One of the ways to reconstruct a nerve defect is to use a biodegradable nerve guide. The aim of this study was to establish a nerve guide constructed of an amorphous copolymer of lactic acid-caprolactone. A pilot study was set up to elucidate the effect of the tube dimensions on nerve regeneration. Four types of nerve guides, with internal diameters ranging from 1.12-1.23 mm and wall thicknesses ranging from 0.34-0.68, were tested for this purpose. We evaluated the biodegradation, foreign body reaction and nerve regeneration by light microscopy, after three different implantation times (1, 2, and 3 months). After 2 months, we observed that all types of nerve guides had changed from a transparent to an opaque and swollen state, and that they had lost their strength. The foreign body reaction was characterized by the presence of giant cells and fibroblasts surrounding the degrading nerve guide. From this pilot study, we conclude that nerve guide type 1, with an internal diameter of 1.23 mm and a wall thickness of 0.34 mm, can ensure nerve regeneration in the case of a 1-cm gap in the sciatic nerve of the rat. Nerve guides types 3 and 4, with relatively small lumens, show nerve compression due to a more pronounced swelling of the degrading tube.

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder, associated with a variable clinical phenotype including café-au-lait spots, intertriginous freckling, Lisch nodules, neurofibromas, optic pathway gliomas and distinctive bony lesions. NF1 is caused by a mutation in the NF1 gene, which codes for neurofibromin, a large protein involved in the MAPK- and the mTOR-pathway through RAS-RAF signalling. NF1 is a known tumour predisposition syndrome, associated with different tumours of the nervous system including low grade gliomas (LGGs) in the paediatric population. The focus of this review is on grade I pilocytic astrocytomas (PAs), the most commonly observed histologic subtype of low grade gliomas in NF1. Clinically, these PAs have a better prognosis and show different localisation patterns than their sporadic counterparts, which are most commonly associated with a KIAA1549:BRAF fusion. In this review, possible mechanisms of tumourigenesis in LGGs with and without NF1 will be discussed, including the contribution of different signalling pathways and tumour microenvironment. Furthermore we will discuss how increased understanding of tumourigenesis may lead to new potential targets for treatment.

J. M. A. Kuijlen, E. Bremer, J. J. A. Mooij, W. F. A. den Dunnen and W. Helfrich (2010) Neuropathology and Applied Neurobiology36, 168–182
On TRAIL for malignant glioma therapy? Glioblastoma (GBM) is a devastating cancer with a median survival of around 15 months. Significant advances in treatment have not been achieved yet, even with a host of new therapeutics under investigation. Therefore, the quest for a cure for GBM remains as intense as ever. Of particular interest for GBM therapy is the selective induction of apoptosis using the pro‐apoptotic tumour necrosis factor‐related apoptosis‐inducing ligand (TRAIL). TRAIL signals apoptosis via its two agonistic receptors TRAIL‐R1 and TRAIL‐R2. TRAIL is normally present as homotrimeric transmembrane protein, but can also be processed into a soluble trimeric form (sTRAIL). Recombinant sTRAIL has strong tumouricidal activity towards GBM cells, with no or minimal toxicity towards normal human cells. Unfortunately, GBM is a very heterogeneous tumour, with multiple genetically aberrant clones within one tumour. Consequently, any single agent therapy is likely to be not effective enough. However, the anti‐GBM activity of TRAIL can be synergistically enhanced by a variety of conventional and novel targeted therapies, making TRAIL an ideal candidate for combinatorial strategies. Here we will, after briefly detailing the biology of TRAIL/TRAIL receptor signalling, focus on the promises and pitfalls of recombinant TRAIL as a therapeutic agent alone and in combinatorial therapeutic approaches for GBM.

We conclude that the presence of neonatal leg movements does not indicate integrity of functional lower motor neuron innervation by spinal segments caudal to the meningomyelocele. Present observations could explain why fetal surgery at the level of the meningomyelocele does not prevent loss of leg movements.

