Design of innovative nanoformulations for topical treatment of psoriasis and evaluation of JAK/STAT pathway inhibition in a mouse model of induced psoriasis

Le psoriasis est une dermatose inflammatoire chronique affectant 2 à 3 % de la population européenne. Les cytokines pro-inflammatoires ont un rôle crucial dans la pathogénèse du psoriasis. Parmi les voies de signalisation cytokinique, l'étude de la voie JAK/STAT a conduit au développement de traitements systémiques efficaces. Cependant, les essais cliniques évaluant les inhibiteurs JAK/STAT impliquent en grande majorité des administrations orales, la voie topique restant marginale. Le développement de formulations innovantes pour application topique contenant des inhibiteurs JAK/STAT semble être une stratégie prometteuse dans le cadre du psoriasis. Les nanoparticules de poly(acide lactique) (NP PLA) développées au laboratoire ont été étudiées pour la délivrance topique de principes actifs. Ce sont des vecteurs efficaces, qui s'accumulent dans les follicules pileux. De plus, l'encapsulation d'actifs dans des NP PLA permet une libération spécifique au niveau du site d'action, et donc une réduction de la toxicité. L'objectif de ce travail est d'élaborer des formulations semi-solides de NP PLA contenant un inhibiteur JAK/STAT pour le traitement topique du psoriasis, tout en caractérisant un modèle in vivo de psoriasis induit par applications d'Imiquimod. Cette caractérisation des lésions psoriasiformes permettra l'évaluation in vivo des nanoformulations topiques contenant des inhibiteurs JAK/STAT. Cinq formulations ont été élaborées puis caractérisées afin de répondre aux attentes galéniques pour une application topique. L'intégrité des NP PLA a été vérifiée, et la pénétration/perméation de molécules modèles à travers de la peau de souris inflammée a été évaluéePsoriasis is a chronic inflammatory skin disease, affecting 2 to 3 % of European population. Inflammatory cytokines play a crucial role in the pathogenesis of psoriasis. Among cytokines signaling pathways, JAK/STAT pathway has been widely investigated, leading to the development of efficient systemic agents. However, current clinical trials evaluating JAK/Sat inhibitors mainly involve oral administrations, with few investigations on topical route. Developing innovative drug delivery systems for topical application of JAK/STAT inhibitors seems a promising strategy for psoriasis treatment. Poly(lactic acid) nanoparticles (PLA NPs) developed in the laboratory have been widely investigated for topical drug delivery and are efficient carriers for local dermatotherapy, especially through hair follicles. Moreover, drug encapsulation in PLA NPs for topical delivery allows a specific delivery to the site of action, and thus a decreased toxicity.The aim of this work was to elaborate semi-solid formulations of PLA NPs containing JAK/STAT inhibitors for topical treatment of psoriasis, while characterizing an in vivo model of Imiquimod-induced psoriasis in mice. This characterization of psoriasis-like skin lesions in Imiquimod treated mice provided key tools for in vivo evaluation of topical nanoformulations containing JAK/STAT inhibitors. Five formulations have been developed and then characterized in order to meet galenic criteria for topical drug administration. PLA NPs integrity was assessed, and penetration/permeation profiles of model dugs through inflamed mice skin were determine

Reasons for delays to orthopaedic and trauma surgery: A retrospective five-year cohort

International audienceBackgroundEarly surgery seeks to decrease peri-operative complication rates and mean hospital stay lengths while also improving patient satisfaction. Few data exist on optimising care before orthopaedic and trauma surgery (OTS), notably regarding delays to surgery after admission. The objective of this study was to identify reasons for OTS delays at a university-hospital OTS centre in France. Surgery was defined as delayed if performed more than 48 h after admission.HypothesisSome reasons for OTS delays are amenable to modification by measures aimed at decreasing the adverse impact of long wait times.Material and methodWe conducted a retrospective single-centre observational study. Of 18 495 who underwent surgery at the OTS centre of the Clermont-Ferrand university hospital in 2015–2019, 1946 had a post-admission wait time longer than 48 h. After exclusion of repeat surgical procedures and dressing changes, 1175 patients remained for the analysis. The records of each patient were reviewed to identify the reason for the surgical delay.ResultsA delay longer than 48 h was noted for 6.3% of OTS procedures. The most common reasons were limited resource availability (e.g., of operating theatres, nurses, or anaesthesia teams) (21.3%) and patient treatment by anticoagulants (20.9%).ConclusionMost delays were due to reasons independent from the patients operating-theatre logistics, delays in obtaining investigations) that could be targeted by those involved with operating-theatre management to diminish both surgical delays and hospital stay lengths.Level of evidenceIV, retrospective observational cohort study

Biodegradable Polymeric Nanoparticles-Based Vaccine Adjuvants for Lymph Nodes Targeting

