[How to recognize a patient with palliative needs : a «surprise¼ question to prevent bad surprises]. / Comment reconnaître un patient en situation palliative ? Une question «surprise¼ pour ne plus se laisser surprendre.

Early discussion on palliative care with patients with advanced, progressive or terminal disease is difficult regardless patient's life expectancy. In Belgium, a Royal Decree sets the criteria to identify patients with palliative needs. For that purpose, the Palliative Care Indicators Tool (PICT) is proposed. This 3-step identification tool designed for physicians begins with the so-called surprise question, «Would you be surprised if your patient died in the next 6 to 12 months?¼. The second and third steps examine the fragility and incurability criteria, respectively. The surprise question intends to encourage the clinician to trust his/her intuition and to promote a reflection on patient's needs. The PICT facilitates communication between caregivers. Also, it makes possible early thinking about advanced care planning. Hence, it allows patients to receive palliative care in due time. In this paper, after reviewing the background of the surprise question, we shall examine the benefits and limitations of the surprise question.

Parler de soins palliatifs précocement chez les patients lorsqu'ils se trouvent à un stade avancé ou terminal d'une maladie grave, évolutive, mettant en péril le pronostic vital, quelle que soit son espérance de vie, reste difficile. La loi belge s'est dotée en octobre 2018 d'un arrêté royal proposant le PICT (Palliative Care Indicators Tool). Cette échelle d'identification, conçue en 3 étapes, débute par la question surprise : «Seriez-vous surpris si votre patient venait à décéder dans les 6 à 12 prochains mois??¼. La deuxième étape et la troisième étape déterminent respectivement les critères de fragilité et d'incurabilité. La question surprise encourage le clinicien à faire confiance à son intuition et valorise une réflexion centrée sur les besoins du patient. L'utilisation de l'outil PICT peut faciliter la communication entre soignants, permettre d'aborder plus tôt la réflexion autour de la planification anticipée des soins et offrira ainsi aux patients des soins palliatifs en temps opportun. Cet article présente l'historique de la question surprise ainsi que ses avantages et ses limites.

[Appropriate care at the end of life : insuring quality of life]. / Une bonne gestion de la fin de vie, ou le respect de la qualité de vie .

Progress of medical knowledge pushed the limits of medicine. This raises major ethical issues. The Belgian lawmaker, concerned to ensure the observance of Human Rights, attempted to regulate some of these issues. It remains essential to listen to the patient and to respect his/her will. Likewise, defining therapeutic goals based on patient's values and priorities is crucial until the end of patient's life.

: Les progrès scientifiques ont reculé les limites de la médecine. Ceci a conduit à d'importants débats éthiques. En Belgique, le législateur, soucieux du respect des Droits de l'Homme, a tenté de réglementer certaines pratiques. L'essentiel est d'écouter le patient et de respecter ses volontés. Il est capital de définir des objectifs thérapeutiques basés sur les valeurs et les priorités du patient, jusqu'à la fin de sa vie.

Solvent-exchange process in MOF ultrathin films and its effect on CO2 and methanol adsorption.

Metal-organic framework (MOF) activation is crucial for the use of MOFs in several applications and solvent-exchange process is a necessary step in many activation methods. In this contribution, we have explored in situ MOF monolayer film formation at the air-water interface. Nanoparticles (NPs) of the Al trimesate MIL-96(Al) retain chloroform into their micropores, which considerably diminishes the CO2 adsorption capacity of MOF films. However, a solvent-exchange process between chloroform and water increases CO2 film adsorption capacity by 30%. Total Reflection X-Ray Fluorescence (TRXF) allows studying the kinetics of this process at the air-water interface, that strongly depends on the NP size. The conclusions derived from in situ studies allow optimizing the ex situ activation procedure of MIL-96(Al) films deposited onto quartz crystal microbalance (QCM) substrates in order to maximize CO2 and methanol adsorption.

Gut microbiota composition modulates inflammation and structure of the vagal afferent pathway.

