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Background and study aims Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) for pancreatic neuroendocrine tumors (NETs) and intraductal pancreatic mucinous neoplasia (IPMN) with worrisome features or high-risk stigmata (WF/HRS) has been evaluated in few series with short-term outcomes. This studyʼs primary endpoint was to assess the long-term efficacy of EUS-RFA in patients with NETs or pancreatic cystic neoplasms (PCNs) over at least 3 years. Patients and methods Twelve patients had 14 NETs with a mean 13.4-mm size (10–20) and 17 patients had a cystic tumor (16 IPMN, 1 MCA) with a 29.1-mm mean size (9–60 were included. They were treated with EUS-guided RFA, evaluated prospectively at 1 year, and followed annually for at least 3 years. Results The mean duration of follow-up was 42.9 months (36–53). Four patients died during follow-up (17–42 months) from unrelated diseases. At 1-year follow-up, and 85.7 % complete disappearance was seen in 12 patients with 14 NETs. At the end of follow-up (45.6 months), complete disappearance of tumors was seen in 85.7 % of cases. One case of late liver metastasis occurred in a patient with initial failure of EUS-RFA. At 1-year follow-up, a significant response was seen in 70.5 % of 15 patients with PCNs. At the end of the follow-up, there was a significant response in 66.6 % with no mural nodules. Two cases of distant pancreatic adenocarcinoma unrelated to IPMN occurred. Conclusions EUS-RFA results for pancreatic NETs or PCNs appear to be stable during 42 months of follow-up.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide since the end of year 2019 and is currently responsive for coronavirus infectious disease 2019 (COVID-19). The first reports considered COVID-19 as a respiratory tract disease responsible for pneumonia, but numerous studies rapidly emerged to warn the medical community of COVID-19-associated neurological manifestations, including encephalopathy at the acute phase and other postinfectious manifestations. Using standard visual analysis or spectral analysis, recent studies reported electroencephalographic (EEG) findings of COVID-19 patients with various neurological symptoms. Most EEG recordings were normal or revealed non-specific abnormalities, such as focal or generalized slowing, interictal epileptic figures, seizures, or status epilepticus. Interestingly, novel EEG abnormalities over frontal areas were also described at the acute phase. Underlying mechanisms leading to brain injury in COVID-19 are still unknown and matters of debate. These frontal EEG abnormalities could emphasize the hypothesis whereby SARS-CoV-2 enters the central nervous system (CNS) through olfactory structures and then spreads in CNS via frontal lobes. This hypothesis is reinforced by the presence of anosmia in a significant proportion of COVID-19 patients and by neuroimaging studies confirming orbitofrontal abnormalities. COVID-19 represents a new viral disease characterized by not only respiratory symptoms but also a systemic invasion associated with extra-respiratory signs. Neurological symptoms must be the focus of our attention, and functional brain evaluation with EEG is crucial, in combination with anatomical and functional brain imaging, to better understand its pathophysiology. Evolution of symptoms together with EEG patterns at the distance of the acute episode should also be scrutinized.

Siderophores are chelators with a high selectivity for Fe(III) and a good affinity for divalent metals, including Cd(II) and Ni(II). Inoculation with siderophore-producing bacteria (SPB) has thus been proposed as an alternative to chelator supply in phytoremediation. Accurate assessments of the potential of this association require a dissection of the interaction of siderophores with metals at the soil-root interface. This study focuses on pyoverdine (Pvd), the main siderophore produced by Pseudomonas aeruginosa. We first assessed the ability of Pvd to coordinate Ni(II). The stability constant of Pvd-Ni(II) (log K = 10.9) was found to be higher than that of Pvd-Cd(II) (log K = 8.2). We then investigated the effect of a direct supply of Pvd on the mobilization, speciation, and phytoavailability of Cd and Ni in hydroponics. When supplied at a concentration of 50 μM, Pvd selectively promoted Ni mobilization from smectite. It decreased plant Ni and Cd contents and the free ionic fractions of these two metals, consistent with the free ion activity model. Pvd had a more pronounced effect for Ni than for Cd, as predicted from its coordination properties. Inoculation with P. aeruginosa had a similar effect on Ni phytoavailability to the direct supply of Pvd. [ABSTRACT FROM AUTHOR]

