The effect of pressurized carbon dioxide as a temporary plasticizer and foaming agent on the hot stage extrusion process and extrudate properties of solid dispersions of itraconazole with PVP-VA 64.

The aim of the current research project was to explore the possibilities of combining pressurized carbon dioxide with hot stage extrusion during manufacturing of solid dispersions of itraconazole and polyvinylpyrrolidone-co-vinyl acetate 64 (PVP-VA 64) and to evaluate the ability of the pressurized gas to act as a temporary plasticizer as well as to produce a foamed extrudate. Pressurized carbon dioxide was injected into a Leistritz Micro 18 intermeshing co-rotating twin-screw melt extruder using an ISCO 260D syringe pump. The physicochemical characteristics of the extrudates with and without injection of carbon dioxide were evaluated with reference to the morphology of the solid dispersion and dissolution behaviour and particle properties. Carbon dioxide acted as plasticizer for itraconazole/PVP-VA 64, reducing the processing temperature during the hot stage extrusion process. Amorphous dispersions were obtained and the solid dispersion was not influenced by the carbon dioxide. Release of itraconazole from the solid dispersion could be controlled as a function of processing temperature and pressure. The macroscopic morphology changed to a foam-like structure due to expansion of the carbon dioxide at the extrusion die. This resulted in increased specific surface area, porosity, hygroscopicity and improved milling efficiency.     

T-cell vaccination in multiple sclerosis: update on clinical application and mode of action

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). Autoreactive T cells specific for myelin antigens are considered to play a prominent role in the initiation of the local inflammatory response, ultimately leading to myelin damage. Several studies indicate that autoreactive T cells are not completely deleted in the thymus, but are part of the normal T cell repertoire. Accidentally activated autoreactive T cells, however, may not automatically lead to autoimmune disease. Several reports support the existence of peripheral regulatory networks that prevent the activation and expansion of pathogenic T cells. Anti-idiotypic and anti-ergotypic T cells are part of this regulatory network and are thought to control autoreactive T cells by recognition of certain clonotypic and ergotypic determinants. These clonotypic networks may not function properly in patients with MS. Immunization with attenuated autoreactive T cells, termed T cell vaccination (TCV), may enhance or restore the regulatory networks to specifically suppress the autoreactive T cells as shown in experimental autoimmune encephalomyelitis (EAE), a commonly used animal model for MS. In the past decade, TCV has been tested for MS in several clinical trails. This review summarizes these clinical trails and updates our current knowledge on the mode of action of T cell vaccination.     

Clonal expansion of myelin basic protein-reactive T cells in patients with multiple sclerosis: Restricted T cell receptor V gene rearrangements and CDR3 sequence

Myelin basic protein (MBP)-reactive T cells are thought to play an important role in the pathogenesis of multiple sclerosis (MS). In some patients with MS, these autoreactive T cells display a limited heterogeneity in their epitope recognition and T cell receptor (TCR) variable (V) gene usage. These individual-dependent properties of MBP-reactive T cells have led to the speculation that they may represent clonal expansion in vivo in some MS patients. In the present study, 51 MBP-reactive T cell clones derived from patients with MS and healthy individuals were examined for their epitope recognition and the TCR Vα and Vβ gene rearrangements. The V gene junctional region sequences of identified α and β genes were further analyzed to probe their clonal origins, as the sequences are unique for individual clones. Our data showed that 26 clones derived from nine patients with MS shared a predominant reactivity to the immunodominant regions of MBP, 84–102, 110–129 and 143–168, and used various TCR Vα and Vβ rearrangements. The V gene usage of the clones was restricted to certain Vα Vβ combination(s) in a given MS patient, but varied among different patients. The sequence analysis revealed that the clones generated from a given patient shared a limited or a single junctional region sequence pattern(s), indicating their oligoclonal or monoclonal origin(s). In contrast, 25 MBP-reactive T cell clones derived from normal individuals exhibited unfocused epitope recognition and V gene usage. Thus, the limited heterogeneity of MBP-reactive T cells in their structural and functional charactertistics reflects their clonal expansion in vivo in some patients with MS.     

Osteoprotegerin and receptor activator of nuclear factor-kappaB ligand mRNA expression in patients with rheumatoid arthritis and healthy controls

OBJECTIVE: To further understand the role of osteoprotegerin (OPG) and receptor activator of nuclear factor-kappaB ligand (RANK-L) in rheumatoid arthritis (RA), we studied the levels of RANK-L and OPG mRNA in peripheral blood mononuclear cells (PBMC) and synovial tissue of patients with RA and controls. METHODS: RANK-L and OPG mRNA levels were measured in PBMC and CD4+/CD8+ T cell subsets of patients with chronic RA, osteoarthritis (OA), and healthy controls, using quantitative real-time polymerase chain reaction. OPG and RANK-L mRNA levels were measured in paired blood and synovial tissue samples of patients with early, untreated RA at 2 timepoints with an interval of 16 weeks. RESULTS: RANK-L mRNA levels were significantly higher in PBMC of patients with early and chronic RA compared to healthy controls. Contrary to healthy controls, RANK-L mRNA levels in patients with chronic RA were mainly of CD4+ T cell origin. OPG mRNA was observed in the blood of all (17/17) early RA patients, but could not be detected in chronic RA patients (0/14) or in patients with OA (0/8). Three out of 17 healthy controls showed measurable levels of OPG mRNA. The OPG/RANK-L ratio tended to be higher in the synovium than in the PBMC of early RA patients. RANK-L mRNA in synovial tissue was mainly of non-T cell origin. CONCLUSION: Since RANK-L and OPG mRNA levels are elevated in PBMC of RA patients, and CD4+ T cells are the major contributors to RANK-L mRNA expression, mononuclear cells in patients with RA may be involved in the pathways that regulate bone metabolism.     

Extended,virtual and augmented reality in thoracic surgery: a systematic review

 Open in a separate windowOBJECTIVESExtended reality (XR), encompassing both virtual reality (VR) and augmented reality, allows the user to interact with a computer-generated environment based on reality. In essence, the immersive nature of VR and augmented reality technology has been warmly welcomed in all aspects of medicine, gradually becoming increasingly feasible to incorporate into everyday practice. In recent years, XR has become increasingly adopted in thoracic surgery, although the extent of its applications is unclear. Here, we aim to review the current applications of XR in thoracic surgery.METHODSA systematic database search was conducted of original articles that explored the use of VR and/or augmented reality in thoracic surgery in EMBASE, MEDLINE, Cochrane database and Google Scholar, from inception to December 2020.RESULTSOur search yielded 1494 citations, of which 21 studies published from 2007 to 2019 were included in this review. Three main areas were identified: (i) the application of XR in thoracic surgery training; (ii) preoperative planning of thoracic procedures; and (iii) intraoperative assistance. Overall, XR could produce progression along the learning curve, enabling trainees to reach acceptable standards before performing in the operating theatre. Preoperatively, through the generation of 3D-renderings of the thoracic cavity and lung anatomy, VR increases procedural accuracy and surgical confidence through familiarization of the patient’s anatomy. XR-assisted surgery may have therapeutic use particularly for complex cases, where conventional methods would yield inadequate outcomes due to inferior accuracy.CONCLUSIONXR represents a salient step towards improving thoracic surgical training, as well as enhancing preoperative planning and intraoperative guidance.