Omeprazole induces apoptosis in normal human polymorphonuclear leucocytes.

We investigated in vitro apoptosis in human polymorphonuclear neutrophils (PMN) induced by omeprazole. This drug, both in the native (OM) and acidified (OM-HCl) form, is a potent inducer of PMN apoptosis. The effect is time- and dose-dependent. OM-HCl is more efficient than OM in inducing PMN apoptosis. In fact, after 24 h incubation in vitro at 1×10 −4M OM-HCl induces apoptosis in 70% of the cell population compared to 37% induced by OM. Apoptosis induced by both forms of the drug is caspase dependent being significantly reduced by pretreating cells with the caspase 3 inhibitor (DEVDH-CHO). However, some differences in the apoptosis mechanisms between the two forms of the drug seem to exist because PMN treatment with the specific caspase 8 inhibitor (Z-IETD-FMK) only blocks OM-HCl mediated apoptosis. We observed cleavage of caspase 8 only in the cells incubated with OM-HCl while the executioner caspase 3 was activated with both forms of the drug. Furthermore, pretreatment with GM-CSF, a known activator of intracellular survival pathways in PMN, partially protected cells from OM-HCl induced apoptosis but did not contrast the apoptotic effect of OM. Cysteine cathepsin proteases also seem involved in the apoptotic mechanism of both drug forms since the specific inhibitor E64d gave a significant protection. To verify if OM-HCl induced apoptosis was dependent on the sulfenamide bound with the cell sulfhydryl groups we used molecules with thiol groups such as β-mercaptoethanol (β-ME) and reduced glutathione (GSH). Reactions of OM-HCl with cellular sulfhydryl groups are strongly involved in both the triggering and evolving phase of the apoptotic mechanism since significant protection from apoptosis was obtained when PMN were pretreated for 1h with β-ME (lipid-permeable) or GSH (lipid-impermeable). These results show that OM and OM-HCl induce apoptosis in human PMN and suggest that the second binds the sulfhydryl groups, present on the cell membrane, to then penetrate the cell thus causing a further significant increase in apoptosis. OM-induced PMN apoptosis during the treatment of gastric inflammatory disease could be an advantage for the resolution of the phlogosis state. However, this aspect should be further elucidated to assess the optimal therapeutical regimen for gastric diseases which are related to infective agents

Herschel-ATLAS: the far-infrared properties and star-formation rates of broad absorption line quasi-stellar objects

We have used data from the Herschel-ATLAS at 250, 350 and 500 \mu m to determine the far-infrared (FIR) properties of 50 Broad Absorption Line Quasars (BAL QSOs). Our sample contains 49 high-ionization BAL QSOs (HiBALs) and 1 low-ionization BAL QSO (LoBAL) which are compared against a sample of 329 non-BAL QSOs. These samples are matched over the redshift range 1.5 \leq z < 2.3 and in absolute i-band magnitude over the range -28 \leq M_{i} \leq -24. Of these, 3 BAL QSOs (HiBALs) and 27 non-BAL QSOs are detected at the > 5 sigma level. We calculate star-formation rates (SFR) for our individually detected HiBAL QSOs and the non-detected LoBAL QSO as well as average SFRs for the BAL and non-BAL QSO samples based on stacking the Herschel data. We find no difference between the HiBAL and non-BAL QSO samples in the FIR, even when separated based on differing BAL QSO classifications. Using Mrk 231 as a template, the weighted mean SFR is estimated to be \approx240\pm21 M_{\odot} yr^{-1} for the full sample, although this figure should be treated as an upper limit if AGN-heated dust makes a contribution to the FIR emission. Despite tentative claims in the literature, we do not find a dependence of {\sc C\,iv} equivalent width on FIR emission, suggesting that the strength of any outflow in these objects is not linked to their FIR output. These results strongly suggest that BAL QSOs (more specifically HiBALs) can be accommodated within a simple AGN unified scheme in which our line-of-sight to the nucleus intersects outflowing material. Models in which HiBALs are caught towards the end of a period of enhanced spheroid and black-hole growth, during which a wind terminates the star-formation activity, are not supported by the observed FIR properties.Comment: 11 pages, 4 figures, 4 tables. Accepted for publication in MNRA