Abstract Background The prognosis for pancreatic cancer remains poor despite diagnostic advances and treatments with new chemotherapeutic regimens. The five year survival rate remains below 3%. Consequently, there is an urgent need for new treatments to significantly improve the prognosis. In addition, there is a big gap in terms of the screening, early diagnosis and prevention of pancreatic cancer the incidence of which is increasing dramatically. Methods Design: the BACAP cohort is a prospective multicenter pancreatic cancer cohort (pancreatic ductal carcinoma) with clinical and multiple biological samples; Participating centers: 15 French academic and private hospitals; Study Population: any cytologically and/or histologically proven pancreatic carcinoma regardless of the stage (resectable, borderline, locally advanced or metastatic) or treatment (surgery, palliative chemotherapy, best supportive care). At least 1500 patients will be included. Clinical data collected include: disease presentation, epidemiological and social factors, baseline biology, radiology, endoscopic ultrasound, staging, pathology, treatments, follow-up (including biological and radiological), and survival. All these data are collected and stored through an e-observation system at a centralized data center. Biological samples and derived products (i.e. before any treatment): blood, saliva, endoscopic ultrasound-guided fine needle aspiration materials from the primary tumor, fine needle biopsy of metastases and surgically resected tissue. DNA and RNA are extracted from fine needle aspiration materials and are quantified and characterized for quality. Whole blood, plasma and serum are isolated from blood samples. Frozen tissues were specifically allocated to the cohort. All derived products and saliva are stored at − 80 °C. Main end-points: i) to centralize clinical data together with multiple biological samples that are harmonized in terms of sampling, the post sampling process and storage; ii) to identify new molecular markers for the diagnosis, prognosis and possibly the predictive response to pancreatic cancer surgery and or chemotherapy. Discussion The BACAP cohort is a unique prospective biological clinical database that provides the opportunity to identify correlations between the presence/expression of a broad panel of biomarkers (DNA, RNA, miRNA, proteins, etc.), epidemiological and social data, various clinical situations, various stages and the differentiation of the tumor, treatments and survival. Trial registration ClinicalTrials.gov Identifier: NCT02818829. Registration date: June 30, 2016.

Abstract: Cytarabine (Ara-C) is the backbone of acute myeloid leukemia (AML) chemotherapy. Little is known about possible risk factors predictive for the frequent (ie, up to 16%) life-threatening or lethal toxicities caused by Ara-C. Ara-C is detoxified in the liver by a single enzyme, cytidine deaminase (CDA), coded by a gene known to be highly polymorphic. In this proof-of-concept study, we particularly investigated the role of the CDA poor metabolizer (PM) phenotype in Ara-C toxicities. CDA phenotyping (measurement of CDA residual activity in serum) and genotyping (search for the CDA*2 allelic variant) were performed in 58 adult patients with AML treated with the standard 7+3 (Ara-C + anthracyclines) protocol. Statistically significantly lower CDA activity was observed in patients experiencing severe/lethal toxicities as compared with patients who did not (1.5 ± 0.7 U/mg vs 3.95 ± 3.1 U/mg; Student t test P < .001). Subsequent receiver operating characteristic analysis identified a threshold in CDA activity (ie, 2 U/mg) associated with PM syndrome and increased risk of developing severe toxicities. Five percent of patients experienced lethal toxicities, all displaying CDA PM status (1.3 ± 0.5 U/mg). In terms of efficacy, a trend toward higher response rates and longer progression-free survival and overall survival were observed in patients with low CDA activity. Taken together, the results of this study strongly suggest that CDA is a predictive marker of life-threatening toxicities in patients with AML receiving induction therapy with standard Ara-C.

The monoamine serotonin (5-HT), a well-known neurotransmitter, is also important in peripheral tissues. Several studies have suggested that 5-HT is involved in bone metabolism. Starting from our original observation of increased 5-HT2B receptor (5- HT2BR) expression during in vitro osteoblast differentiation, we investigated a putative bone phenotype in vivo in 5-HT2B knockout mice. Of interest, 5-HT2BR mutant female mice displayed reduced bone density that was significant from age 4 months and had intensified by 12 and 18 months. This histomorphometrically confirmed osteopenia seems to be due to reduced bone formation because I) the alkaline phosphatase-positive colony-forming unit capacity of bone marrow precursors was markedly reduced in the 5-HT2BR mutant mice from 4 to 12 months of age, 2) ex vivo primary osteoblasts from mutant mice exhibited reduced proliferation and delayed differentiation, and 3) calcium incorporation was markedly reduced in osteoblasts after 5-HT2BR depletion (produced genetically or by pharmacological inactivation). These findings support the hypothesis that the 5-HT2BR receptor facilitates osteoblast recruitment and proliferation and that its absence leads to osteopenia that worsens with age. We show here, for the first time, that the 5-HT2BR receptor is a physiological mediator of 5-HT in bone formation and, potentially, in the onset of osteoporosis in aging women. [ABSTRACT FROM AUTHOR]

