Genesis and evolution of the San Manuel iron skarn deposit (Betic Cordillera, SW Spain)

The San Manuel magnesian skarn is an iron deposit hosted in dolomitic marbles from a tectonic slice imbricated within the Ronda peridotites, in the westernmost part of the Betic Cordillera, Spain. According to the dominant mineral assemblage, the skarn is subdivided into three different zones, (1) forsterite +/- calcite skarn, (2) calcite +/- chlorite +/- serpentine skarn, and (3) Ca-amphibole skarn. The main ore in the skarn is a similar to 2.5 m thick, massive ore body situated in the middle of the sequence. In this paper, we firstly report a comprehensive major to trace element composition, texture, microstructure, and mineralogy characterization for zoned magnesioferritemagnetite grains of the San Manuel deposit using a combination of (1) laser ablation inductively coupled plasma mass spectrometer, (2) focused ion beam combined with transmission electron microscopy, and (3) electron back-scattered diffraction. We have defined four different magnesioferrite-magnetite generations. A complete sequence of zoning includes cores of magnesioferrite (Mag-1; MgO up to 10.6 wt%) overprinted by three successive generations of magnetite, namely Mag-2, Mag-3, Mag-4. Mag-2 (MgO < 4 wt%), hosts composite forsterite +/- calcite +/- chlorite inclusions, consistently with high Si, Ca, and Sr (average: 8204 ppm, 8980 ppm, and 49 ppm respectively) contents detected by in situ laser ablation inductively coupled plasma (LA-ICP-MS). Mag-3 replacing former Mag-1 and Mag-2 includes nanometric spinel and gahnite exsolutions detected by focused ion beam combined with a transmission electron microscope (FIB-TEM), which is consistent with its high Al, Ti, V, and Ga (average: 5073 ppm, 368 ppm, and 20 ppm, respectively) trace element concentration. Mag-4 is the Fe-richest magnetite (up to 94.16 wt% FeOtotal) forming the outermost rims in magnetite grains, and exhibiting the lowest total trace element contents. Approaches in temperature estimations employing magnetitespinel exsolutions in Mag-3 suggest that the minimum temperature of the prograde stage reached temperatures below 700 degrees C, whereas Mag-4 should be formed during the retrograde stage. Magnetite microstructure studied by electron backscatter diffraction (EBSD) suggests Mag-4 formation under fluid-assisted dynamic conditions, which is consistent with the tectonic evolution of the emplacement. We propose that the San Manuel deposit formed by pulsed hydrothermal fluids derived from anatexis of crustal rocks during peridotite emplacement, promoting reequilibration processes that led to the magnesioferrite-magnetite zoning

Effectiveness and Safety of the Sequential Use of a Second and Third Anti-TNF Agent in Patients With Inflammatory Bowel Disease: Results From the Eneida Registry

Background: The effectiveness of the switch to another anti-tumor necrosis factor (anti-TNF) agent is not known. The aim of this study was to analyze the effectiveness and safety of treatment with a second and third anti-TNF drug after intolerance to or failure of a previous anti-TNF agent in inflammatory bowel disease (IBD) patients. Methods: We included patients diagnosed with IBD from the ENEIDA registry who received another anti-TNF after intolerance to or failure of a prior anti-TNF agent. Results: A total of 1122 patients were included. In the short term, remission was achieved in 55% of the patients with the second anti-TNF. The incidence of loss of response was 19% per patient-year with the second anti-TNF. Combination therapy (hazard ratio [HR], 2.4; 95% confidence interval [CI], 1.8-3; P < 0.0001) and ulcerative colitis vs Crohn's disease (HR, 1.6; 95% CI, 1.1-2.1; P = 0.005) were associated with a higher probability of loss of response. Fifteen percent of the patients had adverse events, and 10% had to discontinue the second anti-TNF. Of the 71 patients who received a third anti-TNF, 55% achieved remission. The incidence of loss of response was 22% per patient-year with a third anti-TNF. Adverse events occurred in 7 patients (11%), but only 1 stopped the drug. Conclusions: Approximately half of the patients who received a second anti-TNF achieved remission; nevertheless, a significant proportion of them subsequently lost response. Combination therapy and type of IBD were associated with loss of response. Remission was achieved in almost 50% of patients who received a third anti-TNF; nevertheless, a significant proportion of them subsequently lost response