Vagal afferent neurons (VAN), located in the nodose ganglion (NG) innervate the gut and terminate in the nucleus of solitary tract (NTS) in the brainstem. They are the primary sensory neurons integrating gut-derived signals to regulate meal size. Chronic high-fat diet (HFD) consumption impairs vagally mediated satiety, resulting in overfeeding. There is evidence that HFD consumption leads to alterations in both vagal nerve function and structural integrity. HFD also leads to marked gut microbiota dysbiosis; in rodent models, dysbiosis is sufficient to induce weight gain. In this study, we investigated the effect of microbiota dysbiosis on gut-brain vagal innervation independently of diet. To do so, we recolonized microbiota-depleted rats with gastrointestinal (GI) contents isolated from donor animals fed either a HFD (45 or 60% fat) or a low fat diet (LFD, 13% fat). We used two different depletion models while maintaining the animals on LFD: 1) conventionally raised Fischer and Wistar rats that underwent a depletion paradigm using an antibiotic cocktail and 2) germ free (GF) raised Fischer rats. Following recolonization, receiver animals were designated as ConvLF and ConvHF. Fecal samples were collected throughout these studies and analyzed via 16S Illumina sequencing. In both models, bacteria that were identified as characteristic of HFD were successfully transferred to recipient animals. Three weeks post-colonization, ConvHF rats showed significant increases in ionized calcium-binding adapter molecule-1 (Iba1) positive immune cells in the NG compared to ConvLF animals. Additionally, using isolectin B4 (IB4) staining to identify c-fibers, we found that, compared to ConvLF animals, ConvHF rats displayed decreased innervation at the level of the medial NTS; c-fibers at this level are believed to be primarily of vagal origin. This alteration in vagal structure was associated with a loss in satiety induced by the gut peptide cholecystokinin (CCK). Increased presence of immunocompetent Iba1+ cells along the gut-brain axis and alterations in NTS innervation were still evident in ConvHF rats compared to ConvLF animals 12 weeks post-colonization and were associated with increases in food intake and body weight (BW). We conclude from these data that microbiota dysbiosis can alter gut-brain vagal innervation, potentially via recruitment and/or activation of immune cells.

[Progressive ataxia and falls in a 62 year old woman]. / La vignette diagnostique de l'étudiant. Ataxie subaiguë et chutes chez une patiente de 62 ans.

We discuss the diagnostic workup of a 62 year old woman without any significant past medical history. We take this opportunity to point out three aspects : 1. The necessary contextualization of the whole process allowing to avoid unrealistic differentials; 2. The requirement to prioritize the diagnostic tests as a function of their expected contribution to the diagnosis, their invasive characteristic and their availability, including their cost and 3. The evolving character of the diagnostic process that, if needed, has to be reconsidered to integrate the information obtained from the first diagnostic tests and the evolution of the patient.

Nous discutons la démarche sémiologique et diagnostique d'un cas d'ataxie chez une patiente de 62 ans, indemne de tout antécédent médical significatif. A l'occasion de cette vignette diagnostique, nous insistons sur trois aspects : 1. La nécessité de contextualiser la démarche pour éviter d'évoquer des diagnostics différentiels irréalistes; 2. La nécessité de choisir les examens complémentaires pertinents en les hiérarchisant en fonction de la probabilité de contribuer au diagnostic, de leur invasivité et de leur disponibilité, y compris de leur coût et 3. Le caractère évolutif de la démarche diagnostique qu'il faut pouvoir remettre en question au fil des informations que fournissent l'évolution du patient et les résultats des investigations.

Intrinsic and extrinsic regulation of human skin melanogenesis and pigmentation.

