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Banded Ca-carbonate veins in travertine deposits are efficient recorders of the compositional fluctuations of geothermal fluids flowing (or flowed) from deep reservoirs up to the surface, within fault zones. In this view, these veins represent key tools for decoding those factors that influenced the geochemical variations. We have analyzed veins developed in fractures channeling geothermal fluids forming travertine deposits. The studied veins cut a fossil travertine fissure ridge, near the Larderello geothermal area (Iano area, southern Tuscany) where geothermal fluid circulation is favored by NE-trending strike-to-oblique-slip faults and their intersections with NW-trending normal ones. U-Th dating indicates that fluid circulation occurred from (at least) 172 ka to 21 ka. In this time span, the geothermal fluid changed in composition, and the banded Ca-carbonate veins recorded these variations in terms of mineralogical and stable isotope composition and temperature (T) of deposition. We also documented for the first time the occurrence of Mn-rich black tree-shaped structures within the veins. Mineralogy coupled with stable and clumped isotope measurements allows the reconstruction of some features (i.e., crystal texture, temperature, and CO2 origin) and the inference of the processes (i.e., pH, T, and pCO2 variations) that have controlled the fluid evolution through time. Multiple-stage and one-stage deposition processes have played an important role in modifying the stable isotope composition of banded Ca-carbonate veins; temperature coupled with pCO2 also influenced their mineralogical composition. Interpreted in the context of the tectonic setting, the data show that the NW-trending faults have mainly controlled travertine deposition. Their intersection with NE-trending faults, interpreted as transfer faults, highlights the important role of transfer zones in channeling the geothermal fluids.

Geothermal systems in terrains affected by polyphase deformation have reservoirs with a 3D geometry that is always difficult to predict. In this paper we describe a fossil exhumed geothermal system exposed in eastern Elba Island that developed in a polyphase folded and faulted setting, which can help us to understand how geothermal fluids circulate in geological bodies with inherited structures. Geothermal circulation at Elba allowed the deposition of Fe-ore deposits (haematite/magnetite and pyrite) and altered rock volumes, which represent tracers of the palaeo-fluid flow. Normal and oblique-slip faults dissected a polyphase folded metasiliciclastic succession and produced a secondary permeability in the range of 5 × 10−13 to 5 × 10−16 m2. From the permeable fault zones acting as feeder conduits, geothermal fluids permeated the hydraulically connected metasiliciclastic rock bodies previously deformed by two generations of folds. Geothermal fluids followed the already defined geometry, thus giving rise to apparent folded mineralized levels. Fluid migration into the metasiliciclastic rocks was possible due to their chemical aggression, which favoured the dissolution and reprecipitation of quartz, and Fe-oxide and sulphide deposition. Renewed fluids maintained their chemical properties (pH value and temperature, mostly). This conclusion provides inputs for reconstructing geothermal conceptual models and evaluating the geothermal potentiality of exploitable areas developing in similar geological settings.

Autologous stem cell transplantation (ASCT), doubled in selected cases, followed by lenalidomide maintenance (LM) remains the standard treatment after induction therapy for newly diagnosed, transplant eligible patients with multiple myeloma (TEMM). Notwithstanding, evidences about how these approaches have been applied and how they have performed in the real-life setting, before the introduction of daratumumab within the induction regimens, are quite limited. Herein, we report the outcome of 300 MM patients, who underwent single (45%) or double (55%) ASCT, and received (42%) or not (58%) lenalidomide maintenance, outside of clinical trials, between December 2001 and February 2020, within the “Rete Ematologica Pugliese”. After a median follow-up of 65 months (range: 9-186), median PFS was significantly longer in patients who underwent double ASCT compared to those who received single ASCT (66 vs. 53 months, respectively, p  = 0.01). Likewise, after a median follow-up of 62 months (range: 9-174), patients who received LM had a significantly better PFS respect to those who did not (72 vs. 36 months, respectively p  < 0.001). Concerning OS, it was not influenced by single or double ASCT (although a trend favoring double ASCT was observed), while LM significantly improved OS (142 vs. 108 months, p  = 0.01). At multivariable analysis factors influencing PFS were achievement of complete remission after first ASCT, double ASCT and LM, while those impacting on OS were high risk cytogenetics, LDH and LM. In the context of a rapidly changing therapeutic scenario, our data might contribute to a real-life, historical benchmark for current and future treatments of TEMM patients.