Background and study aims Capsule endoscopy (CE) is the preferred method for small bowel (SB) exploration. With a mean number of 50,000 SB frames per video, SBCE reading is time-consuming and tedious (30 to 60 minutes per video). We describe a large, multicenter database named CAD-CAP (Computer-Assisted Diagnosis for CAPsule Endoscopy, CAD-CAP). This database aims to serve the development of CAD tools for CE reading. Materials and methods Twelve French endoscopy centers were involved. All available third-generation SB-CE videos (Pillcam, Medtronic) were retrospectively selected from these centers and deidentified. Any pathological frame was extracted and included in the database. Manual segmentation of findings within these frames was performed by two pre-med students trained and supervised by an expert reader. All frames were then classified by type and clinical relevance by a panel of three expert readers. An automated extraction process was also developed to create a dataset of normal, proofread, control images from normal, complete, SB-CE videos. Results Four-thousand-one-hundred-and-seventy-four SB-CE were included. Of them, 1,480 videos (35 %) containing at least one pathological finding were selected. Findings from 5,184 frames (with their short video sequences) were extracted and delimited: 718 frames with fresh blood, 3,097 frames with vascular lesions, and 1,369 frames with inflammatory and ulcerative lesions. Twenty-thousand normal frames were extracted from 206 SB-CE normal videos. CAD-CAP has already been used for development of automated tools for angiectasia detection and also for two international challenges on medical computerized analysis.

A 20-year-old man underwent an outpatient general anesthetic procedure with sevoflurane for the correction of a bilateral gynecomastia. The patient had been first exposed to sevoflurane two years before, without any complication. He presented an overweight with a body mass index (BMI) of 31.4 kg/m2 and had an episode of “binge” drinking a few days before anesthesia. He became icteric from postoperative day 9, and after the worsening of liver function tests, the liver biopsy revealed centrilobular necrosis. The patient became encephalopathic and required urgent liver transplantation on postoperative day 30. The possibility of a sevoflurane-related fulminant hepatic failure is discussed.

The clinical venous thromboembolism (VTE) pattern often shows wide heterogeneity within relatives of a VTE-affected family, although they carry the same thrombophilia defect. It is then mandatory to develop additional tools for assessing VTE risk in families with thrombophilia. This study aims to assess whether common environmental and genetic risk factors for VTE contribute to explain this heterogeneity. A total of 2,214 relatives from 651 families with known inherited thrombophilia were recruited at the referral center for thrombophilia in Marseilles, France, from 1986 to 2013. A thrombophilia screening was systematically performed in all included relatives. According to the severity of the thrombophilia defect, individuals were split into three groups: no familial defect, mild thrombophilia, and severe thrombophilia. In addition, common genetic factors (ABO blood group and 11 polymorphisms selected on the basis of their association with VTE in the general population) were genotyped. Furthermore, body mass index and smoking were collected. VTE incidence was 1.74, 3.64, and 6.40 per 1,000 person-years in individuals with no familial defect, mild thrombophilia, and severe thrombophilia, respectively. Five common risk factors were associated with VTE in this population: obesity, smoking, ABO blood group, and F11_rs2036914 and FGG_rs2066865 polymorphisms. These common factors were then included into a three-level risk score. The score was highly efficient for assessing VTE risk in mild thrombophilia patients by identifying two groups with different VTE risk; individuals with low score had the same risk as individuals with no familial defect whereas individuals with high score had the same risk as individuals with severe thrombophilia. An overall score including the five items plus the thrombophilia status was built and displayed an area under the receiver operating characteristic curve of 0.702 for discriminating VTE and non-VTE relatives. In conclusion, integrating common environmental and genetic risk factors improved VTE risk assessment in relatives from families with thrombophilia.

