cu2+ is discussed in detail.

Pressure Effects on 3dn (n=4, 9) Insulating Compounds: Long Axis Switch in Na3 MnF6 not Due to the Jahn-Teller Effect.

The pressure-induced switch of the long axis of MnF6 3- units in the monoclinic Na3 MnF6 compound and Mn3+ -doped Na3 FeF6 is explored with the help of first principles calculations. Although the switch phenomenon is usually related to the Jahn-Teller effect, we show that, due to symmetry reasons, it cannot take place in 3dn (n=4, 9) systems displaying a static Jahn-Teller effect. By contrast, we prove that in Na3 MnF6 the switch arises from the anisotropic response of the low symmetry lattice to hydrostatic pressure. Indeed, while the long axis of a MnF6 3- unit at ambient pressure corresponds to the Mn3+ -F3 - direction, close to the crystal c axis, at 2.79 GPa the c axis is reduced by 0.29 Šwhile b is unmodified. This fact is shown to force a change of the HOMO wavefunction favoring that the long axis becomes the Mn3+ -F2 - direction, not far from crystal b axis, after the subsequent relaxation process. The origin of the different d-d transitions observed for Na3 MnF6 and CrF2 at ambient pressure is also discussed together with changes induced by pressure in Na3 MnF6 . The present work opens a window for understanding the pressure effects upon low symmetry insulating compounds containing d4 or d9 ions.

NFAT5 Controls the Integrity of Epidermis.

The skin protects the human body against dehydration and harmful challenges. Keratinocytes (KCs) are the most abundant epidermal cells, and it is anticipated that KC-mediated transport of Na+ ions creates a physiological barrier of high osmolality against the external environment. Here, we studied the role of NFAT5, a transcription factor whose activity is controlled by osmotic stress in KCs. Cultured KCs from adult mice were found to secrete more than 300 proteins, and upon NFAT5 ablation, the secretion of several matrix proteinases, including metalloproteinase-3 (Mmp3) and kallikrein-related peptidase 7 (Klk7), was markedly enhanced. An increase in Mmp3 and Klk7 RNA levels was also detected in transcriptomes of Nfat5-/- KCs, along with increases of numerous members of the 'Epidermal Differentiation Complex' (EDC), such as small proline-rich (Sprr) and S100 proteins. NFAT5 and Mmp3 as well as NFAT5 and Klk7 are co-expressed in the basal KCs of fetal and adult epidermis but not in basal KCs of newborn (NB) mice. The poor NFAT5 expression in NB KCs is correlated with a strong increase in Mmp3 and Klk7 expression in KCs of NB mice. These data suggests that, along with the fragile epidermis of adult Nfat5-/- mice, NFAT5 keeps in check the expression of matrix proteases in epidermis. The NFAT5-mediated control of matrix proteases in epidermis contributes to the manifold changes in skin development in embryos before and during birth, and to the integrity of epidermis in adults.

Salt-Sensitive Hypertension of the Renal Tubular Cell-Specific NFAT5 (Nuclear Factor of Activated T-Cells 5) Knockout Mice.

[Figure: see text].

New Ideas for Understanding the Structure and Magnetism in AgF2 : Prediction of Ferroelasticity.

In the search for new high-temperature superconductors, it has been proposed that there are strong similarities between the fluoroargentate AgF2 and the cuprate La2 CuO4 . We explored the origin of the possible layered structure of AgF2 by studying its parent high-symmetry phase and comparing these results with those of a seemingly analogous cuprate, CuF2 . Our findings first stress the large differences between CuF2 and AgF2 . Indeed, the parent structure of AgF2 is found to be cubic, naturally devoid of any layering, even though Ag2+ ions occupy trigonal sites that, nevertheless, allow the existence of a Jahn-Teller effect. The observed Pbca orthorhombic phase is found when the system is cooperatively distorted by a local E⊗e trigonal Jahn-Teller effect around the silver sites that creates both geometrical and magnetic layering. While the distortion implies that two Ag2+ -F- bonds increase their distance by 15 % and become softer, our simulations indicate that covalent bonding and interlayer electron hopping is strong, unlike the situation in cuprate superconductors, and that, in fact, exfoliation of individual planes might be a harder task than previously suggested. As a salient feature, these results prove that the actual magnetic structure in AgF2 is a direct consequence of vibronic contributions involved in the Jahn-Teller effect. Finally, our findings show that, due to the multiple minima intrinsic to the Jahn-Teller energy surface, the system is ferroelastic, a property that is strongly coupled to magnetism in this argentate.

