The SMAD pathway is required for hepcidin response during endoplasmic reticulum stress

Hepcidin, the iron hormone, is regulated by a number of stimulatory and inhibitory signals. The cAMP responsive element binding protein 3-like 3, CREB3L3, mediates hepcidin response to endoplasmic reticulum (ER) stress. In this study we asked whether hepcidin response to ER stress also requires the SMAD1/5/8 pathway that has a major role in hepcidin regulation in response to iron and other stimuli. We analyzed hepcidin mRNA expression and promoter activity in response to ER stressors in HepG2 cells in the presence of the BMP type I receptor inhibitor LDN-193189, mutated hepcidin promoter or siRNA against different SMAD proteins. We then used a similar approach in vivo in wild-type, Smad1/5 or Creb3l3 -/- animals undergoing ER stress. In vitro, LDN-193189 prevented hepcidin mRNA induction by different ER stressors. Seemingly, mutation of a BMP-responsive element in the hepcidin promoter prevented ER stress-mediated upregulation. Moreover, in vitro silencing of SMAD proteins by siRNA, in particular SMAD5, blunted hepcidin response to ER stress. On the contrary, hepcidin induction by ER stress was maintained when using antibodies against canonical BMP receptor ligands. In vivo, hepcidin was induced by ER stress and prevented by LDN-193189. In addition, in Smad1/5 knock-out mice, ER stress was unable to induce hepcidin expression. Finally, in Creb3l3 knock-out mice, in response to ER stress, SMAD1/5 were correctly phosphorylated and hepcidin induction was still appreciable, although to a lesser extent as compared to control mice. In conclusion, our study indicates that hepcidin induction by ER stress involves the central regulatory SMAD1/5 pathway

Grammatikopoulosite, NiVP, a New Phosphide from the Chromitite of the Othrys Ophiolite, Greece

Grammatikopoulosite, NiVP, is a new phosphide discovered in the podiform chromitite and hosted in the mantle sequence of the Othrys ophiolite complex, central Greece. The studied samples were collected from the abandoned chromium mine of Agios Stefanos. Grammatikopoulosite forms small crystals (from 5 μm up to about 80 μm) and occurs as isolated grains. It is associated with nickelphosphide, awaruite, tsikourasite, and an undetermined V-sulphide. It is brittle and has a metallic luster. In plane-polarized light, it is creamy-yellow, weakly bireflectant, with measurable but not discernible pleochroism and slight anisotropy with indeterminate rotation tints. Internal reflections were not observed. Reflectance values of mineral in air (R1, R2 in %) are: 48.8–50.30 at 470 nm, 50.5–53.5 at 546 nm, 51.7–55.2 at 589 nm, and 53.2–57.1 at 650 nm. Five spot analyses of grammatikopoulosite give the average composition: P 19.90, S 0.41, Ni 21.81, V 20.85, Co 16.46, Mo 16.39, Fe 3.83, and Si 0.14, total 99.79 wt %. The empirical formula of grammatikopoulosite—based on Σ(V + Ni + Co + Mo + Fe + Si) = 2 apfu, and taking into account the structural results—is (Ni0.57Co0.32Fe0.11)Σ1.00(V0.63Mo0.26Co0.11)Σ1.00(P0.98S0.02)Σ1.00. The simplified formula is (Ni,Co)(V,Mo)P and the ideal formula is NiVP, which corresponds to Ni 41.74%, V 36.23%, P 22.03%, total 100 wt %. The density, calculated on the basis of the empirical formula and single-crystal data, is 7.085 g/cm3. The mineral is orthorhombic, space group Pnma, with a = 5.8893(8), b = 3.5723(4), c = 6.8146(9) Å, V = 143.37(3) Å3, and Z = 4. The mineral and its name have been approved by the Commission of New Minerals, Nomenclature and Classification of the International Mineralogical Association (IMA 2019-090). The mineral honors Tassos Grammatikopoulos, geoscientist at the SGS Canada Inc., for his contribution to the economic mineralogy and mineral deposits of Greece.This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

Eliopoulosite, V7S8, A New Sulfide from the Podiform Chromitite of the Othrys Ophiolite, Greece

