The development and application of biological models for evaluation of direct nose-to-brain drug delivery systems

The olfactory neuroepithelium is the only part of the central nervous system that is exposed directly to the external environment. Therefore, it is the only non-invasive drug delivery route to the brain. Surface modification of PS nanoparticles with chitosan C-PS), polysorbate 80 (P80-PS) and polysorbate 80+FCS (P80-FCS-PS) changed the toxicity and distribution of these nanoparticles in olfactory mucosae. In addition, a reduction in nanoparticle diameter from 200nm to 20nm increased nanoparticle mucosal penetration and possibly also their cellular toxicity. In vitro vertical Franz diffusion chamber and in vivo mouse models were adapted to investigate the transport of nanoparticles via the olfactory system. For the in vitro model, preliminary studies found that olfactory epithelium lined the caudal portion of the dorsal nasal turbinate in the porcine nasal cavity. To ensure the scientific validity of the diffusion chamber studies, it was necessary to prove that the experimental procedures themselves (without the addition of nanoparticles) had no effect on the mounted tissue. Therefore, viability and cellular morphology of the dissected olfactory epithelia were assessed prior to application of nanoparticles to tissues. Alamar Blueâ„¢ viability and histological findings showed that the diffusion chamber experiment did not affect the olfactory tissue when compared to samples that were not mounted on the apparatus. Citrate buffer (pH6.0) had significantly reduced the viability (PD, Isc and Alamar Blueâ„¢) of the porcine olfactory epithelium compared to SNS buffer (pH7.4) but it did not kill it. Citrate buffer may have depleted the mucosal pH gradient in the epithelium. Overall both SNS buffered and citrate buffered porcine olfactory epithelia were suitable for nanoparticle transport studies in the vertical Franz diffusion cell. The in vitro and in vivo biological models showed surface modification had changed the distribution of nanoparticles within the epithelia. There was good agreement between particle losses from donor chamber, fluorescence microscopy images and stereology results that C-PS particles adhered to extracellular mucus to a greater extent compared to PS and P80-FCS-PS. P80-PS nanoparticles were taken into the nasal epithelial cells to a greater extent than C-PS. Nanoparticles were not transported to the receiver chamber in vitro or the olfactory bulbs in vivo. The size of the nanoparticles was also important. Fluorescence microscopy and stereology showed that greater numbers of 100nm PS and 100nm P80-FCS-PS were taken up into mouse olfactory epithelial cells compared to 200nm diameter equivalents. Larger particles may not have penetrated mucus as effectively as smaller ones. Bright field microscopy images of olfactory epithelia dismounted from the diffusion chamber apparatus after transport study with C-PS nanoparticles showed that these particles caused the greatest amount of cellular damage compared to PS, P80-PS and P80-FCS-PS systems. Greater damage was observed for progressively smaller particles. For example, 20nm C-PS may have accessed subcellular organelles such as mitochondria to cause cell death by oxidative stress. However, similar findings in the mouse model were not observed. It was hypothesised that, unlike the in vitro model, the mouse model may have been able to maintain a pH gradient across the mucous layer by neutralising the acidity from the citrate buffer using blood borne HCO3- ions. This would protect the epithelial cells by causing C-PS to aggregate in the mucus thereby preventing them from accessing the epithelial cells

The development and application of biological models for evaluation of direct nose-to-brain drug delivery systems