The aim of this study was to compare the speed and quality of nerve regeneration after reconstruction using a biodegradable nerve guide or an autologous nerve graft. We evaluated nerve regeneration using light microscopy, transmission electron microscopy and morphometric analysis. Nerve regeneration across a short nerve gap, after reconstruction using a biodegradable nerve guide, is faster and qualitatively better, when compared with nerve reconstruction using an autologous nerve graft. Therefore, we conclude that in the case of a short nerve gap (1 cm), reconstruction should be carried out using a biodegradable nerve guide constructed of a copolymer of DL-lactide and epsilon-caprolactone.

The aim of this study was to evaluate functional nerve recovery following reconstruction of a 1 cm gap in the sciatic nerve of a rat, using a new biodegradable p (DLLA-epsilon-CL) nerve guide. To evaluate both motor and sensory nerve recovery, walking track analysis and electrostimulation tests were carried out after implantation periods, ranging from 3 to 15 weeks post-operatively. The first signs of functional nerve recovery were observed after 3 weeks. After 15 weeks, 70% of the motor- and 90% of the sensory nerve function was re-established. Return of nerve function was better, in comparison with results from other studies. This study demonstrated successful functional nerve recovery after the reconstruction of a 1 cm nerve gap with a biodegradable p(DLLA-epsilon-CL) nerve guide.

Coronavirus disease 2019 (COVID‐19), caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), continues to spread globally despite the worldwide implementation of preventive measures to combat the disease. Although most COVID‐19 cases are characterised by a mild, self‐limiting disease course, a considerable subset of patients develop a more severe condition, varying from pneumonia and acute respiratory distress syndrome (ARDS) to multi‐organ failure (MOF). Progression of COVID‐19 is thought to occur as a result of a complex interplay between multiple pathophysiological mechanisms, all of which may orchestrate SARS‐CoV‐2 infection and contribute to organ‐specific tissue damage. In this respect, dissecting currently available knowledge of COVID‐19 immunopathogenesis is crucially important, not only to improve our understanding of its pathophysiology but also to fuel the rationale of both novel and repurposed treatment modalities. Various immune‐mediated pathways during SARS‐CoV‐2 infection are relevant in this context, which relate to innate immunity, adaptive immunity, and autoimmunity. Pathological findings in tissue specimens of patients with COVID‐19 provide valuable information with regard to our understanding of pathophysiology as well as the development of evidence‐based treatment regimens. This review provides an updated overview of the main pathological changes observed in COVID‐19 within the most commonly affected organ systems, with special emphasis on immunopathology. Current management strategies for COVID‐19 include supportive care and the use of repurposed or symptomatic drugs, such as dexamethasone, remdesivir, and anticoagulants. Ultimately, prevention is key to combat COVID‐19, and this requires appropriate measures to attenuate its spread and, above all, the development and implementation of effective vaccines. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Machado-Joseph disease (MJD) is a fatal, dominantly inherited neurodegenerative disorder associated with an expanded polyglutamine tract within the ataxin-3 protein, and characterized by progressive impairment of motor coordination, associated with neurodegeneration of specific brain regions, including cerebellum and striatum. The currently available therapies do not allow modification of disease progression. Neuropeptide Y (NPY) has been shown to exert potent neuroprotective effects by multiple pathways associated with the MJD mechanisms of disease. Thus, we evaluated NPY levels in MJD and investigated whether raising NPY by gene transfer would alleviate neuropathological and behavioural deficits in cerebellar and striatal mouse models of the disease. For that, a cerebellar transgenic and a striatal lentiviral-based models of MJD were used. NPY overexpression in the affected brain regions in these two mouse models was obtained by stereotaxic injection of adeno-associated viral vectors encoding NPY. Up to 8 weeks after viral injection, balance and motor coordination behaviour and neuropathology were analysed. We observed that NPY levels were decreased in two MJD patients' cerebella and in striata and cerebella of disease mouse models. Furthermore, overexpression of NPY alleviated the motor coordination impairments and attenuated the related neuropathological parameters, preserving cerebellar volume and granular layer thickness, reducing striatal lesion and decreasing mutant ataxin-3 aggregation. Additionally, NPY mediated increase of brain-derived neurotrophic factor levels and decreased neuroinflammation markers. Our data suggest that NPY is a potential therapeutic strategy for MJD.