NFAT5 Amplifies Antipathogen Responses by Enhancing Chromatin Accessibility, H3K27 Demethylation, and Transcription Factor Recruitment.

The ability of innate immune cells to respond to pathogen-associated molecular patterns across a wide range of intensities is fundamental to limit the spreading of infections. Studies on transcription responses to pathogen-activated TLRs have often used relatively high TLR ligand concentrations, and less is known about their regulation under mild stimulatory conditions. We had shown that the transcription factor NFAT5 facilitates expression of antipathogen genes under TLR stimulation conditions corresponding to low pathogen loads. In this study, we analyze how NFAT5 optimizes TLR-activated responses in mouse macrophages. We show that NFAT5 was required for effective recruitment of central effectors p65/NF-κB and c-Fos to specific proinflammatory target genes, such as Nos2, Il6, and Tnf in primary macrophages responding to low doses of the TLR4 ligand LPS. By contrast, NFAT5 was not required for p65/NF-κB recruitment in response to high LPS doses. Using the transposase-accessible chromatin with high-throughput sequencing assay, we show that NFAT5 facilitated chromatin accessibility mainly at promoter regions of multiple TLR4-responsive genes. Analysis of various histone marks that regulate gene expression in response to pathogens identified H3K27me3 demethylation as an early NFAT5-dependent mechanism that facilitates p65 recruitment to promoters of various TLR4-induced genes. Altogether, these results advance our understanding about specific mechanisms that optimize antipathogen responses to limit infections.

The transcription factor NFAT5 limits infection-induced type I interferon responses.

Type I interferon (IFN-I) provides effective antiviral immunity but can exacerbate harmful inflammatory reactions and cause hematopoietic stem cell (HSC) exhaustion; therefore, IFN-I expression must be tightly controlled. While signaling mechanisms that limit IFN-I induction and function have been extensively studied, less is known about transcriptional repressors acting directly on IFN-I regulatory regions. We show that NFAT5, an activator of macrophage pro-inflammatory responses, represses Toll-like receptor 3 and virus-induced expression of IFN-I in macrophages and dendritic cells. Mice lacking NFAT5 exhibit increased IFN-I production and better control of viral burden upon LCMV infection but show exacerbated HSC activation under systemic poly(I:C)-induced inflammation. We identify IFNß as a primary target repressed by NFAT5, which opposes the master IFN-I inducer IRF3 by binding to an evolutionarily conserved sequence in the IFNB1 enhanceosome that overlaps a key IRF site. These findings illustrate how IFN-I responses are balanced by simultaneously opposing transcription factors.

Ground State and Optical Excitations in Compounds with Tetragonal CuF64- Units: Insight into KAlCuF6 and CuFAsF6.

It has been argued that AAlCuF6 (A = K, Cs) and CuFAsF6 are the only known crystals that exhibit compressed CuF64- units due to the Jahn-Teller effect. However, no grounds for this singular behavior have yet been reported. By means of first-principles calculations on such compounds and the isomorphous compounds involving Zn2+ ions instead of Cu2+, we prove that neither the ground state nor the equilibrium geometry of CuF64- complexes in KAlCuF6 and CuFAsF6 is the result of a Jahn-Teller effect. In contrast, it is shown that the internal electric field, ER(r), created by the rest of the lattice ions upon the localized electrons in the complex, plays an important role in understanding this matter as well as the d-d transitions of these two compounds. The energy of an optical transition is shown to involve two contributions: the intrinsic contribution derived for the isolated CuF64- unit at equilibrium and the extrinsic contribution coming from the ER(r) field. Aside from reproduction of the experimental d-d transitions observed for KAlCuF6, it is found that in CuFAsF6 the b1g(x2 - y2) → a1g(3z2 - r2) transition is not the lowest one due to the stronger effects from the internal field. Interestingly, the intrinsic contribution corresponding to that transition can simply be written as ß(Req - Rax) where Req and Rax are the equatorial and axial Cu2+-F- distances and ß = 2.7 eV/Å is the same for all systems involving tetragonal CuF64- units and an average metal-ligand distance close to 2.03 Å. This shows the existence of a common point shared by the Jahn-Teller system KZnF3:Cu2+ and other non-Jahn-Teller systems such as KAlCuF6, CuFAsF6, K2ZnF4:Cu2+, and Ba2ZnF6:Cu2+. Although most Jahn-Teller systems display an elongated geometry, there are however many Cu2+ compounds with a compressed geometry but hidden by an additional orthorhombic instability. The lack of that instability in KAlCuF6 and CuFAsF6 is also discussed.