Autoantibodies against type I IFNs in patients with critical influenza pneumonia

In an international cohort of 279 patients with hypoxemic influenza pneumonia, we identified 13 patients (4.6%) with autoantibodies neutralizing IFN-alpha and/or -omega, which were previously reported to underlie 15% cases of life-threatening COVID-19 pneumonia and one third of severe adverse reactions to live-attenuated yellow fever vaccine. Autoantibodies neutralizing type I interferons (IFNs) can underlie critical COVID-19 pneumonia and yellow fever vaccine disease. We report here on 13 patients harboring autoantibodies neutralizing IFN-alpha 2 alone (five patients) or with IFN-omega (eight patients) from a cohort of 279 patients (4.7%) aged 6-73 yr with critical influenza pneumonia. Nine and four patients had antibodies neutralizing high and low concentrations, respectively, of IFN-alpha 2, and six and two patients had antibodies neutralizing high and low concentrations, respectively, of IFN-omega. The patients' autoantibodies increased influenza A virus replication in both A549 cells and reconstituted human airway epithelia. The prevalence of these antibodies was significantly higher than that in the general population for patients 70 yr of age (3.1 vs. 4.4%, P = 0.68). The risk of critical influenza was highest in patients with antibodies neutralizing high concentrations of both IFN-alpha 2 and IFN-omega (OR = 11.7, P = 1.3 x 10(-5)), especially those <70 yr old (OR = 139.9, P = 3.1 x 10(-10)). We also identified 10 patients in additional influenza patient cohorts. Autoantibodies neutralizing type I IFNs account for similar to 5% of cases of life-threatening influenza pneumonia in patients <70 yr old

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

Vasoactive intestinal peptide, pituitary adenylate cyclase-activating polypeptide and immune system: from basic research to potential clinical application

Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are important immune me­ diators sharing cellular origin, receptors and functions affecting both the innate and the acquired immunity. VIP and PACAP have been clearly identified as potent antiinflammatory factors, which act by regulating the production of both anti- and pro- inflammatory mediators. In this context, both peptides have been described to prevent death by septic shock, an acute high mortality inflammatory disease. Additionally, VIP and PACAP regulate the expression of costimulatory molecules, an action that may be related to modulating the shift toward Th1 and Th2 differentiation. We have recently reported that both peptides prevent the deleterious effects of an experimental model of rheumatoid arthritis, by downregulating both inflammatory and autoimmune components of the disease. Thus, VIP and PACAP represent potential multistep therapeutic agents that provide the mechanisms to act at different levels in the complex network cascade formed by chemokines and cytokines involved in the regulation of inflammatory/Th1 diseases. Based on the protective effects of VIP and PACAP we conclude that the exogenous administration of these peptides could offer an alternative to existing treatments for arthritis and other inflammatory/Th1-autoimmune diseases, such as multiple sclerosis, inflammatory bowel disease, or autoimmune diabetes, as well as endotoxic shock.Biomedical Reviews 2001; 12: 1-9

Double bronchodilation in chronic obstructive pulmonary disease: a crude analysis from a systematic review.

