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This work aimed to evaluate the impact of sarcopenia and sarcopenic obesity on the occurrence of severe pancreatitis and to study the performance of anthropometric indices to predict severe forms. We conducted a single-center retrospective study at Caen University Hospital between 2014 and 2017. Sarcopenia was assessed by measuring the psoas area on an abdominal scan. The psoas area /body mass index ratio reflected sarcopenic obesity. By normalizing the value to the body surface, we obtained an index called sarcopancreatic index, avoiding sex differences in measurements. Among 467 included patients, 65 (13.9%) developed severe pancreatitis. The sarcopancreatic index was independently associated with the occurrence of severe pancreatitis (1.455 95% CI [1.028–2.061]; p = 0.035), as was the Visual Analog Scale, creatinine or albumin. The complication rate was not different depending on sarcopancreatic index value. Based on variables independently associated with the occurrence of severe pancreatitis, we constructed a score called Sarcopenia Severity Index. This score presented an area under the receiver operating characteristics curve of 0.84, comparable to the Ranson score (0.87) and superior to body mass index or the sarcopancreatic index to predict a severe form of acute pancreatitis. Sarcopenic obesity seems to be associated with severe acute pancreatitis. [ABSTRACT FROM AUTHOR]

Acute pancreatitis is one of the main causes of hospitalization for gastroenterological reason in the world. To date, the management of this disease apart from the etiological treatment, remains symptomatic. The correction of the hypovolemia induced in pancreatitis, is a cornerstone of management. Some authors defend the concept that the fluid resuscitation could influence the severity of the disease by limiting pancreatic ischemia and peripheral hypo-perfusion at the origin of organ failure. However, recent data show that aggressive fluid resuscitation can induce deleterious effects, in particular -volume overload, without inflecting the natural history of the disease. If the volume and the optimal modalities remain to be defined, the speed of initiation of the infusions could condition its impact. To date, it seems reasonable to favor balanced crystalloids and in particular Ringer's Lactate, not to exceed 3 ml/kg/h without questioning the relevance of the prescription. It is crucial to evaluate early and regularly in order to adapt prescriptions to initial hemodynamic status of the patient and to his response to infusion. The development of simple and relevant hemodynamic monitoring tools in this indication is a major challenge for the future. This mini-review aims to detail the role of fluid resuscitation in acute pancreatitis, its modalities, the expected benefits and the limits of this therapy. [ABSTRACT FROM AUTHOR]

Background: Chemotherapy options in patients with advanced pancreatic ductal adenocarcinoma (PDAC) after failure of standard chemotherapies are limited. Objectives: We aimed to report the efficacy and safety of the leucovorin and 5-fluorouracil (LV5FU2) and carboplatin combination in this setting. Design: We performed a retrospective study including consecutive patients with advanced PDAC who received LV5FU2–carboplatin between 2009 and 2021 in an expert center. Methods: We measured overall survival (OS) and progression-free survival (PFS), and explored associated factors using Cox proportional hazard models. Results: In all, 91 patients were included (55% male, median age 62), with a performance status of 0/1 in 74% of cases. LV5FU2–carboplatin was mainly used in third (59.3%) or fourth line (23.1%), with three (interquartile range: 2.0–6.0) cycles administered on average. The clinical benefit rate was 25.2%. Median PFS was 2.7 months (95% CI: 2.4–3.0). At multivariable analysis, no extrahepatic metastases (p = 0.083), no ascites or opioid-requiring pain (p = 0.023), <2 prior treatment lines (p < 0.001), full dose of carboplatin (p = 0.004), and treatment initiation >18 months after initial diagnosis (p < 0.001) were associated with longer PFS. Median OS was 4.2 months (95% CI: 3.48–4.92) and was influenced by the presence of extrahepatic metastases (p = 0.058), opioid-requiring pain or ascites (p = 0.039), and number of prior treatment lines (0.065). Prior tumor response under oxaliplatin did not impact either PFS or OS. Worsening of preexisting residual neurotoxicity was infrequent (13.2%). The most common grade 3–4 adverse events were neutropenia (24.7%) and thrombocytopenia (11.8%). Conclusion: Although the efficacy of LV5FU2–carboplatin appears limited in patients with pretreated advanced PDAC, it may be beneficial in selected patients. [ABSTRACT FROM AUTHOR]