Evolving trends in the management of acute appendicitis during COVID-19 waves. The ACIE appy II study

Background: In 2020, ACIE Appy study showed that COVID-19 pandemic heavily affected the management of patients with acute appendicitis (AA) worldwide, with an increased rate of non-operative management (NOM) strategies and a trend toward open surgery due to concern of virus transmission by laparoscopy and controversial recommendations on this issue. The aim of this study was to survey again the same group of surgeons to assess if any difference in management attitudes of AA had occurred in the later stages of the outbreak. Methods: From August 15 to September 30, 2021, an online questionnaire was sent to all 709 participants of the ACIE Appy study. The questionnaire included questions on personal protective equipment (PPE), local policies and screening for SARS-CoV-2 infection, NOM, surgical approach and disease presentations in 2021. The results were compared with the results from the previous study. Results: A total of 476 answers were collected (response rate 67.1%). Screening policies were significatively improved with most patients screened regardless of symptoms (89.5% vs. 37.4%) with PCR and antigenic test as the preferred test (74.1% vs. 26.3%). More patients tested positive before surgery and commercial systems were the preferred ones to filter smoke plumes during laparoscopy. Laparoscopic appendicectomy was the first option in the treatment of AA, with a declined use of NOM. Conclusion: Management of AA has improved in the last waves of pandemic. Increased evidence regarding SARS-COV-2 infection along with a timely healthcare systems response has been translated into tailored attitudes and a better care for patients with AA worldwide

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Learning from other diseases: protection and pathology in chronic fungal infections

Fungal commensals coexist in a complex milieu of bacteria within the human body. An increased understanding of the importance of microbiota in shaping the host’s immune and metabolic activities has rendered fungal interactions with their hosts more complex than previously appreciated. Metagenomics has revealed the complex interactions between fungal and bacterial commensals that, either directly or through the participation of the host immune system, impact on immune homeostasis at mucosal surfaces that, in turn, lead to secondary fungal infections. Metabolomics has captured the dialogue between the mammalian host and its microbiota. It appears that the host tryptophan catabolic enzyme, indoleamine 2,3-dioxygenase 1 (IDO1) plays a dominant role in the interplay between tryptophan catabolism by microbial communities, the host’s own pathway of metabolite production, and the activation of the aryl hydrocarbon receptor (AhR)/IL-22 axis, eventually impacting on mucosal immune homeostasis and host/fungal symbiosis. Thus, the regulatory loop involving AhR and IDO1 may be exploited for the development of multi-pronged host- and microbiota-directed therapeutic approaches for mucosal and systemic fungal diseases

Antioxidant systems and lymphocyte proliferation in the horse, sheep and dog

To better define the species-specific antioxidant systems and to ascertain the influence of the intracellular redox status on the immune system of different animal species, we determined lymphocyte glutathione peroxidase (GSHPx) activity, plasmatic glutathione levels (GSH) and the effect of H$_2$O$_2$ on the responsiveness of lymphocytes to proliferative stimuli. Among the three species considered, sheep presented the lowest plasmatic GSH and the highest lymphocyte GSHPx activity. On the contrary, dogs showed an inverted pattern (high GSH - low GSHPx). Horses displayed intermediate values for both parameters analysed. The effect of H$_2$O$_2$ on the proliferative capacity of lymphocytes was the same for all three species; the 200 $\mu$M dose in particular was strongly inhibiting. Each species, however, showed different rates of inhibition: sheep exhibited the highest sensitivity to the antiproliferative effect of H$_2$O$_2$. Our results confirmed that high H$_2$O$_2$ concentrations (200 $\mu$M) are noxious for the cellular functions of all animals; however this effect is mediated by a rigorously species-specific relationship between the intracellular reactive oxygen species (ROS) and the molecular systems involved in cell proliferation.Systèmes anti-oxydants et prolifération lymphocytaire chez le cheval, le mouton et le chien. Afin de définir l'influence de l'activité oxydo-réductrice intracellulaire sur le système immunitaire de différentes espèces animales, nous avons évalué l'activité de la glutathione peroxydase (GSHPx) lymphocytaire, de la glutathione (GSH) plasmatique et l'effet du peroxyde d'hydrogène (H$_2$O$_2$) sur la réponse des lymphocytes aux stimulations prolifératives. Parmi les trois espèces considérées, les moutons présentaient les plus faibles concentrations mineures en GSH plasmatique et l'activité du GSHPx lymphocytaire la plus élevée. Par contre, les chiens montraient un profil inverse (faible activité du GSHPx et concentration de GSH élevée). Les chevaux présentaient des valeurs moyennes pour les deux paramètres évalués. Les effets du H$_2$O$_2$ sur la capacité proliférative des lymphocytes ont été les mêmes dans les trois espèces étudiées, en particulier une dose de 200 $\mu$M s'est révélée fortement inhibitrice. Cependant, chaque espèce a montré des taux différents d'inhibition ; les moutons ont présenté une sensibilité maximale aux effets antiprolifératifs du H$_2$O$_2$. Nos résultats confirment que les concentrations élevées de H2O2 sont nocives pour la fonction cellulaire de tous les animaux. Par ailleurs, cet effet dépend, dans le contexte de la spécificité d'espèce, de la relation existant entre la concentration des dérivés réactifs à l'oxygène (ROS) intracellulaire et les systèmes moléculaires mis en jeu lors de la prolifération cellulaire