The combination of a long-acting muscarinic antagonist (LAMA) and a long-acting β2-agonist (LABA) in a single inhaler is a viable treatment option for patients with chronic obstructive pulmonary disease (COPD). Here, we systematically review the current knowledge on double bronchodilation for the treatment of COPD, with a specific focus on its efficacy versus placebo and/or monotherapy bronchodilation. A systematic review of clinical trials investigating LABA/LAMA combination therapies was conducted. Articles were retrieved from PubMed, Embase, and Scopus on June 26, 2016. We specifically selected clinical trials with a randomized controlled or crossover design published in any scientific journal showing the following characteristics: 1) comparison of different LABA/LAMA combinations in a single inhaler for patients with COPD, 2) dose approved in Europe, and 3) focus on efficacy (versus placebo and/or bronchodilator monotherapy) in terms of lung function, respiratory symptoms, or exacerbations. We analyzed 26 clinical trials conducted on 24,338 patients. All LABA/LAMA combinations were consistently able to improve lung function compared with both placebo and bronchodilator monotherapy. Improvements in symptoms were also consistent versus placebo, showing some lack of correlation for some clinical end points and combinations versus monotherapy bronchodilation. Albeit being an exploratory end point, exacerbations showed an improvement with LABA/LAMA combinations over placebo in some trials; however, scarce information was available in comparison with bronchodilator monotherapy in most studies. Our data show consistent improvements for LABA/LAMA combinations, albeit with some variability (depending on the clinical end point, the specific combination, and the comparison group). Clinicians should be aware that these are average differences. All treatments should be tailored at the individual level to optimize clinical outcomes

Biomarkers in Fabry Disease. Implications for Clinical Diagnosis and Follow-up

Fabry disease (FD) is a lysosomal storage disorder caused by deficient alpha-galactosidase A activity in the lysosome due to mutations in the GLA gene, resulting in gradual accumulation of globotriaosylceramide and other derivatives in different tissues. Substrate accumulation promotes different pathogenic mechanisms in which several mediators could be implicated, inducing multiorgan lesions, mainly in the kidney, heart and nervous system, resulting in clinical manifestations of the disease. Enzyme replacement therapy was shown to delay disease progression, mainly if initiated early. However, a diagnosis in the early stages represents a clinical challenge, especially in patients with a non-classic phenotype, which prompts the search for biomarkers that help detect and predict the evolution of the disease. We have reviewed the mediators involved in different pathogenic mechanisms that were studied as potential biomarkers and can be easily incorporated into clinical practice. Some accumulation biomarkers seem to be useful to detect non-classic forms of the disease and could even improve diagnosis of female patients. The combination of such biomarkers with some response biomarkers, may be useful for early detection of organ injury. The incorporation of some biomarkers into clinical practice may increase the capacity of detection compared to that currently obtained with the established diagnostic markers and provide more information on the progression and prognosis of the diseas

Guideline Adherence in Outpatient Clinics for Chronic Obstructive Pulmonary Disease: Results from a Clinical Audit.

Journal ArticleOBJECTIVES Previous clinical audits of COPD have provided relevant information about medical intervention in exacerbation admissions. The present study aims to evaluate adherence to current guidelines in COPD through a clinical audit. METHODS This is a pilot clinical audit performed in hospital outpatient respiratory clinics in Andalusia, Spain (eight provinces with more than 8 million inhabitants), including 9 centers (20% of the public centers in the area) between 2013 and 2014. Cases with an established diagnosis of COPD based on risk factors, clinical symptoms, and a post-bronchodilator FEV1/FVC ratio of less than 0.70 were deemed eligible. The performance of the outpatient clinics was benchmarked against three guidance documents available at the time of the audit. The appropriateness of the performance was categorized as excellent (>80%), good (60-80%), adequate (40-59%), inadequate (20-39%), and highly inadequate (<20%). RESULTS During the audit, 621 clinical records were audited. Adherence to the different guidelines presented a considerable variability among the different participating hospitals, with an excellent or good adherence for symptom recording, MRC or CAT use, smoking status evaluation, spirometry, or bronchodilation therapy. The most outstanding areas for improvement were the use of the BODE index, the monitoring of treatments, the determination of alpha1-antitrypsin, the performance of exercise testing, and vaccination recommendations. CONCLUSIONS The present study reflects the situation of clinical care for COPD patients in specialized secondary care outpatient clinics. Adherence to clinical guidelines shows considerable variability in outpatient clinics managing COPD patients, and some aspects of the clinical care can clearly be improved.This study was financially supported by an unrestricted grant from Laboratorios Menarini, SA (Barcelona, Spain).Ye