The new mineral species, eliopoulosite, V7S8, was discovered in the abandoned chromium mine of Agios Stefanos of the Othrys ophiolite, located in central Greece. The investigated samples consist of massive chromitite hosted in a strongly altered mantle tectonite, and are associated with nickelphosphide, awaruite, tsikourasite, and grammatikopoulosite. Eliopoulosite is brittle and has a metallic luster. In plane-reflected polarized light, it is grayish-brown and shows no internal reflections, bireflectance, and pleochroism. It is weakly anisotropic, with colors varying from light to dark greenish. Reflectance values of mineral in air (Ro, Re’ in %) are: 34.8–35.7 at 470 nm, 38–39 at 546 nm, 40–41.3 at 589 nm, and 42.5–44.2 at 650 nm. Electron-microprobe analyses yielded a mean composition (wt.%) of: S 41.78, V 54.11, Ni 1.71, Fe 1.1, Co 0.67, and Mo 0.66, totali 100.03. On the basis of Σatoms = 15 apfu and taking into account the structural data, the empirical formula of eliopoulosite is (V6.55Ni0.19Fe0.12Co0.07Mo0.04)Σ = 6.97S8.03. The simplified formula is (V, Ni, Fe)7S8 and the ideal formula is V7S8, which corresponds to V 58.16%, S 41.84%, total 100 wt.%. The density, based on the empirical formula and unit-cell volume refined form single-crystal structure XRD data, is 4.545 g·cm−3. The mineral is trigonal, space group P3221, with a = 6.689(3) Å, c = 17.403(6) Å, V = 674.4(5) Å3, Z = 3, and exhibits a twelve-fold superstructure (2a × 2a × 3c) of the NiAs-type subcell with V-atoms octahedrally coordinated by S atoms. The distribution of vacancies is discussed in relation to other pyrrhotite-like compounds. The mineral name is for Dr. Demetrios Eliopoulos (1947–2019), a geoscientist at the Institute of Geology and Mineral Exploration (IGME) of Greece and his widow, Prof. Maria Eliopoulos (nee Economou, 1947), University of Athens, Greece, for their contributions to the knowledge of ore deposits of Greece and to the mineralogical, petrographic, and geochemical studies of ophiolites, including the Othrys complex. The mineral and its name have been approved by the Commission of New Minerals, Nomenclature, and Classification of the International Mineralogical Association (No. 2019-96).© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)

Impact of comprehensive pulmonary rehabilitation on anxiety and depression in hospitalized COPD patients.

To prospectively evaluate the effect of inpatient pulmonary rehabilitation (iPR) on anxiety and depression as outcome measures in patients with COPD, we studied 149 consecutive adults COPD referred to our iPR after an exacerbation. Patients were divided according to the GOLD staging into: Group 1 (stage 2a, n = 48, FEV1 63 +/- 9% pred.), Group 2 (stage 2b, n = 53, FEV1 42 +/- 6% pred.) and Group 3 (stage 3, n = 48, FEV1 25 +/- 7% pred.). The iPR consisted of twelve 3-hours daily sessions. Hospital Anxiety Depression (HAD) Scale as well as 6-minute walk (6MWD) with evaluation of dyspnea (D) and leg fatigue (F) at rest and end of effort, and health related quality of life by means of St. George Respiratory Questionnaire (SGRQ) were assessed before (T0) and after (T1) the iPR. 6MWD, D and F at end of effort and SGRQ total score similarly improved (p < 0.001) in all groups after iPR. The mean level of HAD-anxiety (from 9.1 +/- 4.0 to 7.7 +/- 3.5, from 9.0 +/- 4.6 to 7.2 +/- 4.6 and from 8.1 +/- 4.1 to 6.7 +/- 4.3 in group 1,2 and 3 respectively) and HAD-depression (from 9.4 +/- 3.5 to 8.2 +/- 3.5, from 9.1 +/- 4.2 to 8.2 +/- 4.5 and from 9.0 +/- 4.0 to 7.4 +/- 4.5 respectively) similarly changed (p < 0.0001) over time in all groups. The total percentage of patients with abnormal score (> 10) of HAD-anxiety (from 31% to 21%) and HAD-depression (from 30% to 22%) significantly decreased (p < 0.05) after the iPR. Inpatient pulmonary rehabilitation may improve levels of anxiety and depression as well as symptoms, exercise capacity and health related quality of life in moderate to severe COPD patients after an acute exacerbation

Chromite and platinum group elements mineralization in the Santa Elena Ultramafic Nappe (Costa Rica): geodynamic implications

