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Objetivo: Las propiedades de los materiales que constituyen el tejido óseo son determinantes en su resistencia mecánica pero los factores que influyen sobre ella son parcialmente desconocidos en la actualidad. Material y métodos: En esta investigación medimos la dureza ósea mediante ensayos de ultra-microindentación con punta tipo Berkovich y una carga de 150 mN en fémures de ratas Sprague-Dawley sometidas a una fractura transversal o a una osteotomía de sustracción, y comparamos los resultados en diferentes localizaciones óseas y grupos experimentales. El estudio comprende los siguientes cuatro grupos experimentales, cada uno de ellos constituido por cuatro ratas: a) fractura diafisiana estándar; b) fractura más osteotomía de 2 mm; c) osteotomía tratada con hormona paratiroidea humana, PTH (1-84); d) osteotomía tratada con ranelato de estroncio. Resultados: Encontramos que la dureza del material era consistentemente mayor en el hueso cortical que en el hueso trabecular. También fue consistentemente más alto en las epífisis femorales superiores que en las epífisis inferiores (diferencia de 1,2 desviaciones estándar). La cirugía redujo la dureza en el fémur operado (diferencia de 0,3 desviaciones estándar, p=5,5 x10-2). El tratamiento con PTH indujo un aumento leve pero consistente de la dureza en todos los sitios (p=1,8×10-5) mientras que el efecto del ranelato de estroncio fue inconsistente. Conclusiones: Estos datos muestran que la microdureza tisular está influida por una variedad de factores, incluyendo la anatomía, el tipo de tejido óseo, la lesión esquelética y la terapia farmacológica. Por lo tanto, los estudios futuros sobre la calidad del tejido deberían diseñarse cuidadosamente teniendo en cuenta estos factores.

Serum sickness was induced in rats by a modification of previously described methods avoiding i.v. administration of the antigen. All the animals developed a progressive disease characterized by an initial pattern of deposition of IC in the mesangium followed by the appearance of GBM deposits. This change in the deposition of IC was associated with the onset of massive proteinuria and a fall in the titre of precipitating antibodies. Simultaneously, specific desensitization of platelets for a rat PAF could be demonstrated and platelet aggregates were seen in the glomeruli. The presence of homocytotropic IgGa anti-ovalbumin antibodies in rat sera during the induction of the disease was demonstrated by 2 hr PCA. Accordingly, this antibody together with the antigen ovalbumin induced the release of histamine From peritoneal mast cells, suggesting that a similar mechanism might occur in vivo during the induction of the disease. Rat PAF and β glucuronidase could be obtained from peritoneal macrophages under similar conditions to those required for the release of histamine. The data support a role for inflammatory mediators in the increase in vascular permeability needed for the deposition of IC in the GBM and provide evidence for a new role of macrophages and PMNs in glomerular pathology in contributing to an increase in permeability of GBM. [ABSTRACT FROM AUTHOR]

Zymosan coated with complement (Zc) was observed to induce a transient elevation of the intracellular cyclic AMP in human polymorphonuclear cells: a two- to three-fold increase was observed within I min after stimulation and approached prestimulation levels by 2 min incubation. These changes in cyclic AMP were not associated with significant changes in cyclic GMP levels. Zymosan caused the release of PAF and β-glucuronidase and particle uptake, which was initiated about 5 min after stimulation. These results suggest that the transient increase in cyclic AMP content might regulate an early event during mediator release. In an attempt to study further the significance of this rise in cyclic AMP, cells were preincubated with various phosphodiesterase inhibitors. Preincubation of the cells with methylisobutylxanthine (MIX, 10-6 M to 5 ⊗ 10-5 M), theophylline (3 ⊗ 10-5 to 3 ⊗ 10-3 M) or dipyridamole (10-6 M to 10-4 M) enhanced the increase in cyclic AMP levels, but resulted in dose-dependent inhibition of Zc-induced mediator release. Particle uptake and β-glucuronidase release were less sensitive than PAF release to phosphodiesterase inhibitors, which argues in favour of the independence of both phenomena. Synergistic experiments with MIX and cyclic AMP indicate that the effect of this drug is through its action on cyclic AMP levels. These results suggest that while Zc-induced cyclic AMP elevation might occur in an intracellular place critical to its effect; phosphodiesterase inhibitors may elevate cyclic AMP levels throughout the cell and therefore inhibit the biological response. [ABSTRACT FROM AUTHOR]