Innovative pro-regenerative treatment strategies for progressive multiple sclerosis (PMS), combining neuroprotection and immunomodulation, represent an unmet need. Neural precursor cells (NPCs) transplanted in animal models of multiple sclerosis have shown preclinical efficacy by promoting neuroprotection and remyelination by releasing molecules sustaining trophic support and neural plasticity. Here we present the results of STEMS, a prospective, therapeutic exploratory, non-randomized, open-label, single-dose-finding phase 1 clinical trial ( NCT03269071 , EudraCT 2016-002020-86), performed at San Raffaele Hospital in Milan, Italy, evaluating the feasibility, safety and tolerability of intrathecally transplanted human fetal NPCs ( hf NPCs) in 12 patients with PMS (with evidence of disease progression, Expanded Disability Status Scale ≥6.5, age 18–55 years, disease duration 2–20 years, without any alternative approved therapy). The safety primary outcome was reached, with no severe adverse reactions related to hf NPCs at 2-year follow-up, clearly demonstrating that hf NPC therapy in PMS is feasible, safe and tolerable. Exploratory secondary analyses showed a lower rate of brain atrophy in patients receiving the highest dosage of hf NPCs and increased cerebrospinal fluid levels of anti-inflammatory and neuroprotective molecules. Although preliminary, these results support the rationale and value of future clinical studies with the highest dose of hf NPCs in a larger cohort of patients. Phase 1 trial results reveal that intrathecal transplantation of human fetal neural precursor cells in patients with progressive multiple sclerosis is feasible, safe and tolerable.

Mt. Etna is the highest and most active stratovolcano in Europe, located in Catania (Sicily, Italy). Its persistent degassing, frequent explosions, and lava flows release large amounts of ash and gases into the atmosphere. This study aimed to assess whether chronic exposure to local volcanic emissions leads to an increased internal dose of trace elements (As, Ba, Be, Bi, Cd, Co, Cr, Cu, Hg, Li, Mn, Mo, Ni, Pb, Sb, Se, Sn, Sr, Tl, U, V, W, Zn) in Catania adult residents. To this end, urine samples were collected from 167 individuals residing in Catania and compared with 193 residents of other Sicilian areas located farther from the volcano. Results revealed significantly higher urinary concentrations of As, Hg, Mn, Pb, and Tl in the exposed group, suggesting volcanic activity as a relevant source of exposure. The levels of the other elements were instead affected by other factors such as lifestyle habits and the consumption of specific foods and beverages. The urinary concentrations of trace elements were consistent with reference values reported in other European studies, and the levels remained well within the health-based guidance values. There is evidence of an increased internal dose of a few elements in the Sicilian population exposed to volcano activity, but the observed increases are unlikely to pose a significant health risk.

BackgroundSpinal muscular atrophy (SMA) is due to the homozygous absence of SMN1 in around 97% of patients, independent of the severity (classically ranked into types I–III). The high genetic homogeneity, coupled with the excellent results of presymptomatic treatments of patients with each of the three disease-modifying therapies available, makes SMA one of the golden candidates to genetic newborn screening (NBS) (SMA-NBS). The implementation of SMA in NBS national programmes occurring in some countries is an arising new issue that the scientific community has to address. We report here the results of the first Italian SMA-NBS project and provide some proposals for updating the current molecular diagnostic scenario.MethodsThe screening test was performed by an in-house-developed qPCR assay, amplifying SMN1 and SMN2. Molecular prognosis was assessed on fresh blood samples.ResultsWe found 15 patients/90885 newborns (incidence 1:6059) having the following SMN2 genotypes: 1 (one patient), 2 (eight patients), 2+c.859G>C variant (one patient), 3 (three patients), 4 (one patient) or 6 copies (one patient). Six patients (40%) showed signs suggestive of SMA at birth. We also discuss some unusual cases we found.ConclusionThe molecular diagnosis of SMA needs to adapt to the new era of the disease with specific guidelines and standard operating procedures. In detail, SMA diagnosis should be felt as a true medical urgency due to therapeutic implications; SMN2 copy assessment needs to be standardised; commercially available tests need to be improved for higher SMN2 copies determination; and the SMN2 splicing-modifier variants should be routinely tested in SMA-NBS.

Background: The inappropriate use of antibiotics has increased selective pressure and the spread of multi-drug-resistant (MDR) pathogens, which reduces the possibility of effective treatment. A potential alternative therapeutic approach may be represented by essential oils, such as the distilled extract of bergamot (Citrus bergamia Risso et Poiteau). Such natural products exercise numerous biological activities, including antimicrobial effects. Methods: This work aimed to evaluate the kinetics of the bactericidal and fungicidal activity of the distilled extract of bergamot on MDR bacteria and fungi from clinical specimens using the time-kill assay. Furthermore, the antimicrobial activity of the distilled extract of bergamot on the morphology and cellular organization of clinical pathogens was evaluated by confocal laser scanning microscopy. Results: Our results demonstrated that the distilled extract of bergamot exhibited significant antimicrobial activity and a specific bactericidal effect against the bacterial and fungal strains tested. Furthermore, confocal microscope images clearly showed compromised membrane integrity, damage and cell death in bacterial samples treated with the distilled extract of bergamot. In addition, progressive alterations in cell-wall composition, cytoplasmic material and nucleus structure triggered by exposure to the distilled extract of bergamot were identified in the fungal samples considered. Conclusions: Our data suggest that the use of essential oils, such as distilled extract of bergamot (Citrus bergamia Risso et Poiteau), can represent a valid alternative therapeutic strategy to counteract antibiotic resistance of pathogens.