Towards Targeting the Aryl Hydrocarbon Receptor in Cystic Fibrosis

Tryptophan (trp) metabolism is an important regulatory component of gut mucosal homeostasis and the microbiome. Metabolic pathways targeting the trp can lead to a myriad of metabolites, of both host and microbial origins, some of which act as endogenous low-affinity ligands for the aryl hydrocarbon receptor (AhR), a cytosolic, ligand-operated transcription factor that is involved in many biological processes, including development, cellular differentiation and proliferation, xenobiotic metabolism, and the immune response. Low-level activation of AhR by endogenous ligands is beneficial in the maintenance of immune health and intestinal homeostasis. We have defined a functional node whereby certain bacteria species contribute to host/microbial symbiosis and mucosal homeostasis. A microbial trp metabolic pathway leading to the production of indole-3-aldehyde (3-IAld) by lactobacilli provided epithelial protection while inducing antifungal resistance via the AhR/IL-22 axis. In this review, we highlight the role of AhR in inflammatory lung diseases and discuss the possible therapeutic use of AhR ligands in cystic fibrosis

Prevalence, characteristics, and treatment of fatigue in oncological cancer patients in Italy. a cross-sectional study of the Italian Network for Supportive Care in Cancer (NICSO)

Background: Fatigue is one of the most distressing symptoms of cancer patients. Its characteristics and impact on quality of life have not been fully explored and treatment of cancer-related fatigue in Italian oncological centers has not been codified. Methods: A cross-sectional study was carried out on all patients attending for any reason the 24 participating centers in two non-consecutive days. Patients with fatigue filled out the Brief Fatigue Inventory (BFI) questionnaire and reported any pharmacological or non-pharmacological treatment for fatigue. Results: From October 2014 to May 2015, 1394 cancer patients agreed to participate in the study. Fatigue was referred by 866 (62.1%) of patients; its duration was &gt; 4&nbsp;months in 441 patients (50.9%). In the investigators’ opinion, the most important (probable or almost sure) determinants of fatigue were reduced physical activity (271 patients), anxiety (149), pain (131), insomnia (125), anemia (123), and depression (123). Fatigue of moderate/severe intensity was reported by 43%/29.2% of patients, while usual fatigue in the last 24&nbsp;h by 45%/33.1%, and the worst fatigue in the last 24&nbsp;h by 33%/54.8%, respectively. Concerning the impact on quality of life, fatigue interfered moderately/severely with general activity in 30.8%/38.6% of patients, with mood in 26.1%/32.8%, with the ability to work in 27.9%/35.6%, with normal work in 26.7%/38.9%, with relationships with others in 21%/23.4% and with the ability to amuse themselves in 22.2%/33.1%. Only 117/866 patients (13.5%) received a pharmacological treatment represented by a corticosteroid in 101 patients (86.3%) while 188 patients (21.7%) received a non-pharmacological treatment such as physical exercise (120 patients, 63.8%) and various alimentary supplements (52 patients, 27.6%). Conclusions: Cancer-related fatigue is frequently reported by oncological patients; its intensity and impact on quality of life is relevant