In 30 patients with systemic lupus erythematosus the number of a circulating basophils was countered in different stages of activity. An inverse correlation was found between the absolute basophils count and anti-DNA antibodies and presumptive circulating immune complexes (as judged by polyethylene glycol precipitation of serum). A positive correlation was found between the absolute basophil count and C3 or C4 levels. IgE on the basophil surface was determined by radioimmunoassay in 7 patients. All of them showed a significantly higher surface IgE number. When the count of circulating basophils was roughly normal, 5 out of the 6 patients showed a positive basophil degranulation test with native DNA. These results suggest the existence of an anti-DNA specific IgE in lupus patients. Depression of the circulating basophil count may be a useful index of lupus activity. [ABSTRACT FROM PUBLISHER]

The purpose of this study was to characterize circulating IgA and the IgA deposited in the glomeruli of patients with alcoholic liver disease. In the 6 patients studied there was an increased proportion in monomeric IgA (3.5 fold) and IgA between 9-13S (8.94 fold), 13.17S (4.49 fold) and 17.21S (1.63 fold) fractions on 5.40% sucrose density gradient ultracentrifugation at physiological pH. All fractions between 9-21S decreased at acid pH, however a 3.28 fold increase in fractions where polymeric IgA is expected to appear. IgA eluted at acid pH from autopsy kidney was studied by the same procedures. At pH 7.4 about 55% of that IgA have a molecular weight comprised between 9.21S, decreasing to around 25% at acid pH. The existence of true polymeric IgA in serum and kidney was based on the capacity of high molecular weight IgA to bind human secretory component. The amount of Immune complexes with monomeric IgA were higher than those with polymeric IgA in serum as well as in kidney. However, the percentage of heavy IgA (probably polymeric IgA) in kidney were, in each patient, higher than those observed in serum. Our results show the presence of high amounts of monomeric and polymeric IgA, both partially as immune complexes, in serum and kidneys of patients with alcoholic liver disease and IgA glomerulonephritis. Furthermore, our data suggest a role for human liver in the clearance of serum IgA such as has been demonstrated in some animal species, especially in rats. [ABSTRACT FROM AUTHOR]

Background: The LYP tyrosine phosphatase presents a SNP (1858C > T) that increases the risk of developing autoimmune diseases such as type I diabetes and arthritis. It remains unclear how this SNP affects LYP function and promotes the development of these diseases. The scarce information about LYP substrates is in part responsible for the poor understanding of LYP function., Results: In this study, we identify in T lymphocytes several adaptor proteins as potential substrates targeted by LYP, including FYB, SLP-76, HS-1, Vav, SKAP1 and SKAP2. We also show that LYP co-localizes with SLP76 in microclusters, upon TCR engagement., Conclusions: These data indicate that LYP may modulate T cell activation by dephosphorylating several adaptor proteins, such as FYB, SLP-76, HS-1, Vav, SKAP1 and SKAP2 upon TCR engagement., (© 2024. The Author(s).)