In human skin, melanogenesis is a tightly regulated process. Indeed, several extracellular signals are transduced via dedicated signalling pathways and mostly converge to MITF, a transcription factor integrating upstream signalling and regulating downstream genes involved in the various inherent mechanisms modulating melanogenesis. The synthesis of melanin pigments occurs in melanocytes inside melanosomes where melanogenic enzymes (tyrosinase and related proteins) are addressed with the help of specific protein complexes. The melanosomes loaded with melanin are then transferred to keratinocytes. A more elaborate level of melanogenesis regulation comes into play via the action of non-coding RNAs (microRNAs, lncRNAs). Besides this canonical regulation, melanogenesis can also be modulated by other non-specific intrinsic pathways (hormonal environment, inflammation) and by extrinsic factors (solar irradiation such as ultraviolet irradiation, environmental pollution). We developed a bioinformatic interaction network gathering the multiple aspects of melanogenesis and skin pigmentation as a resource to better understand and study skin pigmentation biology.

Fabrication of ultrathin MIL-96(Al) films and study of CO2 adsorption/desorption processes using quartz crystal microbalance.

This contribution reports the fabrication and characterization of ultrathin films of nanoparticles of the water stable microporous Al tricarboxylate metal organic framework MIL-96(Al). The preparation of MOF dispersions in chloroform has been optimized to obtain dense monolayer films of good quality, without nanoparticle agglomeration, at the air-water interface that can be deposited onto solid substrates of different nature without any previous substrate functionalization. The MOF studied shows great interest for CO2 capture because it presents Al3+ Lewis centers and hydroxyl groups that strongly interact with CO2 molecules. A comparative CO2 adsorption study on drop-cast, Langmuir-Blodgett (LB) and Langmuir-Schaefer (LS) films using a Quartz Crystal Microbalance-based setup (QCM) has revealed that the CO2 uptake depends strongly on the film fabrication procedure and the storage conditions. Noteworthy the CO2 adsorption capacity of LB films is increased by 30% using a simple and green treatment (immersion of the film into water during 12 h just after film preparation). Finally, the stability of LB MOF monolayers upon several CO2 adsorption/desorption cycles has been demonstrated, showing that CO2 can be easily desorbed from the films at 303 K by flowing an inert gas (He). These results show that MOF LB monolayers can be of great interest for the development of MOF-based devices that require the use of very small MOF quantities, especially gas sensors.

New insights into the degradation mechanism of metal-organic frameworks drug carriers.

A versatile method based on Raman microscopy was developed to follow the degradation of iron carboxylate Metal Organic Framework (MOF) nano- or micro-particles in simulated body fluid (phosphate buffer). The analysis of both the morphology and chemical composition of individual particles, including observation at different regions on the same particle, evidenced the formation of a sharp erosion front during particle degradation. Interestingly, this front separated an intact non eroded crystalline core from an amorphous shell made of an inorganic network. According to Mössbauer spectrometry investigations, the shell consists essentially of iron phosphates. Noteworthy, neither drug loading nor surface modification affected the integrity of the tridimensional MOF network. These findings could be of interest in the further development of next generations of MOF drug carriers.

Chitosan-coated mesoporous MIL-100(Fe) nanoparticles as improved bio-compatible oral nanocarriers.

Nanometric biocompatible Metal-Organic Frameworks (nanoMOFs) are promising candidates for drug delivery. Up to now, most studies have targeted the intravenous route, related to pain and severe complications; whereas nanoMOFs for oral administration, a commonly used non-invasive and simpler route, remains however unexplored. We propose here the biofriendly preparation of a suitable oral nanocarrier based on the benchmarked biocompatible mesoporous iron(III) trimesate nanoparticles coated with the bioadhesive polysaccharide chitosan (CS). This method does not hamper the textural/structural properties and the sorption/release abilities of the nanoMOFs upon surface engineering. The interaction between the CS and the nanoparticles has been characterized through a combination of high resolution soft X-ray absorption and computing simulation, while the positive impact of the coating on the colloidal and chemical stability under oral simulated conditions is here demonstrated. Finally, the intestinal barrier bypass capability and biocompatibility of CS-coated nanoMOF have been assessed in vitro, leading to an increased intestinal permeability with respect to the non-coated material, maintaining an optimal biocompatibility. In conclusion, the preservation of the interesting physicochemical features of the CS-coated nanoMOF and their adapted colloidal stability and progressive biodegradation, together with their improved intestinal barrier bypass, make these nanoparticles a promising oral nanocarrier.

