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Levels of persistent organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs) were determined in the blood serum of people living and working in the urban area of greater Rio de Janeiro city. Blood samples from 33 volunteers (16 males, 17 females, 19-63 years old) were taken in January 1999. OCP residues (op'DDT, pp'DDT, pp'DDD, pp'DDE, Aldrin, Dieldrin, Endrin, Heptachlor, Heptachlor-epoxide, alpha-, beta- and gamma-Hexachlorocyclo-hexane, Hexachlorobenzene) and PCBs (congeners: 28, 52, 101, 138, 153, 180) were extracted with n-hexane and analyzed by gas chromatography with electron capture detection. Except for pp'DDE (detection limit = 1.4µg/L) no other OCP residue was found in the samples. No PCB congener (detection limit = 2.0µg/L) was detected either. pp'DDE was found in 17 out of 33 samples in concentrations that ranged from 1.4 to 8.4 µg/L of serum or, on a fat basis, from 0.200 to 3.452 µg/g of serum lipids. Percentage of positive samples (%) and levels of pp'DDE (range of positive samples) increased from the youngest to the oldest group ( or = 40 yrs: 77%, 0.257-3.452µg/g).

Real-life data comparing the long-term outcome in patients with different heart diseases carrying an implantable cardioverter defibrillator (ICD) are scarce. This study aimed to compare the long-term risk of the first appropriate ICD intervention and overall survival in patients with ICD and heart disease of different etiologies. Patients with an ICD implanted between January 1, 2010, and December 31, 2022, followed in our center were included. Study outcomes were all-cause mortality and first appropriate ICD intervention. A comparison between ischemic heart disease (IHD) and non-IHD (NIHD) was performed. In NIHD different etiologies of dilated cardiomyopathy (DCM) were analyzed. Overall, 1184 patients (592 IDH; 592 NIHD) were included. During a median follow-up of 53 months all-cause death occurred in 399 patients (34%) whereas first appropriate ICD intervention occurred in 320 (27%). All-cause mortality was significantly higher in IHD vs NIHD patients (60% vs 43%; p <0.0001) but no differences in appropriate ICD intervention rate at 10 years (34% vs 40%; p = 0.125) were observed. In patients with NIHD, a higher 10-year mortality rate was found in valvular heart disease, post-radio/chemotherapy DCM (rctDCM), and hypertensive DCM. Hypertrophic cardiomyopathy, alcoholic DCM, and rctDCM were the least arrhythmic phenotypes in NIHD. Of note, inappropriate interventions in alcoholic DCM and rctDCM were higher than appropriate ones. In conclusion, the rate of ICD-appropriate interventions and mortality is different according to the etiology of heart disease and cardiovascular risk profile; this should be taken into consideration in the prognostic stratification of these patients at the time of implantation., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

VEXAS syndrome is a newly described autoinflammatory entity characterized by somatic mutations in the UBA1 X-linked gene in hematopoietic progenitor cells. Several studies have demonstrated that the presence of vacuoles in progenitor cells from bone marrow aspirates is a hallmark finding for this syndrome. Therefore, this study aimed to characterize leukocytes from VEXAS patients versus patients with ANCA-associated vasculitis (AAV), familial Mediterranean fever (FMF), and healthy donors (HD) to define a specific cytological pattern that can support VEXAS diagnosis. Twelve VEXAS patients were included in the study. Blood samples from FMF (n = 16), AAV (n = 16) and HDs (n = 20) acted as controls. May-Grünwald Giemsa (MGG) staining was used for studying cellular morphology, including cytoplasm, granules, and vacuoles and to perform a cytogenic evaluation of leucocytes. Plasma IL-1β, IL-1α, TNFα, IL-18 and IL-8 were measured using ELISA assay. The cytological analysis from blood smears confirmed the presence of immature neutrophils in VEXAS patients. We found a greater number of vacuoles in VEXAS patients vs. FMF, AAV and HD. Micronuclei (MNi) and cell death rate were higher in VEXAS patients vs. HD. Cell death correlated with IL-1β and IL-8 levels. MNi were positively associated with IL-8 and IL-1β levels, and with the percentage of immature neutrophils and vacuoles. In conclusion, our findings suggested that cytological test may be supportive for VEXAS diagnosis, despite genetical analysis is mandatory for confirming the disease. Finally, we identified several cytological hallmarks that may distinguish the VEXAS "cytotype" not only from HD but also from other inflammatory diseases., Competing Interests: AD received consultancy fees from GSK, Eli Lilly, AstraZeneca, Otsuka. PS received grants from Novartis and Sobi. Authors DC, BP and GP were employed by R&I Genetics srl. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Baggio, Oliviero, Padoan, Iorio, Bixio, Orsolini, Bertoldo, Bernardi, Colavito, Paiero, Pregnolato, Ramonda, Doria, Bindoli and Sfriso.)