There is intensive research using gold nanoparticles for biomedical purposes, which have many advantages such as ease of synthesis and high reactivity. Their possible small size (<10 nm) can lead to the crossing of biological membranes and then to problematic dissemination and storage in organs that must be controlled and evaluated. In this work, a simple isocratic HPLC method was developed and validated to quantify the gold coming from nanoparticles in different biological samples. After a first carbonization step at 900 ®C, the nanoparticles were oxidized by dibroma under acidic conditions, leading to tetrachloroaurate ions that could form ion pairs when adding rhodamine B. Finally, ion pairs were extracted and rhodamine B was evaluated to quantify the corresponding gold concentration by reversed-phase HPLC with visible detection. The method was validated for different organs (liver, spleen, lungs, kidneys, or brain) and fluids (plasma and urine) from rats and mice. Lastly, the developed method was used to evaluate the content of gold in organs and fluids after intravenous (IV) injection of nanoparticles. [ABSTRACT FROM AUTHOR]

Résumé: Les évaluations des risques sanitaires des substances chimiques considèrent de plus en plus fréquemment les expositions agrégées et/ou cumulées afin de caractériser de manière la plus réaliste les risques sanitaires pour la population. L'exposition environnementale aux substances chimiques via la poussière sédimentée sur les surfaces intérieures doit-elle être prise en compte et de quelle manière ? La population est exposée aux substances chimiques présentes dans la poussière sédimentée par ingestion, inhalation et contact cutané. L'ingestion semble la voie d'exposition la plus importante, et la seule à pouvoir être estimée au vu des connaissances actuelles. Pour la mesure, il est recommandé d'utiliser la technique de prélèvement par aspiration sur une surface déterminée, suivie d'un tamisage à 250 μm (taille maximum des particules adhérant aux mains) afin de documenter les concentrations massique et surfacique. La mesure de la bioaccessibilité orale permettrait de mieux estimer l'exposition mais les méthodes ne sont pas validées à ce jour pour la majorité des composés. Les valeurs guides pour les poussières intérieures (VGPI) sont pertinentes si l'exposition via la poussière est non négligeable pour une fraction de la population. Elles pourraient être élaborées simplement en allouant à la poussière une fraction de la valeur toxicologique de référence. Health risk assessments of chemical substances consider aggregate and/or cumulative exposures in order to characterise population health risks realistically. Should environmental exposure to chemical substances via indoor settled dust be taken into account and if so, how? Exposure to the chemicals in settled dust can occur through ingestion, inhalation, and dermal contact. Ingestion appears to be the most important route of exposure, and the only one that can be estimated from current knowledge. The recommended measurement technique is sampling by vacuuming a given surface, then sieving the dust at 250 μm (maximum size of the particles adhering to the hands) to document the mass and surface concentrations. Oral bioaccessibility would provide a better exposure estimate, but its methods have not yet been validated for most compounds. Guideline values for indoor dust are relevant if exposure via dust is non-negligible for a fraction of the population. They could be developed by simply allocating a fraction of the toxicological reference value to dust. [ABSTRACT FROM AUTHOR]

