Dos obras del arquitecto Azpiazu. España

Two recent works of the Architect J. R. Azpiazu are shown in this issue. The interest of each of them is based in punctual aspects with original constructive solutions: — At first, BUSINESS BUILDING IN SANTANDER, the project is very interesting mainly by the planning and design of the structure in wood reenforcement with laminated steel elements. — In the second, BANK OFFICE IN ORIHUELA, the interest of the constructive and formal solution in the helicoidal stair in structural concrete, without central element is the main subject.Se presentan en este trabajo dos obras recientes del Arquitecto José Ramón Azpiazu. El interés de cada una de ellas radica en aspectos puntuales, con soluciones constructivas de cierta originalidad: — En la primera, EDIFICIO DE OFICINAS EN SANTANDER, interesa de modo especial el planteamiento adoptado para el refuerzo de la estructura de madera existente realizado a base de elementos de acero laminado. — En la segunda, SUCURSAL DE BANCO EN ORÍ HUELA, el mayor interés radica en la solución constructiva y formal de la escalera helicoidal de hormigón armado, ejecutada sin vástago central

Hyperbaric Oxygen Therapy Does Not Have a Negative Impact on Bone Signaling Pathways in Humans

Introduction: Oxygen is emerging as an important factor in the local regulation of bone remodeling. Some preclinical data suggest that hyperoxia may have deleterious effects on bone cells. However, its clinical relevance is unclear. Hence, we studied the effect of hyperbaric oxygen therapy (HBOT) on serum biomarkers reflecting the status of the Wnt and receptor activator of NF-?B ligand (RANKL) pathways, two core pathways for bone homeostasis. Materials and methods: This was a prospective study of 20 patients undergoing HBOT (mean age 58 yrs., range 35?82 yrs.) because of complications of radiotherapy or chronic anal fissure. Patients were subjected to HBOT (100% oxygen; 2.4 atmospheres absolute for 90 min). The average number of HBOT sessions was 20 ± 5 (range 8?31). Serum hypoxia-inducible factor 1-? (HIF1-?), osteoprotegerin (OPG), RANKL, and the Wnt inhibitors sclerostin and dickkopf-1 (DKK1) were measured at baseline and after HBOT by using specific immunoassays. Results: HIF-1? in eight patients with measurable serum levels increased from 0.084 (0.098) ng/mL at baseline to 0.146 (0.130) ng/mL after HBOT (p = 0.028). However, HBOT did not induce any significant changes in the serum levels of OPG, RANKL, sclerostin or DKK1. This was independent of the patients? diagnosis, either neoplasia or benign. Conclusion: Despite the potential concerns about hyperoxia, we found no evidence that HBOT has any detrimental effect on bone homeostasis

Wnt pathway genes in osteoporosis and osteoarthritis: differential expression and genetic association study

Producción CientíficaIn comparison with hip fractures, increased expression of genes in the Wnt pathway and increased Wnt activity were found in bone samples and osteoblast cultures from patients with osteoarthritis, suggesting the involvement of this pathway in subchondral bone changes. No consistent differences were found in the genetic association study

Efficacy of Anakinra in Refractory Adult-Onset Still's Disease: Multicenter Study of 41 Patients and Literature Review

Adult-onset Still's disease (AOSD) is often refractory to standard therapy. Anakinra (ANK), an interleukin-1 receptor antagonist, has demonstrated efficacy in single cases and small series of AOSD. We assessed the efficacy of ANK in a series of AOSD patients. Multicenter retrospective open-label study. ANK was used due to lack of efficacy to standard synthetic immunosuppressive drugs and in some cases also to at least 1 biologic agent. Forty-one patients (26 women/15 men) were recruited. They had a mean age of 34.4 ± 14 years and a median [interquartile range (IQR)] AOSD duration of 3.5 [2-6] years before ANK onset. At that time the most common clinical features were joint manifestations 87.8%, fever 78%, and cutaneous rash 58.5%. ANK yielded rapid and maintained clinical and laboratory improvement. After 1 year of therapy, the frequency of joint and cutaneous manifestations had decreased to 41.5% and to 7.3% respectively, fever from 78% to 14.6%, anemia from 56.1% to 9.8%, and lymphadenopathy from 26.8% to 4.9%. A dramatic improvement of laboratory parameters was also achieved. The median [IQR] prednisone dose was also reduced from 20 [11.3-47.5] mg/day at ANK onset to 5 [0-10] at 12 months. After a median [IQR] follow-up of 16 [5-50] months, the most important side effects were cutaneous manifestations (n = 8), mild leukopenia (n = 3), myopathy (n = 1), and infections (n = 5). ANK is associated with rapid and maintained clinical and laboratory improvement, even in nonresponders to other biologic agents. However, joint manifestations are more refractory than the systemic manifestations