Blau syndrome (BS) is a rare autoinflammatory granulomatosis characterized by granulomatous arthritis, uveitis, and dermatitis. Ocular complications are particularly severe in BS, significantly contributing to morbidity. This study aims to identify potential biomarkers for BS ocular degeneration through proteomic profiling of tear samples from affected patients. Seven subjects from the same family, including four carriers of the BS-associated NOD2 mutation (p.E383K), were recruited alongside healthy controls. Tear samples were collected using Schirmer strips and analyzed via mass spectrometry. A total of 387 proteins were identified, with significant differences in protein expression between BS patients, healthy familial subjects, and healthy controls. Key findings include the overexpression of alpha-2-macroglobulin (A2M) and immunoglobulin heavy constant gamma 4 (IGHG4) in BS patients. Bioinformatic analysis revealed that differentially expressed proteins are involved in acute-phase response, extracellular exosome formation, and protein binding. Notably, neutrophils' azurophilic granule components, as azurocidin (AZU1), myeloperoxidases (MPO), and defensins (DEFA3), were highly expressed in the most severely affected subject, suggesting a potential role of neutrophils in BS ocular severity. These proteins might be promising biomarkers for ocular involvement in BS, facilitating early detection and tailored treatment strategies.

VEXAS syndrome is a recently described monogenic autoinflammatory disease capable of manifesting itself with a wide array of organs and tissues involvement. Orbital/ocular inflammatory manifestations are frequently described in VEXAS patients. The objective of this study is to further describe orbital/ocular conditions in VEXAS syndrome while investigating potential associations with other disease manifestations. In the present study, twenty-seven out of 59 (45.8 %) VEXAS patients showed an inflammatory orbital/ocular involvement during their clinical history. The most frequent orbital/ocular affections were represented by periorbital edema in 8 (13.6 %) cases, episcleritis in 5 (8.5 %) patients, scleritis in 5 (8.5 %) cases, uveitis in 4 (6.8 %) cases, conjunctivitis in 4 (6.8 %) cases, blepharitis in 3 (5.1 %) cases, orbital myositis in 2 (3.4 %) cases. A diagnosis of systemic immune-mediated disease was observed in 15 (55.6 %) cases, with relapsing polychondritis diagnosed in 12 patients. A significant association was observed between relapsing polychondritis and orbital/ocular involvement in VEXAS syndrome (Relative Risk: 2.37, 95 % C.I. 1.03-5.46, p = 0.048). Six deaths were observed in the whole cohort of patients after a median disease duration of 1.2 (IQR=5.35) years, 5 (83.3 %) of which showed orbital/ocular inflammatory involvement. In conclusion, this study confirms that orbital/ocular inflammatory involvement is a common finding in VEXAS patients, especially when relapsing polychondritis is diagnosed. This makes ophthalmologists a key figure in the diagnostic process of VEXAS syndrome. The high frequency of deaths observed in this study seems to suggest that patients with orbital/ocular involvement may require increased attention and more careful follow-up., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest for this work., (Copyright © 2024. Published by Elsevier Inc.)

Several novel and effective cysteine targeting (Cys) covalent drugs are in clinical use. However, the target area containing a druggable Cys residue is limited. Therefore, methods for creating covalent drugs that target different residues are being looked for; examples of such ligands include those that target the residues lysine (Lys) and tyrosine (Tyr). Though the histidine (His) side chain is more frequently found in protein binding locations and has higher desirable nucleophilicity, surprisingly limited research has been done to specifically target this residue, and there are not many examples of His-targeting ligands that have been rationally designed. In the current work, we created novel stapled peptides that are intended to target hMcl-1 His 252 covalently. We describe the in vitro (biochemical, NMR, and X-ray) and cellular design and characterization of such agents. Our findings further suggest that the use of electrophiles to specifically target His residues is warranted.