Chromitites associated with strongly altered peridotite from six distinct localities in the Santa Elena ultramafic nappe (Costa Rica) have been investigated for the first time. Santa Elena chromitites commonly display a compositional variation from extremely chromiferous (Cr/(Cr+Al)=0.81) to intermediate and aluminous (Cr/(Cr+Al)=0.54). This composition varies along a continuous trend, corresponding to calculated parental liquids which may have been derived from the differentiation of a single batch of boninitic magma with Cr-rich and (Al, Ti)-poor initial composition. Fractional precipitation of chromite probably occurred during differentiation of the boninitic melt and progressive metasomatic reaction with mantle peridotite. The distribution of platinum group elements (PGE) displays the high (Os+Ir+Ru)/(Rh+Pt+Pd) ratio typical of ophiolitic chromitites and, consistently, the platinum group minerals (PGM) encountered are mainly Ru-Os-Ir sulfides and arsenides. Textural relations of most of the platinum group elements suggest crystallization at magmatic temperatures, possibly under relatively high sulfur fugacity as indicated by the apparent lack of primary Os-Ir-Ru alloys. The chemical and mineralogical characteristics of chromitites from the Santa Elena ultramafic nappe have a strong affinity to podiform chromitites in the mantle section of supra-subduction-zone ophiolites. Calculated parental melts of the chromitites are consistent with the differentiation of arc-related magmas, and do not support the oceanic spreading center geodynamic setting previously proposed by some authors

Out-of-hospital helmet CPAP in acute respiratory failure reduces mortality: a study led by nurses

Background and Aim. Acute respiratory failure (ARF) is a condition that must be treated as quickly as possible. Continuous Positive Airway Pressure (CPAP) is a common method used to treat ARF in hospital. The main objective of our study was to investigate the effect of CPAP prior to admission to the emergency room, on the reduction of endotracheal intubation, in-hospital mortality and on the length of stay in hospital (HLOS). Methods. A prospective, observational (non-randomised) study with a historical control group. Data from 3 groups of patients with ARF, irrespective of cause, was collected: pre-hospital CPAP (PHCPAP) group, i.e. 35 patients treated with a helmet CPAP in the ambulance, by trained nurses (mean age, years 80.1±7.9 SD; 14 males); hospital CPAP (HCPAP) group, i.e. 46 patients treated with helmet CPAP in the hospital emergency room (mean age 78.6±6.9 SD; 27 males), and a historical control group of 125 patients treated with medical therapy only (mean age 76.7±5.5 SD; 52 males). CPAP was delivered via a helmet interface. Results. Compared with standard medical therapy, helmet CPAP (pre and in-hospital) reduced mortality by 77 % (p=0.005), while pre-hospital helmet CPAP reduced it by 94% (p=0.011), after adjustment for age, sex, severity of clinical conditions at entry and diagnosis upon admission. HLOS was reduced, compared with standard medical therapy, by 63.5% and by 66% (adjusting for age, sex, severity of clinical conditions at entry and diagnosis at admission) with helmet CPAP (pre and in-hospital) and with helmet CPAP in the ambulance, respectively (p<0.0001). Conclusions. Treating patients with ARF of any cause, with CPAP by trained nurses, before hospital admission, is safe, reduces mortality and the length of stay needed in hospital

Heart and Lungs in COPD. Close friends in real life - separate in daily medical practice?

Chronic obstructive pulmonary disease (COPD) is associated with a 2-3 times higher rate of cardiovascular disorders (CVD) which is independent of other risk factors. A low FEV1 is a specific predictor of mortality as a result of cardiac causes, even stronger than increased cholesterol: for each 10% reduction of FEV1, cardiovascular mortality increases by 28%. The main causes of death among COPD patients are of cardiovascular origin. COPD and CVD have two major risk factors in common - advanced age and tobacco smoking. The search for a pathogenetic link between the two conditions focuses mainly on systemic extension of pulmonary inflammation. Despite such a frequent association, pulmonologists and cardiologists in both the clinical and the research settings often underestimate the importance of a correct diagnosis and severity stratification of the two combined conditions. Spirometry, in particular, is largely underprescribed. Missed diagnosis and severity stratification, incomplete knowledge of adverse drug events and lack of resources lead to undertreatment of patients combining COPD and CVD, and in particular, the underuse of beta-blockers, inhaled bronchodilators and rehabilitation. Clinical studies focusing on this group of patients should be promoted in the future to test therapies and manage options. Furthermore, efforts must be made to improve the present standards of care, which falls short of recommended levels, starting from the often-neglected use of spirometry to confirm a diagnosis of COPD

Primary and secondary prevention to effectively reduce the risk of bisphosphonate-related osteonecrosis of the jaw in patients with bone metastases .