Systematic review of prophylaxis for venous thromboembolism after knee arthroplasty: enoxaparin versus rivaroxaban. / Revisão sistemática da profilaxia para tromboembolismo venoso após artroplastia do joelho: enoxaparina versus rivaroxabana.

Total knee arthroplasty is an elective procedure performed on relatively healthy individuals. However, due to the inherent risk of venous thromboembolism, drugs are used for its prophylaxis. The objective of the present study was to conduct a systematic review of the literature to compare the efficacy of enoxaparin and rivaroxaban in preventing this complication and the risk of intraoperative bleeding. We reviewed the SciELO, Pubmed and Cochrane databases with the descriptors knee arthroplasty, rivaroxaban and enoxaparin through the PICO search strategy. Inclusion criteria were the articles during the study period comparing both drugs in knee arthroplasty. Relevant criteria to study eligibility were articles published since 2010 and with a sample of more than 20 patients; studies obtained in their entirety; and studies with follow-up of more than 12 months. The variables used to compare the articles were the most common postoperative complications of knee arthroplasties: venous thromboembolism and bleeding. We used the Review Man software, version 5.3, for structuring the review. In the studies analyzed, considering symptomatic venous thromboembolism, rivaroxaban resulted in higher benefits when compared to enoxaparin.

A artroplastia total do joelho é um procedimento eletivo, realizado em indivíduos relativamente saudáveis. Porém, devido ao risco inerente de tromboembolismo venoso, são utilizados fármacos para sua profilaxia. O objetivo do presente trabalho foi conduzir uma revisão sistemática da literatura para comparar a eficácia da enoxaparina e da rivaroxabana na prevenção desta complicação e no risco de sangramento intraoperatório. Foi feita uma revisão no site SciELO, Pubmed e Cochrane através dos descritores, artroplastia de joelho, rivaroxabana e enoxaparina através da estratégia de busca PICO. Os critérios de inclusão foram os artigos no período estudado, que comparavam ambas as drogas em cirurgias de artroplastia do joelho. Os critérios de relevância para tornar o estudo elegível foram definidos como: somente artigos publicados a partir 2010 e com casuística com mais de 20 pacientes foram considerados; somente estudos obtidos em sua íntegra foram analisados; somente estudos com seguimento maior do que 12 meses foram considerados relevantes. As variáveis utilizadas para a comparação dos artigos foram as complicações mais comuns no pós-operatório de artroplastias do joelho: tromboembolismo venoso e sangramento. Foi utilizado o Review Man 5.3 para estruturação da revisão. Os autores observaram que nos estudos analisados, considerando tromboembolismo venoso sintomático, a rivaroxabana resultou em maiores benefícios quando comparada com a enoxaparina.

Regulation of Inflammatory Functions of Macrophages and T Lymphocytes by NFAT5.

The transcription factor NFAT5, also known as TonEBP, belongs to the family of Rel homology domain-containing factors, which comprises the NF-κB proteins and the calcineurin-dependent NFAT1 to NFAT4. NFAT5 shares several structural and functional features with other Rel-family factors, for instance it recognizes DNA elements with the same core sequence as those bound by NFAT1 to 4, and like NF-κB it responds to Toll-like receptors (TLR) and activates macrophage responses to microbial products. On the other hand, NFAT5 is quite unique among Rel-family factors as it can be activated by hyperosmotic stress caused by elevated concentrations of extracellular sodium ions. NFAT5 regulates specific genes but also others that are inducible by NF-κB and NFAT1 to 4. The ability of NFAT5 to do so in response to hypertonicity, microbial products, and inflammatory stimuli may extend the capabilities of immune cells to mount effective anti-pathogen responses in diverse microenvironment and signaling conditions. Recent studies identifying osmostress-dependent and -independent functions of NFAT5 have broadened our understanding of how NFAT5 may modulate immune function. In this review we focus on the role of NFAT5 in macrophages and T cells in different contexts, discussing findings from in vivo mouse models of NFAT5 deficiency and reviewing current knowledge on its mechanisms of regulation. Finally, we propose several questions for future research.

Understanding the Structure and Ground State of the Prototype CuF2 Compound Not Due to the Jahn-Teller Effect.