OBJECTIVE: The incidence of postinfectious irritable bowel syndrome (IBS) ranges between 4% and 32% of individuals after bacterial or parasitic infection. This study analyzed IBS symptoms in hospitalized patients three months after a symptomatic Clostridium difficile infection.

Background and study aims: To assess experimentally endoscopic submucosal tunnel dissection (ESTD) as an alternative technique of endoscopic submucosal resection. Patients and methods: This was a prospective, randomized, comparative experimental animal study carried out over a period of 9 months at the surgical research and teaching center of Aix-Marseille University, France. Virtual esophageal and gastric lesions measuring 3 cm in diameter were resected in pigs weighing 25 to 30 kg. The primary aim was to evaluate ESTD’s efficacy compared with endoscopic submucosal dissection (ESD). The secondary aims were to determine complication rates as well as to assess procedure time and procedure speed, histologic quality of the resected specimen, and procedure cost. Results: Eighteen procedures (9 ESD and 9 ESTD) were performed in nine pigs. The technical success rate was 88.9 % for both techniques, with one single failure in each. The en bloc resection rate was 100 % for ESTD and 88.9 % for ESD (one failure). The complication rate (22 %) and median procedure time were similar but dissection speed was quicker with ESTD in the esophagus (P = 0.03). Median procedure cost (728 Euros for ESD and ESTD) did not differ. On histologic examination, the lateral margins were healthy in 100 % of ESTD and in 88.9 % of ESD (P = 0.49). Deep resection margins were of better quality in ESTD (median submucosal thickness: 1307.1 µm vs. 884.7 µm; P = 0.039). Conclusions: ESTD is feasible and safe but not superior in the treatment of superficial esophageal/gastric lesions in porcine models compared with ESD. Nevertheless it provides a better quality histologic specimen.

Inflammation significantly influences cellular communication in the oral environment, impacting tissue repair and regeneration. This study explores the role of small extracellular vesicles (sEVs) derived from lipopolysaccharide (LPS)-treated stem cells from the apical papilla (SCAP) in modulating macrophage polarization and osteoblast differentiation. SCAPs were treated with LPS for 24 h, and sEVs from untreated (SCAP-sEVs) and LPS-treated SCAP (LPS-SCAP-sEVs) were isolated via ultracentrifugation and characterized using transmission electron microscopy, Western blot, and Tunable Resistive Pulse Sensing. LPS-SCAP-sEVs exhibited characteristic exosome morphology (~100 nm diameter) and expressed vesicular markers (CD9, CD63, CD81, and HSP70). Functional analysis revealed that LPS-SCAP-sEVs promoted M1 macrophage polarization, as evidenced by the increased pro-inflammatory cytokines (IL-6 and IL-1β) and the reduced anti-inflammatory markers (IL-10 and CD206), while impairing the M2 phenotype. Additionally, LPS-SCAP-sEVs had a minimal impact on SCAP metabolic activity or osteogenic gene expression but significantly reduced mineralization capacity in osteogenic conditions. These findings suggest that sEVs mediate the inflammatory interplay between SCAP and macrophages, skewing macrophage polarization toward a pro-inflammatory state and hindering osteoblast differentiation. Understanding this sEV-driven communication axis provides novel insights into the cellular mechanisms underlying inflammation in oral tissues and highlights potential therapeutic targets for modulating extracellular vesicle activity during acute inflammatory episodes.

Much of the human genetics variant repertoire is composed of single nucleotide variants (SNV) and small insertion/deletions (indel) but structural variants (SV) remain a major part of our modified DNA. SV detection has often been a complex question to answer either because of the necessity to use different technologies (array CGH, SNP array, Karyotype, Optical Genome Mapping…) to detect each category of SV or to get an appropriate resolution (Whole Genome Sequencing). Thanks to the deluge of pangenomic analysis, Human geneticists are accumulating SV and their interpretation remains time consuming and challenging. The AnnotSV webserver (https://www.lbgi.fr/AnnotSV/) aims at being an efficient tool to (i) annotate and interpret SV potential pathogenicity in the context of human diseases, (ii) recognize potential false positive variants from all the SV identified and (iii) visualize the patient variants repertoire. The most recent developments in the AnnotSV webserver are: (i) updated annotations sources and ranking, (ii) three novel output formats to allow diverse utilization (analysis, pipelines), as well as (iii) two novel user interfaces including an interactive circos view., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Bardet-Biedl syndrome (BBS) is an autosomal recessive ciliopathy that affects multiple organs, leading to retinitis pigmentosa, polydactyly, obesity, renal anomalies, cognitive impairment, and hypogonadism. Until now, biallelic pathogenic variants have been identified in at least 24 genes delineating the genetic heterogeneity of BBS. Among those, BBS5 is a minor contributor to the mutation load and is one of the eight subunits forming the BBSome, a protein complex implied in protein trafficking within the cilia. This study reports on a European BBS5 patient with a severe BBS phenotype. Genetic analysis was performed using multiple next-generation sequencing (NGS) tests (targeted exome, TES and whole exome, WES), and biallelic pathogenic variants could only be identified using whole-genome sequencing (WGS), including a previously missed large deletion of the first exons. Despite the absence of family samples, the biallelic status of the variants was confirmed. The BBS5 protein's impact was confirmed on the patient's cells (presence/absence and size of the cilium) and ciliary function (Sonic Hedgehog pathway). This study highlights the importance of WGS and the challenge of reliable structural variant detection in patients' genetic explorations as well as functional tests to assess a variant's pathogenicity.