Abstract: Myocarditis is an inflammatory disease of the myocardium characterized by a great heterogeneity of presentation and evolution. Treatment of myocarditis is often supportive, and the evidence for immunosuppression is scarce and debated. Conventional treatment is based on clinical presentation, ranging from conservative to advanced mechanical assist devices. In this setting, immunosuppression and immunomodulation therapies are mostly reserved for patients presenting with major clinical syndromes. In this review, we will summarize the current evidence and strategies for conventional and immunosuppressive treatments for patients presenting with acute myocarditis., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Adult-onset Still's disease (AOSD) is a multisystemic complex disorder clinically characterised by episodes of spiking fever, evanescent rash, polyarthritis or diffuse arthralgias; multiorgan involvement may develop according to the hyper-inflammatory extent. The pathogenesis of AOSD is not completely recognised. The central role of macrophage activation, which results in T helper 1 (Th1) cell cytokine activation, is well established. Pro-inflammatory cytokines such as interleukin (IL)-1, IL-6 and IL-18 play a fundamental role in disease onset and progression. The disease may develop in both children and adults with overlapping clinical features, and although several subsets depending on the clinical manifestations and the cytokines expressed have been identified, the dichotomy between systemic juvenile idiopathic arthritis (sJIA) and AOSD nowadays has been overcome, and the pathology is considered a disease continuum between ages. Various therapeutic approaches have been evaluated thus far, and different compounds are under assessment for AOSD treatment. Historically, glucocorticoids have been employed for treating systemic manifestations of Still's disease, while conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs) demonstrated efficacy in controlling the articular manifestations. Currently, biological (b) DMARDs are widely employed; IL-1 inhibitors such as anakinra and canakinumab have proven to have high efficacy and an excellent safety profile and the anti-IL-6 tocilizumab is approved for sJIA, with several trials and longitudinal studies confirming its efficacy and safety. Moreover, in the light of the 'window of opportunity', new evidence showed that the earlier these treatments are initiated, the sooner clinical inactivity can be achieved. Other treatment options are being considered since several molecules involved in the disease pathophysiology can be targeted through various mechanisms. This review will provide a broad overview of AOSD pathophysiology, insights into specific organ manifestations and the currently available treatments with the identification of potential therapeutic targets involved in AOSD pathogenesis will be outlined., (© 2024. The Author(s).)

Uranium (U) contamination of terrestrial and aquatic ecosystems poses a significant threat to the environment and human health due to the chemotoxicity of this actinide. The characterization of organisms that tolerate and accumulate U is crucial to decipher the mechanisms evolved to cope with the radionuclide and to propose new effective strategies for the bioremediation of U-contaminated environments. Here, we isolated a unicellular green microalga of the genus Coelastrella from U-contaminated wastewater. We showed that Coelastrella sp. PCV is much more tolerant to U than Chlamydomonas reinhardtii and Chlorella vulgaris. Coelastrella sp. PCV is able to accumulate U very rapidly and then gradually release it into the medium, behaving as an excluder to limit the toxic effects of U. The ability of Coelastrella sp. PCV to accumulate U is remarkably high, with up to 240 mg of tightly bound U per g of dry biomass. Coelastrella sp. PCV is able to grow and maintain high photosynthesis in natural metal-contaminated waters from a wetland near a reclaimed U mine. In a single one-week growth cycle, Coelastrella sp. PCV is able to capture 25-55 % of the U from the contaminated waters and shows lipid droplet accumulation. Coelastrella sp. PCV is a very promising microalga for the remediation of polluted waters with valorization of algal biomass that accumulates lipids., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Snake envenoming is a major, but neglected, tropical disease. Among venomous snakes, those inducing neurotoxicity such as kraits (Bungarus genus) cause a potentially lethal peripheral neuroparalysis with respiratory deficit in a large number of people each year. In order to prevent the development of a deadly respiratory paralysis, hospitalization with pulmonary ventilation and use of antivenoms are the primary therapies currently employed. However, hospitals are frequently out of reach for envenomated patients and there is a general consensus that additional, non-expensive treatments, deliverable even long after the snake bite, are needed. Traumatic or toxic degenerations of peripheral motor neurons cause a neuroparalysis that activates a pro-regenerative intercellular signaling program taking place at the neuromuscular junction (NMJ). We recently reported that the intercellular signaling axis melatonin-melatonin receptor 1 (MT1) plays a major role in the recovery of function of the NMJs after degeneration of motor axon terminals caused by massive Ca2+ influx. Here we show that the small chemical MT1 agonists: Ramelteon and Agomelatine, already licensed for the treatment of insomnia and depression, respectively, are strong promoters of the neuroregeneration after paralysis induced by krait venoms in mice, which is also Ca2+ mediated. The venom from a Bungarus species representative of the large class of neurotoxic snakes (including taipans, coral snakes, some Alpine vipers in addition to other kraits) was chosen. The functional recovery of the NMJ was demonstrated using electrophysiological, imaging and lung ventilation detection methods. According to the present results, we propose that Ramelteon and Agomelatine should be tested in human patients bitten by neurotoxic snakes acting presynaptically to promote their recovery of health. Noticeably, these drugs are commercially available, safe, non-expensive, have a long bench life and can be administered long after a snakebite even in places far away from health facilities., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 D’Este et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The role of calcium pyrophosphate (CPP) crystals in osteoarthritis (OA) is still a matter of debate. With this study we aimed to investigate the inflammatory features of synovial fluid (SF) collected from patients with OA with CPP crystals compared with those without crystals. We also explored the effect of OA SF on monocytes response. SFs were collected from adult patients with OA and subdivided according to the presence of crystals. Local cellular and humoral inflammatory mediators were analysed in the SF samples. The expression levels of IL-1β, IL-18, CASP-1, NLRP3, and GAPDH were measured by RT-PCR in the cells obtained by pelleting the SF samples. For the in vitro study, a monocytic cell line was treated with selected SF samples. SF with CPP crystals showed a significant increase in inflammatory cellular indices and higher levels of IL-1β, IL-8, and caspase-1 transcript with respect to SF without crystals. Higher concentrations of VEGF were also observed in the early stages of the whole OA patients. THP-1 cells stimulated with OA SF released a significant amount of IL-1 β in culture supernatants. This study demonstrated that SF collected from patients with OA shows different inflammatory features depending on the presence of CPP crystals.