H3K4me1 marks DNA regions hypomethylated during aging in human stem and differentiated cells

In differentiated cells, aging is associated with hypermethylation of DNA regions enriched in repressive histone post-translational modifications. However, the chromatin marks associated with changes in DNA methylation in adult stem cells during lifetime are still largely unknown. Here, DNA methylation profiling of mesenchymal stem cells (MSCs) obtained from individuals aged 2 to 92 yr identified 18,735 hypermethylated and 45,407 hypomethylated CpG sites associated with aging. As in differentiated cells, hypermethylated sequences were enriched in chromatin repressive marks. Most importantly, hypomethylated CpG sites were strongly enriched in the active chromatin mark H3K4me1 in stem and differentiated cells, suggesting this is a cell type-independent chromatin signature of DNA hypomethylation during aging. Analysis of scedasticity showed that interindividual variability of DNA methylation increased during aging in MSCs and differentiated cells, providing a new avenue for the identification of DNA methylation changes over time. DNA methylation profiling of genetically identical individuals showed that both the tendency of DNA methylation changes and scedasticity depended on nongenetic as well as genetic factors. Our results indicate that the dynamics of DNA methylation during aging depend on a complex mixture of factors that include the DNA sequence, cell type, and chromatin context involved and that, depending on the locus, the changes can be modulated by genetic and/or external factors

Golimumab in refractory uveitis related to spondyloarthritis. Multicenter study of 15 patients

Objective: To assess the efficacy of golimumab (GLM) in refractory uveitis associated to spondyloarthritis (SpA). Methods: Multicenter study of SpA-related uveitis refractory to at least one immunosuppressive drug. The main outcome variables were degree of anterior and posterior chamber inflammation, visual acuity, and macular thickness. Results: Fifteen patients (13 men/2 women; 18 affected eyes; mean age 39±6 years) were evaluated. The underlying SpA subtypes were ankylosing spondylitis (n=8), psoriatic arthritis (n=6) and non-radiographic axial SpA (n=1). The ocular involvement patterns were recurrent anterior uveitis in 8 patients and chronic anterior uveitis in 7. Before GLM they have received methotrexate (n=13), sulfasalazine (n=6), pulses of methylprednisolone (n=4), azathioprine (n=3), leflunomide (n=2) and cyclosporine (n=1). Ten of them had also been treated with TNF-? blockers; etanercept (n=7), adalimumab (n=7), infliximab (n=6), and certolizumab (n=1). GLM was given at the standard dose (50 mg/sc/monthly) as monotherapy (n=7) or in combination with conventional immunosuppressive drugs (n=8), mainly methotrexate. Most patients had rapid and progressive improvement of intraocular inflammation parameters. The median number of cells in the anterior chamber at 2 years (0 [0-0]) was significantly reduced compared to baseline findings (1 [0-3]); p=0.04). The mean best corrected visual acuity value also improved (0.84±0.3 at 2 years versus 0.62±0.3 at baseline; p=0.03). Only minor side effects were observed after a mean follow-up of 23±7 months. Conclusions: Our results indicate that GLM may be a useful therapeutic option in refractory SpA-related uveitis

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Erdheim-Chester disease due to a novel internal duplication of NRAS: response to targeted therapy with cobimetinib

Histiocytoses encompass a group of exceptionally rare disorders characterized by the abnormal infiltration of tissues by histocytes. Among these, Erdheim-Chester disease (ECD) stands out as a multisystem histiocytosis that typically affects bones and various other tissues. Historically, the treatment of ECD has been challenging. However, recent breakthroughs in our understanding, particularly the discovery of somatic mutations in the RAS-MAPK pathway, have opened new opportunities for targeted therapy in a significant subset of patients with ECD and other histiocytoses. In this report, we present the case of a patient with ECD harboring a previously unidentified microduplication in the NRAS gene in a small fraction of skin cells. This discovery played a pivotal role in tailoring an effective therapeutic approach involving kinase inhibitors downstream of NRAS. This case underscores the crucial role of deep sequencing of tissue samples in ECD, enabling the delivery of personalized targeted therapy to patients.Funding: This work was supported by National Institutes of Health/National Cancer Institute grant P30 CA008748, and National Cancer Institute grant R37CA259260 (E.L.D. and K.S.P.). This work was also supported by the Frame Family Fund (E.L.D.), the Joy Family West Foundation (E.L.D.), the Applebaum Foundation (E.L.D.), and the Erdheim-Chester Disease Global Alliance (E.L.D.). Acknowledgments: The grammar and style of this manuscript were checked with ChatGPT (GPT-3.5), available at https://chat.openai.com/, accessed on 8 September 2023