Monocyte-derived dendritic cells (MDDCs) are key players in the defense against fungal infection because of their outstanding capacity for non-opsonic phagocytosis and phenotypic plasticity. Accordingly, MDDCs rewire metabolism to meet the energetic demands for microbial killing and biomass synthesis required to restore homeostasis. It has been commonplace considering the metabolic reprogramming a mimicry of the Warburg effect observed in tumor cells. However, this may be an oversimplification since the offshoots of glycolysis and the tricarboxylic acid (TCA) cycle are connected in central carbon metabolism. Zymosan, the external wall of Saccharomyces cerevisiae, contains β-glucan and α-mannan chains that engage the C-type lectin receptors dectin-1/2 and Toll-like receptors. This makes it an optimal fungal surrogate for experimental research. Using real-time bioenergetic assays and [U- 13 C]glucose labeling, central hubs connected to cytokine expression were identified. The pentose phosphate pathway (PPP) exhibited a more relevant capacity to yield ribose-5-phosphate than reducing equivalents of NADPH, as judged from the high levels of isotopologues showing 13 C-labeling in the ribose moiety and the limited contribution of the oxidative arm of the PPP to the production of ROS by NADPH oxidases (NOX). The finding of 13 C-label in the purine ring and in glutathione unveiled the contribution of serine-derived glycine to purine ring and glutathione synthesis. Serine synthesis also supported the TCA cycle. Zymosan exhausted NAD + and ATP, consistent with intracellular consumption and/or extracellular export. Poly-ADP-ribosylated proteins detected in the nuclear fractions of MDDCs did not show major changes upon zymosan stimulation, which suggests its dependence on constitutive Fe(II)/2-oxoglutarate-dependent demethylation of 5-methylcytosine by TET translocases and/or demethylation of histone H3 lysine 27 by JMJD demethylases rather than on NOX activities. These results disclose a unique pattern of central carbon metabolism following fungal challenge, characterized by the leverage of glycolysis offshoots and an extensive recycling of NAD + and poly(ADP-ribose)., Competing Interests: Declaration of competing interest The authors declare that there are not conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Introduction: The treatment of rhizarthrosis using trapeziometacarpal prostheses (TMP) is increasing. Complications may lead to loss of the implant and result in salvage surgery. Our aim was to assess major complications with the use of some TMP models and their rescue., Material and Method: Retrospective study on TMP implanted between 2006 and 2021. Models studied: Arpe®, Elektra®, Ivory®, Maïa®, Isis® and Touch®. Demographic data were assessed, implant placement by radiographic study, technical data, complications, salvage surgeries and final survival., Results: Review of 224 TMP, 45 Arpe® (95.5% survival, rate follow-up [R] 6-16 years), 5 Elektra® (80% survival, R 13-14), 14 Ivory® (92.8% survival, R 9-11), 7 Maïa® (100% survival, R 8-9), 115 Isis® (99.1% survival, R 1-8), 38 Touch® (100% survival, R 1-4). The medial angle of the dome with the proximal articular surface of the trapezium in the lateral plane, was: Arpe®: 8.85°, Elektra®: not assessable, Ivory®: 6.6°, Maïa®: 14.4°, Isis®: 3.8°, and Touch®: 5.95°. The Isis® was placed 100% with scopic guidance presenting a significantly lower angle respect to the medial angle of the dome with the proximal articular surface of the trapezium. As main complications, we observed 3.5% of dislocations and 4% of mobilisations, with the Elektra® being responsible for 47% of these. Nineteen salvage surgeries were performed, with 3% of the implants being lost., Conclusions: Dislocation and mobilisation are the most observed complications, the Elektra® responsible for almost half of them. Correct placement and implant design appear to be crucial to avoid them in the short and long term., (Copyright © 2023 SECOT. Publicado por Elsevier España, S.L.U. All rights reserved.)

Introduction: The treatment of rhizarthrosis using trapeziometacarpal prostheses (TMP) is increasing. Complications may lead to loss of the implant and result in salvage surgery. Our aim was to assess major complications with the use of some TMP models and their rescue., Material and Method: Retrospective study on TMP implanted between 2006 and 2021. Models studied: Arpe®, Elektra®, Ivory®, Maïa®, Isis® and Touch®. Demographic data were assessed, implant placement by radiographic study, technical data, complications, salvage surgeries and final survival., Results: Review of 224 TMP, 45 Arpe® (95.5% survival, rate follow-up [R] 6-16 years), 5 Elektra® (80% survival, R 13-14), 14 Ivory® (92.8% survival, R 9-11), 7 Maïa® (100% survival, R 8-9), 115 Isis® (99.1% survival, R 1-8), 38 Touch® (100% survival, R 1-4). The medial angle of the dome with the proximal articular surface of the trapezium in the lateral plane, was: Arpe®: 8.85°, Elektra®: not assessable, Ivory®: 6.6°, Maïa®: 14.4°, Isis®: 3.8°, and Touch®: 5.95°. The Isis® was placed 100% with scopic guidance presenting a significantly lower angle respect to the medial angle of the dome with the proximal articular surface of the trapezium. As main complications, we observed 3.5% of dislocations and 4% of mobilisations, with the Elektra® being responsible for 47% of these. Nineteen salvage surgeries were performed, with 3% of the implants being lost., Conclusions: Dislocation and mobilisation are the most observed complications, the Elektra® responsible for almost half of them. Correct placement and implant design appear to be crucial to avoid them in the short and long term., (Copyright © 2023 SECOT. Publicado por Elsevier España, S.L.U. All rights reserved.)