Towards improved HIV-microbicide activity through the co-encapsulation of NRTI drugs in biocompatible metal organic framework nanocarriers.

The efficacy of the routinely used anti-HIV (Human Immunodeficiency Virus) therapy based on nucleoside reverse transcriptase inhibitors (NRTIs) is limited by the poor cellular uptake of the active triphosphorylated metabolites and the low efficiency of intracellular phosphorylation of their prodrugs. Nanoparticles of iron(iii) polycarboxylate Metal-Organic Frameworks (nanoMOFs) are promising drug nanocarriers. In this study, two active triphosphorylated NRTIs, azidothymidine triphosphate (AZT-Tp) and lamivudine triphosphate (3TC-Tp), were successfully co-encapsulated into the biocompatible mesoporous iron(iii) trimesate MIL-100(Fe) nanoMOF in order to improve anti-HIV therapies. The drug loaded nanoMOFs could be stored for up to 2-months and reconstituted after freeze drying, retaining similar physicochemical properties. Their antiretroviral activity was evidenced in vitro on monocyte-derived macrophages experimentally infected with HIV, making these co-encapsulated nanosystems excellent HIV-microbicide candidates.

Knockdown of Neuropeptide Y in the Dorsomedial Hypothalamus Promotes Hepatic Insulin Sensitivity in Male Rats.

Recent evidence has shown that alterations in dorsomedial hypothalamic (DMH) neuropeptide Y (NPY) signaling influence glucose homeostasis, but the mechanism through which DMH NPY acts to affect glucose homeostasis remains unclear. Here we report that DMH NPY descending signals to the dorsal motor nucleus of the vagus (DMV) modulate hepatic insulin sensitivity to control hepatic glucose production in rats. Using the hyperinsulinemic-euglycemic clamp, we revealed that knockdown of NPY in the DMH by adeno-associated virus-mediated NPY-specific RNAi promoted insulin's action on suppression of hepatic glucose production. This knockdown silenced DMH NPY descending signals to the DMV, leading to an elevation of hepatic vagal innervation. Hepatic vagotomy abolished the inhibitory effect of DMH NPY knockdown on hepatic glucose production, but this glycemic effect was not affected by vagal deafferentation. Together, these results demonstrate a distinct role for DMH NPY in the regulation of glucose homeostasis through the hepatic vagal efferents and insulin action on hepatic glucose production.

In vivo behavior of MIL-100 nanoparticles at early times after intravenous administration.

Metal-organic frameworks have shown interesting features for biomedical applications, such as drug delivery and imaging agents. The benchmarked mesoporous iron(III) trimesate MIL-100 MOF nanocarrier combines progressive release of high drug cargoes with absence of visible in vivo toxicity. Although in a previous study pharmacokinetics and biodistribution of MIL-100 nanoparticles were evaluated in the long term (from 24h to 1 month), the crucial times for drug targeting and delivery applications are shorter (up to 24h). Thus, this work aims to study the blood circulating profile and organ accumulation of MIL-100 nanocarrier at early times after administration. For this purpose, after intravenous administration to rats, both constitutive components of MIL-100 (trimesate and iron) were quantified by high performance liquid chromatography and a spectrophotometric method, respectively. The pharmacokinetic profile suggested that the nanoparticles act as a depot in the blood stream during the first hours before being cleared. Accumulation took mainly place in the liver and, in some extent, in the spleen. Nevertheless, histological studies demonstrated the absence of morphological alterations due to the presence of the particles in these organs. Liver function was however slightly altered as reflected by the increased plasma aspartate aminotransferase concentrations. Finally trimesate was progressively eliminated in urine.

Percutaneous absorption of benzophenone-3 loaded lipid nanoparticles and polymeric nanocapsules: A comparative study.