Insulating CuF2 is considered a prototype compound displaying a Jahn-Teller effect (JTE) which gives rise to elongated CuF64- units. By means of first-principles calculations together with an analysis of experimental data of both CuF2 and Cu2+-doped ZnF2, we demonstrate that such an idea is not correct. For ZnF2:Cu2+, we find that CuF64- units are compressed always along the Z local axis with a hole essentially in a 3 z2- r2 antibonding orbital, in agreement with experimental EPR data that already underline the absence of a JTE. The structure of the monoclinic CuF2 crystal also comes from compressed CuF64- complexes, although hidden by an additional orthorhombic instability due to a negative force constant of b2g and b3g local modes. The associated distortion, similar to that involved in K2CuF4 and other layered Cu2+ compounds, is also shown to be developed for ZnF2:Cu2+ upon increasing the copper concentration. The origin of this cooperative effect is discussed together with the differences between non-Jahn-Teller systems like ZnF2:Cu2+ and CuF2 and true Jahn-Teller systems like KZnF3:Cu2+. From present results and those on layered compounds, the usual assumption of a JTE for explaining the properties of d9 ions in low-symmetry lattices can hardly be right.

Revisão sistemática da profilaxia para tromboembolismo venoso após artroplastia do joelho: enoxaparina versus rivaroxabana / Systematic review of prophylaxis for venous thromboembolism after knee arthroplasty: enoxaparin versus rivaroxaban

RESUMO A artroplastia total do joelho é um procedimento eletivo, realizado em indivíduos relativamente saudáveis. Porém, devido ao risco inerente de tromboembolismo venoso, são utilizados fármacos para sua profilaxia. O objetivo do presente trabalho foi conduzir uma revisão sistemática da literatura para comparar a eficácia da enoxaparina e da rivaroxabana na prevenção desta complicação e no risco de sangramento intraoperatório. Foi feita uma revisão no site SciELO, Pubmed e Cochrane através dos descritores, artroplastia de joelho, rivaroxabana e enoxaparina através da estratégia de busca PICO. Os critérios de inclusão foram os artigos no período estudado, que comparavam ambas as drogas em cirurgias de artroplastia do joelho. Os critérios de relevância para tornar o estudo elegível foram definidos como: somente artigos publicados a partir 2010 e com casuística com mais de 20 pacientes foram considerados; somente estudos obtidos em sua íntegra foram analisados; somente estudos com seguimento maior do que 12 meses foram considerados relevantes. As variáveis utilizadas para a comparação dos artigos foram as complicações mais comuns no pós-operatório de artroplastias do joelho: tromboembolismo venoso e sangramento. Foi utilizado o Review Man 5.3 para estruturação da revisão. Os autores observaram que nos estudos analisados, considerando tromboembolismo venoso sintomático, a rivaroxabana resultou em maiores benefícios quando comparada com a enoxaparina.

ABSTRACT Total knee arthroplasty is an elective procedure performed on relatively healthy individuals. However, due to the inherent risk of venous thromboembolism, drugs are used for its prophylaxis. The objective of the present study was to conduct a systematic review of the literature to compare the efficacy of enoxaparin and rivaroxaban in preventing this complication and the risk of intraoperative bleeding. We reviewed the SciELO, Pubmed and Cochrane databases with the descriptors knee arthroplasty, rivaroxaban and enoxaparin through the PICO search strategy. Inclusion criteria were the articles during the study period comparing both drugs in knee arthroplasty. Relevant criteria to study eligibility were articles published since 2010 and with a sample of more than 20 patients; studies obtained in their entirety; and studies with follow-up of more than 12 months. The variables used to compare the articles were the most common postoperative complications of knee arthroplasties: venous thromboembolism and bleeding. We used the Review Man software, version 5.3, for structuring the review. In the studies analyzed, considering symptomatic venous thromboembolism, rivaroxaban resulted in higher benefits when compared to enoxaparin.

Analgesia linked to Nav1.7 loss of function requires µ- and δ-opioid receptors.