Platelet-activating factor (PAF, 1-alkyl-2-acetyl-sn-glycero-3-phosphorylcholine) was discovered when the mechanisms involved in the deposition of immune complex in tissues were being scrutinized in the experimental model of rabbit serum sickness. The initial adscription of PAF to IgE-dependent anaphylaxis was soon extended after disclosing its release from phagocytes stimulated by calcium mobilizing agents, formylated peptides, and phagocytosable particles. This explains why ongoing research in the field turned to the analysis of immune cell types and stimuli involved in PAF production with the purpose of establishing its role in pathology. This was spurred by the identification of the chemical structure of PAF and the enzymic mechanisms involved in its biosynthesis and degradation, which showed commonalities with those involved in eicosanoid production and the Lands' cycle of phospholipid fatty acid remodeling. The reassignment of PAF function in immunopathology is explained by the finding that the most robust mechanisms leading to PAF production are associated with opsonic and non-opsonic phagocytosis, depending on the cell type. While polymorphonuclear leukocytes exhibit opsonic phagocytosis, monocyte-derived dendritic cells show a marked preference for non-opsonic phagocytosis associated with C-type lectin receptors. This is particularly relevant to the defense against fungal invasion and explains why PAF exerts an autocrine feed-forwarding mechanism required for the selective expression of some cytokines., (© 2022 The Authors. BioFactors published by Wiley Periodicals LLC on behalf of International Union of Biochemistry and Molecular Biology.)

Mutations in the adaptor protein PSTPIP1 cause a spectrum of autoinflammatory diseases, including PAPA and PAMI; however, the mechanism underlying these diseases remains unknown. Most of these mutations lie in PSTPIP1 F-BAR domain, which binds to LYP, a protein tyrosine phosphatase associated with arthritis and lupus. To shed light on the mechanism by which these mutations generate autoinflammatory disorders, we solved the structure of the F-BAR domain of PSTPIP1 alone and bound to the C-terminal homology segment of LYP, revealing a novel mechanism of recognition of Pro-rich motifs by proteins in which a single LYP molecule binds to the PSTPIP1 F-BAR dimer. The residues R228, D246, E250, and E257 of PSTPIP1 that are mutated in immunological diseases directly interact with LYP. These findings link the disruption of the PSTPIP1/LYP interaction to these diseases, and support a critical role for LYP phosphatase in their pathogenesis., (© 2022. The Author(s).)

Calcific aortic valve disease (CAVD) is the most prevalent valvulopathy worldwide. Growing evidence supports a role for viral and cell-derived double-stranded (ds)-RNA in cardiovascular pathophysiology. Poly(I:C), a dsRNA surrogate, has been shown to induce inflammation, type I interferon (IFN) responses, and osteogenesis through Toll-like receptor 3 in aortic valve interstitial cells (VIC). Here, we aimed to determine whether IFN signaling via Janus kinase (JAK)/Signal transducers and activators of transcription (STAT) mediates dsRNA-induced responses in primary human VIC. Western blot, ELISA, qPCR, calcification, flow cytometry, and enzymatic assays were performed to evaluate the mechanisms of dsRNA-induced inflammation and calcification. Poly(I:C) triggered a type I IFN response characterized by IFN-regulatory factors gene upregulation, IFN-β secretion, and STAT1 activation. Additionally, Poly(I:C) promoted VIC inflammation via NF-κB and subsequent adhesion molecule expression, and cytokine secretion. Pretreatment with ruxolitinib, a clinically used JAK inhibitor, abrogated these responses. Moreover, Poly(I:C) promoted a pro-osteogenic phenotype and increased VIC calcification to a higher extent in cells from males. Inhibition of JAK with ruxolitinib or a type I IFN receptor blocking antibody blunted Poly(I:C)-induced calcification. Mechanistically, Poly(I:C) promoted VIC apoptosis in calcification medium, which was inhibited by ruxolitinib. Moreover, Poly(I:C) co-operated with IFN-γ to increase VIC calcification by synergistically activating extracellular signal-regulated kinases and hypoxia-inducible factor-1α pathways. In conclusion, JAK/STAT signaling mediates dsRNA-triggered inflammation, apoptosis, and calcification and may contribute to a positive autocrine loop in human VIC in the presence of IFN-γ. Blockade of dsRNA responses with JAK inhibitors may be a promising therapeutic avenue for CAVD., (© 2021 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)