Background: Lipoxin A4 (LXA4) is a specialized pro-resolving mediator involved in the resolution phase of inflammation that is crucial for the return of tissues to homeostasis, healing, and regenerative processes. LXA4 can modify the microenvironment via its receptor, formyl peptide receptor 2 (FPR2) and thus modulate the inflammatory response. However, the effect of exogeneous LXA4 application on polarized macrophages remains unstudied. The objective of this study was to assess the effect of LXA4 on macrophage activity and on the phenotype modulation of polarized M1 and M2 macrophages derived from THP-1 monocytes., Methods and Results: Once differentiated, human macrophages were incubated with interleukin 4 (IL-4) and IL-13 to obtain M2-polarized macrophages or with interferon gamma and lipopolysaccharide for classical macrophage activation. The mRNA and protein expression of M1 and M2 markers confirmed the polarization of THP-1-derived macrophages. LXA4 (0-100 nM) did not affect the viability of M1 and M2 macrophages or the phagocytic activity of these cells. Gene expression of FPR2, referred as a receptor for the LXA4, was higher in M1 compared with M2, and was not modified by the LXA4 at the doses used. Moreover, LXA4 exhibited anti-inflammatory properties illustrated by the decreasing in the gene expression of pro-inflammatory cytokines (IL-6, tumor necrosis factor alpha, IL-1β) in M1 and by the increase in the expression of anti-inflammatory cytokines (IL-10) in M2 macrophages., Conclusions: These results provide new insights regarding the potential of LXA4 to regulate the polarization state of macrophages., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Background/aims: Interleukin 33 (IL-33) plays a significant role in immunity but its role in bone physiology and periodontitis needs to be further investigated. The aim of this study was to decipher the contribution of IL-33 to bone homeostasis under physiological conditions, and to alveolar bone loss associated with experimental periodontitis (EP) in IL-33 knockout (KO) mice and their wildtype (WT) littermates., Methods: The bone phenotype of IL-33 KO mice was studied in the maxilla, femur, and fifth lumbar vertebra by micro-computed tomography (micro-CT). EP was induced by a ligature soaked with the periopathogen Porphyromonas gingivalis (Pg) around a maxillary molar. Alveolar bone loss was quantified by micro-CT. The resorption parameters were assessed via toluidine blue staining on maxillary sections. In vitro osteoclastic differentiation assays using bone marrow cells were performed with or without lipopolysaccharide from Pg (LPS-Pg)., Results: First, we showed that under physiological conditions, IL-33 deficiency increased the trabecular bone volume/total volume ratio (BV/TV) of the maxillary bone in male and female mice, but not in the femur and fifth lumbar vertebra, suggesting an osteoprotective role for IL-33 in a site-dependent manner. The severity of EP induced by Pg-soaked ligature was increased in IL-33 KO mice but in female mice only, through an increase in the number of osteoclasts. Moreover, osteoclastic differentiation from bone marrow osteoclast progenitors in IL-33-deficient female mice is enhanced in the presence of LPS-Pg., Conclusion: Taken together, our data demonstrate that IL-33 plays a sex-dependent osteoprotective role both under physiological conditions and in EP with Pg., Competing Interests: The authors have no conflicts of interest to declare., (© Copyright by the Author(s). Published by Cell Physiol Biochem Press.)