Background: Functional deletion of the Scn9a (sodium voltage-gated channel alpha subunit 9) gene encoding sodium channel Nav1.7 makes humans and mice pain-free. Opioid signalling contributes to this analgesic state. We have used pharmacological and genetic approaches to identify the opioid receptors involved in this form of analgesia. We also examined the regulation of proenkephalin expression by the transcription factor Nfat5 that binds upstream of the Penk gene. Methods: We used specific µ-, δ- and κ-opioid receptor antagonists alone or in combination to examine which opioid receptors were necessary for Nav1.7 loss-associated analgesia in mouse behavioural assays of thermal pain. We also used µ- and δ-opioid receptor null mutant mice alone and in combination in behavioural assays to examine the role of these receptors in Nav1.7 knockouts pain free phenotype. Finally, we examined the levels of Penk mRNA in Nfat5-null mutant mice, as this transcription factor binds to consensus sequences upstream of the Penk gene. Results: The pharmacological block or deletion of both µ- and δ-opioid receptors was required to abolish Nav1.7-null opioid-related analgesia. κ-opioid receptor antagonists were without effect. Enkephalins encoded by the Penk gene are upregulated in Nav1.7 nulls. Deleting Nfat5, a transcription factor with binding motifs upstream of Penk, induces the same level of enkephalin mRNA expression as found in Nav1 .7 nulls, but without consequent analgesia. These data confirm that a combination of events linked to Scn9a gene loss is required for analgesia. Higher levels of endogenous enkephalins, potentiated opioid receptors, diminished electrical excitability and loss of neurotransmitter release together contribute to the analgesic phenotype found in Nav1.7-null mouse and human mutants. Conclusions: These observations help explain the failure of Nav1.7 channel blockers alone to produce analgesia and suggest new routes for analgesic drug development.

Macrophage-specific MHCII expression is regulated by a remote Ciita enhancer controlled by NFAT5.

MHCII in antigen-presenting cells (APCs) is a key regulator of adaptive immune responses. Expression of MHCII genes is controlled by the transcription coactivator CIITA, itself regulated through cell type-specific promoters. Here we show that the transcription factor NFAT5 is needed for expression of Ciita and MHCII in macrophages, but not in dendritic cells and other APCs. NFAT5-deficient macrophages showed defective activation of MHCII-dependent responses in CD4+ T lymphocytes and attenuated capacity to elicit graft rejection in vivo. Ultrasequencing analysis of NFAT5-immunoprecipitated chromatin uncovered an NFAT5-regulated region distally upstream of Ciita This region was required for CIITA and hence MHCII expression, exhibited NFAT5-dependent characteristics of active enhancers such as H3K27 acetylation marks, and required NFAT5 to interact with Ciita myeloid promoter I. Our results uncover an NFAT5-regulated mechanism that maintains CIITA and MHCII expression in macrophages and thus modulates their T lymphocyte priming capacity.

NFAT5-Regulated Macrophage Polarization Supports the Proinflammatory Function of Macrophages and T Lymphocytes.

Macrophages are exquisite sensors of tissue homeostasis that can rapidly switch between pro- and anti-inflammatory or regulatory modes to respond to perturbations in their microenvironment. This functional plasticity involves a precise orchestration of gene expression patterns whose transcriptional regulators have not been fully characterized. We had previously identified the transcription factor NFAT5 as an activator of TLR-induced responses, and in this study we explore its contribution to macrophage functions in different polarization settings. We found that both in classically and alternatively polarized macrophages, NFAT5 enhanced functions associated with a proinflammatory profile such as bactericidal capacity and the ability to promote Th1 polarization over Th2 responses. In this regard, NFAT5 upregulated the Th1-stimulatory cytokine IL-12 in classically activated macrophages, whereas in alternatively polarized ones it enhanced the expression of the pro-Th1 mediators Fizz-1 and arginase 1, indicating that it could promote proinflammatory readiness by regulating independent genes in differently polarized macrophages. Finally, adoptive transfer assays in vivo revealed a reduced antitumor capacity in NFAT5-deficient macrophages against syngeneic Lewis lung carcinoma and ID8 ovarian carcinoma cells, a defect that in the ID8 model was associated with a reduced accumulation of effector CD8 T cells at the tumor site. Altogether, detailed analysis of the effect of NFAT5 in pro- and anti-inflammatory macrophages uncovered its ability to regulate distinct genes under both polarization modes and revealed its predominant role in promoting proinflammatory macrophage functions.