The olfactory neuroepithelium is the only part of the central nervous system that is exposed directly to the external environment. Therefore, it is the only non-invasive drug delivery route to the brain. Surface modification of PS nanoparticles with chitosan C-PS), polysorbate 80 (P80-PS) and polysorbate 80+FCS (P80-FCS-PS) changed the toxicity and distribution of these nanoparticles in olfactory mucosae. In addition, a reduction in nanoparticle diameter from 200nm to 20nm increased nanoparticle mucosal penetration and possibly also their cellular toxicity. In vitro vertical Franz diffusion chamber and in vivo mouse models were adapted to investigate the transport of nanoparticles via the olfactory system. For the in vitro model, preliminary studies found that olfactory epithelium lined the caudal portion of the dorsal nasal turbinate in the porcine nasal cavity. To ensure the scientific validity of the diffusion chamber studies, it was necessary to prove that the experimental procedures themselves (without the addition of nanoparticles) had no effect on the mounted tissue. Therefore, viability and cellular morphology of the dissected olfactory epithelia were assessed prior to application of nanoparticles to tissues. Alamar Blueâ„¢ viability and histological findings showed that the diffusion chamber experiment did not affect the olfactory tissue when compared to samples that were not mounted on the apparatus. Citrate buffer (pH6.0) had significantly reduced the viability (PD, Isc and Alamar Blueâ„¢) of the porcine olfactory epithelium compared to SNS buffer (pH7.4) but it did not kill it. Citrate buffer may have depleted the mucosal pH gradient in the epithelium. Overall both SNS buffered and citrate buffered porcine olfactory epithelia were suitable for nanoparticle transport studies in the vertical Franz diffusion cell. The in vitro and in vivo biological models showed surface modification had changed the distribution of nanoparticles within the epithelia. There was good agreement between particle losses from donor chamber, fluorescence microscopy images and stereology results that C-PS particles adhered to extracellular mucus to a greater extent compared to PS and P80-FCS-PS. P80-PS nanoparticles were taken into the nasal epithelial cells to a greater extent than C-PS. Nanoparticles were not transported to the receiver chamber in vitro or the olfactory bulbs in vivo. The size of the nanoparticles was also important. Fluorescence microscopy and stereology showed that greater numbers of 100nm PS and 100nm P80-FCS-PS were taken up into mouse olfactory epithelial cells compared to 200nm diameter equivalents. Larger particles may not have penetrated mucus as effectively as smaller ones. Bright field microscopy images of olfactory epithelia dismounted from the diffusion chamber apparatus after transport study with C-PS nanoparticles showed that these particles caused the greatest amount of cellular damage compared to PS, P80-PS and P80-FCS-PS systems. Greater damage was observed for progressively smaller particles. For example, 20nm C-PS may have accessed subcellular organelles such as mitochondria to cause cell death by oxidative stress. However, similar findings in the mouse model were not observed. It was hypothesised that, unlike the in vitro model, the mouse model may have been able to maintain a pH gradient across the mucous layer by neutralising the acidity from the citrate buffer using blood borne HCO3- ions. This would protect the epithelial cells by causing C-PS to aggregate in the mucus thereby preventing them from accessing the epithelial cells

#BlackLivesMatter (2020)

‘6 foot 9?’ Another guess going wide of the mark from our third conscious and breathing patient of the shift—a guess coming a few minutes after my sigh of relief and stand down of helimed as it had come through as a confirmed choking. The life of a black paramedic in England is slightly difficult to contextualise. It is easy to say ‘my experience is my experience only’, but more often than not, I feel my experience is probably a carbon copy of that of other black staff. https://www.magonlinelibrary.com/doi/full/10.12968/jpar.2020.12.7.290 Abstract published with permission

Chondromyxoid fibroma of the iliac bone: a brief radiological review

Chondromyxoid fibroma (CMF) is a rare, benign bone tumour most commonly located within the metaphyseal region of the long bones surrounding the knee joint. Here, we present an interesting case of a young woman in her early 20s with CMF of the left iliac bone and include a literature review of comparable studies with an emphasis on radiological findings and important differential diagnoses to be aware of in this atypical location