Background Bone is one of the most frequent sites of metastasis in patients with advanced cancer. Nearly all patients with myeloma, 65–75% of patients with prostate or breast cancer, and 30–40% of patients with lung cancer or other solid tumors, eventually develop bone metastases. Bisphosphonates (BP), particularly zoledronic acid and denosumab, were demonstrated to effectively reduce skeletal complications in patients with bone metastases. However, bisphosphonate-related osteonecrosis of the jaw (BRONJ) can occur spontaneously, favored by dental extraction, dental implant surgery, or denture wearing. The purpose of this study was to underline the role of dental prevention as an effective tool to reduce the risk of BRONJ. Material and methods BRONJ was identified with the standardized query “osteonecrosis” among all data from patients treated at Modena Cancer Center from 2005 to 2016. For each case, demographic and medical information were analyzed, as well as data about notification (year of occurrence, outcome), type and duration of BP exposure, and associated risk factors (dento-alveolar surgery, chemotherapy, antiangiogenics). Data were differently analyzed taking into account the implementation of a Dental Prevention Service in patients who are candidates for BP therapy.Results Among 1663 patients treated with BP, 63 cases of BRONJ were identified (3.8%). 44 female and 19 men with a median age of 69 years (range 47-90 years), have been treated with BP for bone metastases from breast cancer (54%), hematologic malignancy (21%), prostate cancer (13%), renal cancer (5%), lung cancer (2%) and other tumors (5%). 15 maxillae and 48 mandibles were involved. The trigger event was a dental extraction in 29% of the cases, being spontaneously the other 71%. The median time to BRONJ was 28 months (range 1-89.1 months) from the first dose of BP, and 25 was the mean number of BP doses administered before BRONJ. Overall, a preliminary odontoiatric evaluation was performed in only 14 cases (22%). All but one of these dentistry opinions were obtained after 2010 when the Dental Prevention Service was created, which is a drop out of the risk of BRONJ from 4.1 to 1.9%. Conclusions. Prevention of the BRONJ is critical in in bone metastatic patients. The incidence of BRONJ over time can drop to 1.9% when primary and secondary prevention measures are implemented in routine clinical practice

Plasma Cell-Free DNA Integrity Assessed by Automated Electrophoresis Predicts the Achievement of Pathologic Complete Response to Neoadjuvant Chemotherapy in Patients with Breast Cancer

PURPOSE The study of plasma cell-free DNA integrity (cfDI) has shown potential for providing useful information in neoplastic patients. The aim of this study is to estimate the accuracy of an electrophoresis-based method for cfDI evaluation in the assessment of pathologic complete response (pCR) in patients with breast cancer (BC) undergoing neoadjuvant chemotherapy (NACT). PATIENTS AND METHODS Fifty-one patients with BC undergoing anthracycline-/taxane-based NACT were recruited. Plasma samples were collected from each patient at diagnosis (t0), after anthracycline administration (t1), and after NACT completion (t2). The concentration of differently sized cell-free DNA fragments was assessed by automated electrophoresis. cfDI, expressed as cfDI index, was calculated as the ratio of 321-1,000 bp sized fragment concentration to 150-220 bp sized fragment concentration assessed at t2. cfDI index was then used to build an exploratory classifier for BC response to NACT, directly comparing its sensitivity and specificity with magnetic resonance imaging (MRI), through bootstrapped logistic regression. RESULTS cfDI index was assessed on 38 plasma samples collected from as many patients at t2, maintaining a 30/70 ratio between pCR and non-pCR patients. cfDI index showed an area under the receiver operating characteristic curve in predicting the achievement of pCR of 81.6, with a cutoff above 2.71 showing sensitivity = 81.8 and specificity = 81.5. The combination of cfDI index and MRI showed, in case of concordance, an area under the receiver operating characteristic curve of 92.6 with a predictive value of complete response of 87.5 and a predictive value of absence of complete response of 94.7. CONCLUSION cfDI index measured after NACT completion shows great potential in the assessment of pCR in patients with BC. The evaluation of its use in combination with MRI is strongly warranted in prospective studies