Necrolisis epidérmica tóxica: un paradigma de enfermedad crítica / Toxic epidermal necrolysis: a paradigm of critical illness

RESUMEN La necrolisis epidérmica tóxica es una reacción cutánea adversa de tipo inmunológico secundaria en la mayor parte de los casos a la administración de un fármaco. La necrolisis epidérmica tóxica, el síndrome de Steven Johnson y el eritema exudativo multiforme forman parte del mismo espectro de enfermedad. La mortalidad de la necrolisis epidérmica tóxica es alrededor del 30%. La fisiopatología de la necrolisis epidérmica tóxica es semejante en muchos aspectos a la de las quemaduras dérmicas superficiales. La afectación mucosa del epitelio ocular y genital se asocia con secuelas graves si no se trata de forma temprana. Se acepta en general que los pacientes con necrolisis epidérmica tóxica son tratados mejor en unidades de grandes quemados, donde existe experiencia en el manejo de enfermos con pérdida cutánea extensa. El tratamiento es de soporte, eliminación y cobertura con derivados biosintéticos de la piel de las zonas afectadas, tratamiento de la afectación mucosa, y tratamiento inmunosupresor específico. De los tratamientos ensayados sólo se usa actualmente en la mayor parte de los centros la inmunoglobulina G y la ciclosporina A, aun cuando no existe evidencia sólida para recomendar ningún tratamiento específico. Entre los aspectos particulares del tratamiento de esta enfermedad se encuentra la prevención de secuelas relacionadas con la formación de sinequias, los cuidados oculares para prevenir secuelas graves que pueden conducir a la ceguera, y el tratamiento específico inmunosupresor. Un mejor conocimiento de los principios del manejo de la necrolisis epidérmica tóxica llevará a un mejor manejo de la enfermedad, a una mayor supervivencia y una menor prevalencia de las secuelas.

ABSTRACT Toxic epidermal necrolysis is an adverse immunological skin reaction secondary in most cases to the administration of a drug. Toxic epidermal necrolysis, Stevens-Johnson syndrome, and multiform exudative erythema are part of the same disease spectrum. The mortality rate from toxic epidermal necrolysis is approximately 30%. The pathophysiology of toxic epidermal necrolysis is similar in many respects to that of superficial skin burns. Mucosal involvement of the ocular and genital epithelium is associated with serious sequelae if the condition is not treated early. It is generally accepted that patients with toxic epidermal necrolysis are better treated in burn units, which are experienced in the management of patients with extensive skin loss. Treatment includes support, elimination, and coverage with biosynthetic derivatives of the skin in affected areas, treatment of mucosal involvement, and specific immunosuppressive treatment. Of the treatments tested, only immunoglobulin G and cyclosporin A are currently used in most centers, even though there is no solid evidence to recommend any specific treatment. The particular aspects of the treatment of this disease include the prevention of sequelae related to the formation of synechiae, eye care to prevent serious sequelae that can lead to blindness, and specific immunosuppressive treatment. Better knowledge of the management principles of toxic epidermal necrolysis will lead to better disease management, higher survival rates, and lower prevalence of sequelae.

Predictors of diffuse alveolar damage in patients with acute respiratory distress syndrome: a retrospective analysis of clinical autopsies.

BACKGROUND: Although diffuse alveolar damage (DAD) is considered the typical histological pattern of acute respiratory distress syndrome (ARDS), only half of patients exhibit this morphological hallmark. Patients with DAD may have higher mortality than those without DAD. Therefore, we aimed to identify the factors associated with DAD in patients with ARDS. METHODS: We analyzed autopsy samples of 356 patients who had ARDS at the time of death. DAD was assessed by two pathologists, and ARDS criteria were evaluated by two intensivists. Criteria for severe ARDS included the degree of hypoxemia and the ancillary variables of the current Berlin definition assessed within 48 h before death: radiographic severity, high positive end-expiratory pressure (PEEP) level, and physiological variables (i.e., altered respiratory system compliance and large anatomic dead space). RESULTS: After multivariable analysis, high PEEP levels, physiological variables, and opacities involving only three quadrants on chest radiographs were not associated with DAD. The four markers independently associated with DAD were (1) duration of evolution (OR 3.29 [1.95-5.55] for patients with ARDS ≥ 3 days, p < 0.001), (2) degree of hypoxemia (OR 3.92 [1.48-10.3] for moderate ARDS and 6.18 [2.34-16.3] for severe ARDS, p < 0.01 for both), (3) increased dynamic driving pressure (OR 1.06 [1.04-1.09], p = 0.007), and (4) radiographic severity (OR 2.91 [1.47-5.75] for patients with diffuse opacities involving the four quadrants, p = 0.002). DAD was found in two-thirds of patients with a ratio of partial pressure of arterial oxygen to fraction of inspired oxygen ≤ 100 mmHg and opacities involving the four quadrants. CONCLUSIONS: In addition to severe hypoxemia, diffuse opacities involving the four quadrants were a strong marker of DAD.