Topic-based search systems retrieve items by contextualizing the information seeking process on a topic of interest to the user. A key issue in topic-based search of text resources is how to automatically generate multiple queries that reflect the topic of interest in such a way that precision, recall, and diversity are achieved. The problem of generating topic-based queries can be effectively addressed by Multi-Objective Evolutionary Algorithms, which have shown promising results. However, two common problems with such an approach are loss of diversity and low global recall when combining results from multiple queries. This work proposes a family of Multi-Objective Genetic Programming strategies based on objective functions that attempt to maximize precision and recall while minimizing the similarity among the retrieved results. To this end, we define three novel objective functions based on result set similarity and on the information theoretic notion of entropy. Extensive experiments allow us to conclude that while the proposed strategies significantly improve precision after a few generations, only some of them are able to maintain or improve global recall. A comparative analysis against previous strategies based on Multi-Objective Evolutionary Algorithms, indicates that the proposed approach is superior in terms of precision and global recall. Furthermore, when compared to query-term-selection methods based on existing state-of-the-art term-weighting schemes, the presented Multi-Objective Genetic Programming strategies demonstrate significantly higher levels of precision, recall, and F1-score, while maintaining competitive global recall. Finally, we identify the strengths and limitations of the strategies and conclude that the choice of objectives to be maximized or minimized should be guided by the application at hand., Competing Interests: Ana G. Maguitman is an Academic Editor of PeerJ Computer Science., (© 2023 Baggio et al.)

Aims: In Italy, 12-month survival in the general population between 90 and 94 years old is 26%. In very old patients, the benefit of pacemaker implantation in terms of quality and duration of life is unclear. The aim of our study was to analyse clinical characteristics, outcome and factors associated with survival in patients at least 90 years old at the time of the first pacemaker implant., Methods: Clinical parameters, device characteristics, survival and predictors of outcome in patients at least 90 years old treated with a pacemaker in our centre in 2019-2020 were evaluated., Results: Among the 554 patients undergoing pacemaker implantation in our centre during the study interval, 69 (12%) were at least 90 years old; a complete/advanced atrioventricular block was present in 65%. A cardiological comorbidity (excluding atrial fibrillation) was present in 22 patients (32%). Oncological, pulmonary and neurological comorbidities were present in 12 (17%), 19 (28%) and 32 (46%), respectively. Renal impairment was present in 25 patients (36%). After pacemaker implantation, a pneumothorax developed in two patients and lead dislodgment in one. During follow-up (median 17 months, interquartile range: 13-24), 32 patients died (46%), with a 12-month mortality probability of 24.6%. At multivariate analysis, the presence of oncological (hazard ratio (HR) 5.31; P < 0.001) and neurological (HR 6.44; P < 0.001) comorbidities was associated with mortality. Truncating the outcome at 6 months, renal impairment (HR 8.01; P = 0.003), anticoagulant therapy (HR 8.14; P = 0.003), oncological comorbidities (HR 14.1; P < 0.001) and left ventricular function (5% increase of left ventricular ejection fraction: HR 0.66; P < 0.001) were significantly associated with outcome., Conclusion: At our centre, patients at least 90 years old underwent pacemaker implantation mainly for advanced atrioventricular block. One-year survival was excellent, even better than expected in the general population., (Copyright © 2023 Italian Federation of Cardiology - I.F.C. All rights reserved.)