Vaccines have successfully eradicated a large number of diseases. However, some infectious diseases (such as HIV, Chlamydia trachomatis or Bacillus anthracis) keep spreading since there is no vaccine to prevent them. One way to overcome this issue is the development of new adjuvant formulations which are able to induce the appropriate immune response without sacrificing safety. Lymph nodes are the site of lymphocyte priming by antigen-presenting cells and subsequent adaptive immune response, and are a promising target for vaccine formulations. In this review, we describe the properties of different polymer-based (e.g., poly lactic-co-glycolic acid, poly lactic acid …) particulate adjuvants as innovative systems, capable of co-delivering immunopotentiators and antigens. We point out how these nanoparticles enhance the delivery of antigens, and how their physicochemical properties modify their uptake by antigen-presenting cells and their migration into lymph nodes. We describe why polymeric nanoparticles increase the persistence into lymph nodes and promote a mature immune response. We also emphasize how nanodelivery directs the response to a specific antigen and allows the induction of a cytotoxic immune response, essential for the fight against intracellular pathogens or cancer. Finally, we highlight the interest of the association between polymer-based vaccines and immunopotentiators, which can potentiate the effect of the molecule by directing it to the appropriate compartment and reducing its toxicity

Short stems reproduce femoral offset better than standard stems in total hip arthroplasty: a case-control study

International audienceIntroduction: In total hip arthroplasty (THA), altering the original offset can lead to poor outcome or even complications or revision when the changes are too great. The aim of the present study was to compare femoral offset between short and standard stems. The hypothesis was that the short stems studied provide better control of postoperative femoral offset. Patients and methods: We retrospectively reviewed 100 consecutive THAs using uncemented optimys™ short stems (Mathys, Bettlach, Switzerland), matched to 100 standard-stem THAs performed during the same period. The primary endpoint was femoral offset; secondary endpoints were limb length and cervico-diaphyseal angle. Results: Mean femoral offset increased by 6.0 +/-7.2 mm overall (p< 0.0001): 4.7 +/-6.7 mm in the short-stem group (p<0.0001), and 7.2 +/-7.5 mm in the standard-stem group (p<0.0001), with a significant inter-group difference (p=0.0152). Limb length showed no significant inter-group difference (p=0.8425). Cervico-diaphyseal angle was increased by surgery overall, and more by standard than by short stems (p<0.05). Conclusion: Measurement of femoral offset revealed significant lateralization. It is critical that offset should be maintained in THA. The technique we use increases femoral offset, but the present study showed less increase using short than standard stems. These findings must be borne in mind to achieve good outcome

Advanced Characterization of Imiquimod-Induced Psoriasis-Like Mouse Model

Many autoimmune disorders such as psoriasis lead to the alteration of skin components which generally manifests as unwanted topical symptoms. One of the most widely approved psoriasis-like animal models is the imiquimod (IMQ)-induced mouse model. This representation mimics various aspects of the complex cutaneous pathology and could be appropriate for testing topical treatment options. We perform a thorough characterization of this model by assessing some parameters that are not fully described in the literature, namely a precise description of skin disruption. It was evaluated by transepidermal water loss measurements and analyses of epidermis swelling as a consequence of keratinocyte hyperproliferation. The extent of neo-angiogenesis and hypervascularity in dermis were highlighted by immunostaining. Moreover, we investigated systemic inflammation through cytokines levels, spleen swelling and germinal centers appearance in draining lymph nodes. The severity of all parameters was correlated to IMQ concentration in skin samples. This study outlines new parameters of interest useful to assess this model. We highlight the skin barrier disruption and report a systemic inflammatory reaction occurring at distance both in spleen and lymph nodes. These newly identified biological endpoints could be exploited to investigate the efficacy of therapeutic candidates for psoriasis and more extensively for several other skin inflammatory diseases

Management of pain induced by exercise and mobilization during physical therapy programs: views of patients and care providers

<p>Abstract</p> <p>Background</p> <p>The expectations of patients for managing pain induced by exercise and mobilization (PIEM) have seldom been investigated. We identified the views of patients and care providers regarding pain management induced by exercise and mobilization during physical therapy programs.</p> <p>Methods</p> <p>We performed a qualitative study based on semi-structured interviews with a stratified sample of 12 patients (7 women) and 14 care providers (6 women): 4 general practitioners [GPs], 1 rheumatologist, 1 physical medicine physician, 1 geriatrician, 2 orthopedic surgeons, and 5 physical therapists.</p> <p>Results</p> <p>Patients and care providers have differing views on PIEM in the overall management of the state of disease. Patients' descriptions of PIEM were polymorphic, and they experienced it as decreased health-related quality of life. The impact of PIEM was complex, and patient views were sometimes ambivalent, ranging from denial of symptoms to discontinuation of therapy. Care providers agreed that PIEM is generally not integrated in management strategies. Care providers more often emphasized the positive and less often the negative dimensions of PIEM than did patients. However, the consequences of PIEM cited included worsened patient clinical condition, fears about physical therapy, rejection of the physical therapist and refusal of care. PIEM follow-up is not optimal and is characterized by poor transmission of information. Patients expected education on how better to prevent stress and anxiety generated by pain, education on mobilization, and adaptations of physical therapy programs according to pain intensity.</p> <p>Conclusion</p> <p>PIEM management could be optimized by alerting care providers to the situation, improving communication among care providers, and providing education to patients and care providers.</p