Background: Increasing evidence support a key role of peripheral immune processes in the pathophysiology of Alzheimer's disease (AD), highlighting an intricate interplay between brain resident glial cells and both innate and adaptive peripheral immune effectors. We previously showed that regulatory T cells (Tregs) have a beneficial impact on disease progression in AD‐like pathology, notably by modulating the microglial response associated with Ab deposits in a mouse model of amyloid pathology. Besides microglia, reactive astrocytes also play a critical role in neuroinflammatory processes associated with AD. Different phenotypes of reactive astrocytes have recently been characterized, including A1 neurotoxic and A2 neuroprotective subtypes. However, the precise impact of Tregs on astrocyte reactivity and phenotypes in AD still remains poorly defined. Methods: We assessed the impact of Treg immunomodulation on astrocyte reactivity in a mouse model of AD‐like amyloid pathology. Using 3D imaging we carried out extensive morphological analyses of astrocytes following either depletion or amplification of Tregs. We further assessed the expression of several A1‐ and A2‐like markers by immunofluorescence and RT‐qPCR. Results: Modulation of Tregs did not significantly impact the magnitude of global astrocyte reactivity in the brain nor in the close vicinity of cortical amyloid deposits. We did not observe changes in the number, morphology, or branching complexity of astrocytes according to immunomodulation of Tregs. However, early transient depletion of Tregs modulated the balance of reactive astrocyte subtypes, resulting in increased C3‐positive A1‐like phenotypes associated with amyloid deposits. Conversely, early depletion of Tregs decreased A2‐like phenotypes of reactive astrocytes associated with larger amyloid deposits. Intriguingly, modulation of Tregs also impacted the cerebral expression of several markers of A1‐like subsets in healthy mice. Conclusions: Our study suggests that Tregs contribute to modulate and fine tune the balance of reactive astrocyte subtypes in AD‐like amyloid pathology, by dampening A1‐like astrocytes in favor of A2‐like phenotypes. This effect of Tregs may partly relate to their capacity at modulating steady state astrocyte reactivity and homeostasis. Our data further highlight the need for refined markers of astrocytes subsets and strategy of analysis for better deciphering the complexity of astrocyte reactivity in neurodegeneration. [ABSTRACT FROM AUTHOR]

Objective: Recent studies have underlined the effect of systemic inflammation on the pathophysiology of Alzheimer's disease (AD). Neutrophils are key components of early innate immunity and contribute to uncontrolled systemic inflammation if not tightly regulated. The aim of our study was to fully characterize human circulating neutrophils at different disease stages in AD.Methods: We analyzed neutrophil phenotypes and functions in 42 patients with AD (16 with mild cognitive impairment and 26 with dementia), and compared them to 22 age-matched healthy subjects. This study was performed directly in whole blood to avoid issues with data interpretation related to cell isolation procedures.Results: Blood samples from AD patients with dementia revealed neutrophil hyperactivation associated with increased reactive oxygen species production and increased levels of intravascular neutrophil extravascular traps. The homeostasis of circulating neutrophils in these patients also changed: The ratio between the harmful hyperreactive CXCR4high /CD62Llow senescent and the CD16bright /CD62Ldim immunosuppressive neutrophil subsets rose in the later stage of the disease. These abnormalities were greater in fast-decliner than in slow-decliner patients.Interpretation: Our results indicate that the inflammatory properties of circulating neutrophils shift as the percentage of aged neutrophils expands in patients with AD-changes that may play an instrumental role in establishing systemic chronic inflammation. Most important, our data strongly suggest that the neutrophil phenotype may be associated with the rate of cognitive decline and may thus constitute an innovative and prognostic blood biomarker in patients with AD. Ann Neurol 2018;83:387-405. [ABSTRACT FROM AUTHOR]