Settings and indications of ultrasound in imaging of shoulder, foot, and ankle

Ultrasonography is a well-established musculoskeletal imaging technique with a multitude of advantages when compared to other modalities. It provides great spatial resolution in the evaluation of superficial articular and peri-articular structures including tendons, ligaments, bursae, and nerves. Given that it is the only modality which allows dynamic assessment, it also plays a crucial role in diagnosing impingement, subluxation/dislocation, and instability. The purpose of this article is to review the settings and indications of US in the imaging of shoulder, foot, and ankle in particular. Relevant literature, predominantly in the form of peer-reviewed journal articles was obtained from the electronic databases such as PubMed and MEDLINE and reviewed in a structured manner. This was combined with background knowledge and expertise in this field

Incidental findings in sports imaging

This narrative review presents a series of cases of less common incidental findings discovered on magnetic resonance imaging of elite athletes, who have presented for investigation of either muscle or joint sports-related injuries or for presigning imaging. The presented incidental findings include anatomical variants of osseous structures and muscles; incidental bone lesions; examples of systemic disease, and nonorthopedic findings found within the imaging field of view. This review will emphasize to the reader about the importance of interrogating the imaging in its entirety and avoiding the common pitfall of 'satisfaction of search' within diagnostic radiology

A Unique Case of Melorheostosis Presenting with Two Radiologically Distinct Lesions in the Shoulder.

Melorheostosis is a rare, nonhereditary, benign, mesenchymal condition of unknown aetiology affecting the bones and surrounding tissues. A male patient complaining of left shoulder pain, swelling, and mildly limited range of motion has an exclusive combination of the classic dripping wax lesion in the scapula and the myositis ossificans-like lesion in the deltoid muscle; this combination is the first to be reported in the shoulder. Both lesions showed typical findings of melorheostosis in radiographs, CT, MRI, and bone scan. This case has a stationary course over the follow-up period, and no specific treatment is needed in due course

Ultrasound Guided Cryoablation of Morton’s Neuroma: Case Series Including Post-Ablation MRI Appearances

Category: Midfoot/Forefoot; Other Introduction/Purpose: Morton’s neuroma (MN) is a very common compressive neuropathy of the interdigital nerve. Non- operative management is recommended initially and many therapies have been described. Cryoablation has shown promising results, however there are limited published studies in the literature. The purpose of this study was to assess the safety and efficacy of Cryoablation in patients with MN. A secondary aim was to evaluate post-procedure MRI appearances. Methods: A retrospective analysis was completed for 24 MN treated between June 2021 and September 2022. All patients had refractory MN symptoms after previous US guided steroid and LA injection within the previous year. Three patients also had refractory symptoms after prior alcohol ablation. Cryoablation was performed as a single outpatient procedure under continuous US monitoring and local anesthesia with 1 cycle for average of 2 minutes. Telephone follow up by radiology department with a 0–10 visual analogue scale (VAS) score was performed at 6 weeks and 3 months post-ablation. The patients were also encouraged to submit patient reported outcomes to a British Foot and Ankle Society (BOFAS) online scoring database as facilitated by the surgical team. Post-ablation MRI was performed to evaluate for post-procedure appearances at various intervals between 3 to 14 months. Results: 24 MN were treated. The mean size of MN treated was 12.3mm. Technical success was 100% and all patients tolerated the procedure well under local anesthesia. Mean pre-procedure VAS pain score was 8, which reduced to 1 at 6 weeks, and 2 at 3 months follow up in the treated MN. There is high patient satisfaction with 20 cases (83%) very satisfied. Four cases had various persistent symptoms and would want to have it done again (17%). Post-ablation MRI showed various bone and soft tissue changes in the ablation zone. There were two cases of fibrosis in the intermetatarsal space and one residual neuroma observed on MRI, although the patients were asymptomatic in the ablation site. No complications occurred e.g. infection, fracture or thermal injury. Conclusion: In this small series, ultrasound guided Cryoablation was deemed safe and effective treatment for MN. Clinical advantages of the procedure are good patient tolerance, single outpatient procedure, high patient satisfaction and reduced risk of scarring or residual neuroma. Further controlled prospective studies would be beneficial