For the last years, the increase of the number of skin cancer cases led to a growing awareness of the need of skin protection against ultraviolet (UV) radiations. Chemical UV filters are widely used into sunscreen formulations as benzophenone-3 (BP-3), a usually used broad spectrum chemical UV filter that has been shown to exercise undesirable effects after topical application. Innovative sunscreen formulations are thus necessary to provide more safety to users. Lipid carriers seem to be a good alternative to formulate chemical UV filters reducing their skin penetration while maintaining good photo-protective abilities. The aim of this work was to compare percutaneous absorption and cutaneous bioavailability of BP-3 loaded into solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC), nanostructured polymeric lipid carriers (NPLC) and nanocapsules (NC). Particle size, zeta potential and in vitro sun protection factor (SPF) of nanoparticle suspensions were also investigated. Results showed that polymeric lipid carriers, comprising NPLC and NC, significantly reduced BP-3 skin permeation while exhibiting the highest SPF. This study confirms the interesting potential of NPLC and NC to formulate chemical UV filters.

Thermodynamics of the structural transition in metal-organic frameworks.

A thermodynamic study of the structural large-pore (LP) to narrow pore (NP) transition in various Metal Organic Frameworks (MOFs) is presented. First, the pressure induced transition at a constant temperature is investigated using a Tian-Calvet microcalorimeter set-up equipped with a high pressure cell. This device permits simultaneous measurements of the mechanical work and heat associated with the LP → NP transition. It is shown that MIL-53(Al) and MIL-53(Cr) have similar thermodynamic and mechanical behaviour whilst the MIL-47(V) system is characterized by much higher transition energy and mechanical work. Second, the temperature induced transition at ambient pressure is studied by means of differential scanning calorimetry (DSC) combined with X-ray absorption spectroscopy. This set-up enables one to follow simultaneously the structural changes associated with the phase transition detected by DSC. The MIL-53(Cr)-Br functionalized MOF is chosen here as a case study where both energetics and structural changes are discussed.

Antineoplastic busulfan encapsulated in a metal organic framework nanocarrier: first in vivo results.

Nanoparticles of a mesoporous iron(iii) trimesate MIL-100 nanocarrier encapsulating high amounts of the challenging antineoplastic busulfan were administered to rats and compared with the commercial Busilvex®. Large differences in serum concentration of both busulfan and trimesate revealed the great impact of drug encapsulation both on the drug and on nanoparticle pharmacokinetics during the first 24 h of administration.

Functionalization of Zr-based MOFs with alkyl and perfluoroalkyl groups: the effect on the water sorption behavior.

Stability and sorption of Metal-Organic Frameworks (MOFs) towards water are critical in many applications, and can a priori be modulated through the introduction of suitable organic functional groups on their backbone. We report here the preparation of a series of Zr(iv)-based MOFs functionalized with alkyl and perfluoroalkyl groups and their characterization by X-ray powder diffraction, multi-nuclei ((1)H, (13)C, (19)F) solid state nuclear magnetic resonance analyses, and nitrogen sorption measurements at 77 K. Their water sorption behavior was evaluated at 298 K and related to their physico-chemical features, highlighting both the effect of the confinement and the nature of the functional groups on the hydrophilic/hydrophobic balance.

Direct accessibility of mixed-metal (III/II) acid sites through the rational synthesis of porous metal carboxylates.

The scalable and environmentally-friendly synthesis of mixed Fe(III)/M(II) (M = Ni, Co, Mg) polycarboxylate porous MOFs based on the Secondary Building Unit approach is reported. A combination of in situ infrared spectroscopy, (57)Fe Mössbauer spectrometry and adsorption microcalorimetry confirms the direct accessibility of the iron(III) and metal(II) sites under low temperature activation conditions.

Neurochemical and electrophysiological deficits in the ventral hippocampus and selective behavioral alterations caused by high-fat diet in female C57BL/6 mice.