Recent studies highlight the implication of innate and adaptive immunity in the pathophysiology of Alzheimer's disease, and foster immunotherapy as a promising strategy for its treatment. Vaccines targeting amyloid-β peptide provided encouraging results in mouse models, but severe side effects attributed to T cell responses in the first clinical trial AN1792 underlined the need for better understanding adaptive immunity in Alzheimer's disease. We previously showed that regulatory T cells critically control amyloid-β-specific CD4(+) T cell responses in both physiological and pathological settings. Here, we analysed the impact of regulatory T cells on spontaneous disease progression in a murine model of Alzheimer's disease. Early transient depletion of regulatory T cells accelerated the onset of cognitive deficits in APPPS1 mice, without altering amyloid-β deposition. Earlier cognitive impairment correlated with reduced recruitment of microglia towards amyloid deposits and altered disease-related gene expression profile. Conversely, amplification of regulatory T cells through peripheral low-dose IL-2 treatment increased numbers of plaque-associated microglia, and restored cognitive functions in APPPS1 mice. These data suggest that regulatory T cells play a beneficial role in the pathophysiology of Alzheimer's disease, by slowing disease progression and modulating microglial response to amyloid-β deposition. Our study highlights the therapeutic potential of repurposed IL-2 for innovative immunotherapy based on modulation of regulatory T cells in Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Background: Active immunization against Aβ was reported to have a therapeutic effect in murine models of Alzheimer's disease. Clinical Aβ vaccination trial AN1792 was interrupted due to the development in 6 % of the patients of meningoencephalitis likely involving pro-inflammatory CD4+ T cells. However, the potential implication of auto-aggressive anti-Aβ CD8+ T cells has been poorly investigated. Methods: Potential MHC-I-restricted Aβ-derived epitopes were first analyzed for their capacity to recruit functional CD8+ T cell responses in mouse models. Their impact on migration of CD8+ T cells into the brain parenchyma and potential induction of meningoencephalitis and/or neuronal damage was investigated upon vaccination in the APPPS1 mouse model of AD. Results: We identified one nonamer peptide, Aβ33-41, which was naturally processed and presented in association with H-2-Db molecule on neurons and CD11b+ microglia. Upon optimization of anchor residues for enhanced binding to H-2-Db, immunization with the modified Aβ33-41NP peptide elicited Aβ-specific IFNγ-secreting CD8+ T cells, which are cytotoxic towards Aβ-expressing targets. Whereas T cell infiltration in the brain of APPPS1 mice is dominated by CD3+CD8- T cells and increases with disease evolution between 4 and 7 months of age, a predominance of CD3+CD8+ over CD3+CD8- cells was observed in 6- to 7-month-old APPPS1 but not in WT animals, only after vaccination with Aβ33-41NP. The number of CD11b+ mononuclear phagocytes, which significantly increases with age in the brain of APPPS1 mice, was reduced following immunization with Aβ33-41NP. Despite peripheral activation of Aβ-specific CD8+ cytotoxic effectors and enhanced infiltration of CD8+ T cells in the brain of Aβ33-41NP-immunized APPPS1 mice, no clinical signs of severe autoimmune neuroinflammation were observed. Conclusions: Altogether, these results suggest that Aβ-specific CD8+ T cells are not major contributors to meningoencephalitis in response to Aβ vaccination. [ABSTRACT FROM AUTHOR]

Abstract: Prion diseases are caused by the transconformation of the host cellular prion protein PrPc into an infectious neurotoxic isoform called PrPSc. While vaccine-induced PrP-specific CD4+ T cells and antibodies partially protect scrapie-infected mice from disease, the potential autoreactivity of CD8+ cytotoxic T lymphocytes (CTLs) received little attention. Beneficial or pathogenic influence of PrPc-specific CTL was evaluated by stimulating a CD8+ T-cell-only response against PrP in scrapie-infected C57BL/6 mice. To circumvent immune tolerance to PrP, five PrP-derived nonamer peptides identified using prediction algorithms were anchored-optimized to improve binding affinity for H-2Db and immunogenicity (NP-peptides). All of the NP-peptides elicited a significant number of IFNγ secreting CD8+ T cells that better recognized the NP-peptides than the natives; three of them induced T cells that were lytic in vivo for NP-peptide-loaded target cells. Peptides 168 and 192 were naturally processed and presented by the 1C11 neuronal cell line. Minigenes encoding immunogenic NP-peptides inserted into adenovirus (rAds) vectors enhanced the specific CD8+ T-cell responses. Immunization with rAd encoding 168NP before scrapie inoculation significantly prolonged the survival of infected mice. This effect was attributable to a significant lengthening of the symptomatic phase and was associated with enhanced CD3+ T cell recruitment to the CNS. However, immunization with Ad168NP in scrapie-incubating mice induced IFNγ-secreting CD8+ T cells that were not cytolytic in vivo and did not influence disease progression nor infiltrated the brain. In conclusion, the data suggest that vaccine-induced PrP-specific CD8+ T cells interact with prions into the CNS during the clinical phase of the disease. [Copyright &y& Elsevier]