The new 2019 coronavirus or SARS-CoV-2 has been the first biological agent to generate, in this millennium, such a global health emergency as to determine the adoption of public health measures. During this sanitary emergency, the emotional experience of healthcare workers (HCWs) has been hugely tested by several factors. In fact, HCWs have been exposed to greatly tiring physical, psychological and social conditions. The authors investigated the cardiocirculatory activity of a group of HCWs as well as how they perceived stress while working in COVID-19 wards. In particular, every HCW underwent a medical check, an electrocardiographic base exam, systolic and diastolic pressure measurement, and cardio frequency measurement. Furthermore, each HCW was provided with a cardiac Holter device (HoC) and a pressure Holter (Hop). Some psychological factors were considered in order to quantify the stress perceived by each HCW while at work through the administration of two questionnaires: the “Social Stigma towards Patients due to COVID Scale (SSPCS)” and the “Professional Quality of Life Scale (ProQOL)”. The HoC and HoP analysis results for HCWs working in COVID-19 OU wards showed significant variations in cardiocirculatory activity. From the analysis of the SSPCS questionnaire answers, it is clear that all of them showed a sense of duty towards their patients. The analysis of the ProQOL questionnaire answers showed that the prevailing attitude is fear; however, HCWs did not absolutely discriminate against those who had COVID-19 nor did they refuse to help those in need. Continuous monitoring of these employees, also carried out through occupational medicine surveillance, allows for the detection of critical conditions and the implementation of actions aimed at preventing chronic processes.

Background Intravenous (IV) zanamivir could be a suitable alternative for the treatment of severe influenza A(H1N1)pdm09 infection in patients who are unable to take oral or inhaled medication, for example, those on mechanical ventilation and extracorporeal membrane oxygenation (ECMO). However, data on the clinical outcomes of such patients is limited. Case presentation We report the clinical outcomes of four patients who were admitted at the intensive care unit during the 2017–2018 influenza season with severe sepsis (SOFA score > 11) and acute respiratory distress syndrome requiring ECMO and mechanical ventilation. Two patients were immune-compromised. The A(H1N1)pdm09 genome was confirmed by polymerase chain reaction (PCR) on nasopharyngeal specimen swabs prior to administration of IV zanamivir at a dose of 600 mg twice daily. Weekly qualitative PCR analysis was done to monitor viral clearance, with zanamivir treatment being discontinued upon receipt of negative results. In addition, the patients were managed for concomitant multidrug-resistant bacterial infections, with infection resolution confirmed with blood cultures. The median time for zanamivir treatment was 10 days (IQR 10–17). The clinical outcome was favourable with all four patients surviving and improving clinically. All four patients achieved viral clearance of A(H1N1)pdm09 genome, and resolution of multidrug-resistant bacterial infections. Conclusions IV zanamivir could be a good therapeutic option in patients with severe influenza A(H1N1)pdm09 infection who are unable to take oral or aerosolised antiviral medication. We recommend prospective randomized control trials to support this hypothesis.

Hirschsprung disease (HSCR) is a rare congenital anomaly characterized by the absence of enteric ganglia in the distal intestinal tract. While classified as a multigenic disorder, the altered function of the RET tyrosine kinase receptor is responsible for the majority of the pathogenesis of HSCR. Recent evidence demonstrate a strong association between RET and the homeostasis of immune system. Here, we utilize a unique cohort of fifty HSCR patients to fully characterize the expression of RET receptor on both innate (monocytes and Natural Killer lymphocytes) and adaptive (B and T lymphocytes) human peripheral blood mononuclear cells (PBMCs) and to explore the role of RET signaling in the immune system. We show that the increased expression of RET receptor on immune cell subsets from HSCR individuals correlates with the presence of loss-of-function RET mutations. Moreover, we demonstrate that the engagement of RET on PBMCs induces the modulation of several inflammatory genes. In particular, RET stimulation with glial-cell line derived neurotrophic factor family (GDNF) and glycosyl-phosphatidylinositol membrane anchored co-receptor α1 (GFRα1) trigger the up-modulation of genes encoding either for chemokines (CCL20, CCL2, CCL3, CCL4, CCL7, CXCL1) and cytokines (IL-1β, IL-6 and IL-8) and the down-regulation of chemokine/cytokine receptors (CCR2 and IL8-Rα). Although at different levels, the modulation of these \"RET-dependent genes\" occurs in both healthy donors and HSCR patients. We also describe another set of genes that, independently from RET stimulation, are differently regulated in healthy donors versus HSCR patients. Among these \"RET-independent genes\", there are CSF-1R, IL1-R1, IL1-R2 and TGFβ-1, whose levels of transcripts were lower in HSCR patients compared to healthy donors, thus suggesting aberrancies of inflammatory responses at mucosal level. Overall our results demonstrate that immune system actively participates in the physiopathology of HSCR disease by modulating inflammatory programs that are either dependent or independent from RET signaling.