Mounting experimental evidence, predominantly from male rodents, demonstrates that high-fat diet (HFD) consumption and ensuing obesity are detrimental to the brain. To shed additional light on the neurological consequences of HFD consumption in female rodents and to determine the relatively early impact of HFD in the likely continuum of neurological dysfunction in the context of chronic HFD intake, this study investigated effects of HFD feeding for up to 12weeks on selected behavioral, neurochemical, and electrophysiological parameters in adult female C57BL/6 mice; particular focus was placed on the ventral hippocampus (vHIP). Selected locomotor, emotional and cognitive functions were evaluated using behavioral tests after 5weeks on HFD or control (low-fat diet) diets. One week later, mice were sacrificed and brain regional neurochemical (monoamine) analysis was performed. Behaviorally naïve mice were maintained on their respective diets for an additional 5-6weeks at which time synaptic plasticity was determined in ex vivo slices from the vHIP. HFD-fed female mice exhibited increased: (i) locomotor activity in the open field testing, (ii) mean turn time on the pole test, (iii) swimming time in the forced swim test, and (iv) number of marbles buried in the marble burying test. In contrast, the novel object recognition memory was unaffected. Mice on HFD also had decreased norepinephrine and dopamine turnover, respectively, in the prefrontal cortex and the vHIP. HFD consumption for a total of 11-12weeks altered vHIP synaptic plasticity, evidenced by significant reductions in the paired-pulse ratio and long-term potentiation (LTP) magnitude. In summary, in female mice, HFD intake for several weeks induced multiple behavioral alterations of mainly anxiety-like nature and impaired monoamine pathways in a brain region-specific manner, suggesting that in the female, certain behavioral domains (anxiety) and associated brain regions, i.e., the vHIP, are preferentially targeted by HFD.

A "green" strategy to construct non-covalent, stable and bioactive coatings on porous MOF nanoparticles.

Nanoparticles made of metal-organic frameworks (nanoMOFs) attract a growing interest in gas storage, separation, catalysis, sensing and more recently, biomedicine. Achieving stable, versatile coatings on highly porous nanoMOFs without altering their ability to adsorb molecules of interest represents today a major challenge. Here we bring the proof of concept that the outer surface of porous nanoMOFs can be specifically functionalized in a rapid, biofriendly and non-covalent manner, leading to stable and versatile coatings. Cyclodextrin molecules bearing strong iron complexing groups (phosphates) were firmly anchored to the nanoMOFs' surface, within only a few minutes, simply by incubation with aqueous nanoMOF suspensions. The coating procedure did not affect the nanoMOF porosity, crystallinity, adsorption and release abilities. The stable cyclodextrin-based coating was further functionalized with: i) targeting moieties to increase the nanoMOF interaction with specific receptors and ii) poly(ethylene glycol) chains to escape the immune system. These results pave the way towards the design of surface-engineered nanoMOFs of interest for applications in the field of targeted drug delivery, catalysis, separation and sensing.

Measurement, analysis and prediction of topical UV filter bioavailability.

The aim of the present study was to objectively quantify and predict bioavailability of three sunscreen agents (i.e., benzophenone-3, 2-ethylhexylsalicylate, and 2 ethylhexyl-4-methoxycinnamate) in epidermis treated by petrolatum and emulsion-based formulations for 7 and 30min on four human volunteers. Profiles of sunscreen agents through stratum corneum (SC), derived from the assessment of chemical amounts in SC layers collected by successive adhesive tape-stripping, were successfully fitted to Fick's second law of diffusion. Therefore, permeability coefficients of sunscreen agents were found lower with petrolatum than with emulsion based formulations confirming the crucial role of vehicle in topical delivery. Furthermore, the robustness of that methodology was confirmed by the linear relationship between the chemical absorption measured after 30min and that predicted from the 7-min exposure experiment. Interestingly, in this dermatopharmacokinetic method, the deconvolution of permeability coefficients in their respective partition coefficients and absorption constants allowed a better understanding of vehicle effects upon topical bioavailability mechanisms and bioequivalence of skin products.