Several hurdles must be overcome in order to achieve efficient and safe immunotherapy against conformational neurodegenerative diseases. In prion diseases, the main difficulty is that the prion protein is tolerated as a self protein, which prevents powerful immune responses. Passive antibody therapy is effective only during early, asymptomatic disease, well before diagnosis is made. If efficient immunotherapy of prion diseases is to be achieved, it is crucial to understand precisely how immune tolerance against the prion protein can be overcome and which effector pathways may delay disease progression. To this end, we generated a transgenic mouse that expresses the β-chain of a T cell receptor recognizing a PrP epitope presented by the class II major histocompatibility complex. The fact that the constraint is applied to only one TCR chain allows adaptation of the other chain according to the presence or absence of tolerogenic PrP. We first show that transgene-bearing T cells, pairing with rearranged α-chains conferring anti-PrP specificity, are systematically eliminated during ontogeny in PrP+ mice, suggesting that precursors with good functional avidity are rare in a normal individual. Second, we show that transgene-bearing T cells with anti-PrP specificity are not suppressed when transferred into PrP+ recipients and proliferate more extensively in a prion-infected host. Finally, such T cells provide protection through a cell-mediated pathway involving IL-4 production. These findings support the idea that cell-mediated immunity in neurodegenerative conditions may not be necessarily detrimental and may even contribute, when properly controlled, to the resolution of pathological processes. [ABSTRACT FROM AUTHOR]

In prion diseases, PrPc, a widely expressed protein, is transformed into a pathogenic form called PrPSc, which is in itself infectious. Antibodies directed against PrPc have been shown to inhibit PrPc to PrPSc conversion in vitro and protect in vivo from disease. Other effectors with potential to eliminate PrPSc-producing cells are cytotoxic T cells directed against PrPderived peptides but their ability to protect or to induce deleterious autoimmune reactions is not known. The natural tolerance to PrPc makes difficult to raise efficient adaptive responses. To break tolerance, adenovirus (Ad) encoding human PrP (hPrP) or control Ad were administered to wild-type mice by direct injection or by transfer of Ad-transduced dendritic cells (DCs). Control Ad-transduced DCs from Tg650 mice overexpressing hPrP were also used for immunization. DCmediated but not direct administration of AdhPrP elicited antibodies that bound to murine native PrPc. Frequencies of PrPspecific IFNγ-secreting T cells were low and in vivo lytic activity only targeted cells strongly expressing hPrP. Immunohistochemical analysis revealed that CD3+ T cell infiltration was similar in the brain of vaccinated and unvaccinated 139A-infected mice suggesting the absence of autoimmune reactions. Early splenic PrPSc replication was strongly inhibited ten weeks post infection and mean survival time prolonged from 209 days in untreated 139A-infected mice to 246 days in mice vaccinated with DCs expressing the hPrP. The efficacy appeared to be associated with antibody but not with cytotoxic cell-mediated PrP-specific responses. [ABSTRACT FROM AUTHOR]

NORX is an authenticated encryption scheme with associated data that was selected, along with 14 other primitives, for the third phase of the ongoing CAESAR competition. It is based on the sponge construction and relies on a simple permutation that allows efficient and versatile implementations. Thanks to research on the security of the sponge construction, the design of NORX, whose permutation is inspired from the permutations used in BLAKE and ChaCha, has evolved throughout three main versions (v1.0, v2.0 and v3.0). The main result of this paper is a cryptanalysis of the full NORX v2.0 that successfully passed, in 2016, the second round of the CAESAR competition. We exhibit a strong symmetry preservation property of the underlying sponge permutation and show that this property can be turned into an attack on the full primitive. This attack yields a ciphertext-only forgery with time and data complexity 2 66 (resp. 2 130 ) for the variant of NORX v2.0 using 128-bit (resp. 256-bit) keys and breaks the designers' claim of a 128-bit (resp. 256-bit) security. We further show that this forgery attack can be extended to a key-recovery attack on the full NORX v2.0 with the same time and data complexities. We have implemented and experimentally verified the correctness of the attacks on a toy version of NORX v2.0. We also investigate the security of the NORX v3.0, a tweaked version of NORX v2.0 introduced at the beginning of the third round of the CAESAR competition. The introduction in NORX v3.0 of an extra initial and final key addition thwarts the former forgery and key-recovery attacks. We exhibit, however, a long-message forgery attack on both NORX v2.0 and NORX v3.0 that, given the ciphertext of a 2 m -block message, allows to forge another 2 m -block ciphertext with a success probability of about 2 m - 128 (resp. 2 m - 256 ) instead of 2 - 128 (resp. 2 - 256 ) as one would ideally expect. We further show that since the symmetry preservation of the NORX v2.0 permutation persists in NORX v3.0, the former long-message forgery attack can be extended in both versions to a state-recovery attack. This high-complexity attack does not threaten the practical security of NORX v3.0, but show that the security loss once a successful forgery has been issued is larger than one would expect. [ABSTRACT FROM AUTHOR]

Background: One of the main issues in biobanking is the establishment of standard operating procedures for specimen collection, preparation and storage to control for pre-analytical variation. For biological fluids such as serum, there is currently a lack of sensitive biomarkers for the quality control of cryopreservation conditions. Methods: The process approach was used to establish an ISO 9001:2000 quality management system. Immunoenzymatic and functional assays were used to assess the stability of the following candidate quality control biomarkers: secretory phospholipase A2, matrix metalloprotease 7, transforming growth factor β1 and anti-HBs immunoglobulin. Results: Five product processes and their corresponding indicators were identified. In the preparation-aliquoting-storage process, no quality control indicator for serum was identified. Only matrix metalloprotease 7 showed moderate susceptibility to freeze-thaw cycles. Conclusions: Biomarkers that have an on-off response to temperature variation could serve as quality indicators for the core processes of biobanking, which are the preparation and storage of biological fluids. The identification of such biomarkers is needed. Clin Chem Lab Med 2007;45:1390–5. [ABSTRACT FROM AUTHOR]

• Weakly stabilized and positively charged AuNP aggregate with proteins. • Antifouling ability carried by strongly capped, neutral and negatively charged AuNP. • Hemolysis increased by weakly stabilized and positively charged particles. • Hemolysis decreased by strongly capped and negatively charged particles. Gold nanoparticle (AuNP) interaction with the blood compartment as a function of their charge and the binding energy of their surface ligand was explored. Citrate, polyallylamine and cysteamine stabilized AuNP along with dihydrolipoic acid and polyethylene glycol capped AuNP were synthesized and fully characterized. Their interactions with model proteins (human albumin and human fibrinogen) were studied. Complexes formed between AuNP and protein revealed several behaviors ranging from corona formation to aggregation. Protein fluorescence quenching as a function of temperature and AuNP concentration allowed the determination of the thermodynamic parameters describing these interactions. The hemolysis induced by AuNP was also probed: an increasing or a decreasing of hemolysis ratio induced by AuNP was observed as of function of protein corona formation. Taken together, our results drew up a composite sketch of an ideal surface ligand for blood compatible AuNP. This capping agent should be strongly bound to the gold core by one or more thiol groups and it must confer a negative charge to the particles. [ABSTRACT FROM AUTHOR]