Targeted evolution of adeno-associated virus capsids for systemic transgene delivery to microglia and tissue-resident macrophages.

Tissue macrophages, including microglia, are notoriously resistant to genetic manipulation. Here, we report the creation of Adeno-associated viruses (AAV) variants that efficiently and widely transduce microglia and tissue macrophages in vivo following intravenous delivery, with transgene expression of up to 80%. We use this technology to demonstrate manipulation of microglia gene expression and microglial ablation, thereby providing invaluable research tools for the study of these important cells.

Problems and Pitfalls of Identifying Remyelination in Multiple Sclerosis.

Regenerative medicines that promote remyelination in multiple sclerosis (MS) are making the transition from laboratory to clinical trials. While animal models provide the experimental flexibility to analyze mechanisms of remyelination, here we discuss the challenges in understanding where and how remyelination occurs in MS.

Remyelination and ageing: Reversing the ravages of time.

Remyelination is a neuroprotective regenerative response to demyelination that restores saltatory conduction and decreases the vulnerability of axons to irreversible degeneration. It is a highly efficient process: however, as with all regenerative processes, its efficiency declines with ageing. Here we argue that this age-related decline in remyelination has a major impact on the natural history of multiple sclerosis (MS), a disease often of several decades' duration. We describe recent work on (1) how ageing changes the function of oligodendrocyte progenitor cells (OPCs), the cells primarily responsible for generating new myelin-forming oligodendrocytes in remyelination, (2) how these changes are induced by age-related changes in the OPC niche and (3) how these changes can be reversed, thereby opening up the possibility of therapeutically maintaining remyelination efficiency throughout the disease, preserving axonal health and treating the progressive phase of MS.

Oligodendrocyte progenitor cells: the ever mitotic cells of the CNS.

Oligodendrocyte Progenitor Cells (OPCs) first appear at mid embryogenic stages during development of the mammalian CNS and a mitotically active population of them remains present even into late adulthood. During the life-time of the organism they initially proliferate and migrate in order to populate the whole nervous tissue, then they massively generate oligodendrocytesand finally they switch to a less mitotically active phase generating new oligodendrocytes at a slow rate in the adult brain; importantly, they can regenerate acutely or chronically destroyed myelin. All the above depend on the capacity of OPCs to regulate their cell cycle within different contexts. In this review we describe the development of OPCs, their differential mitotic behavior in various conditions (embryo, disease, ageing), we discuss what is known about the mechanisms that control their cell cycle and wehighlightfew interesting and still open questions.

JNK signalling is necessary for a Wnt- and stem cell-dependent regeneration programme.

Regeneration involves the integration of new and old tissues in the context of an adult life history. It is clear that the core conserved signalling pathways that orchestrate development also play central roles in regeneration, and further study of conserved signalling pathways is required. Here we have studied the role of the conserved JNK signalling cascade during planarian regeneration. Abrogation of JNK signalling by RNAi or pharmacological inhibition blocks posterior regeneration and animals fail to express posterior markers. While the early injury-induced expression of polarity markers is unaffected, the later stem cell-dependent phase of posterior Wnt expression is not established. This defect can be rescued by overactivation of the Hh or Wnt signalling pathway to promote posterior Wnt activity. Together, our data suggest that JNK signalling is required to establish stem cell-dependent Wnt expression after posterior injury. Given that Jun is known to be required in vertebrates for the expression of Wnt and Wnt target genes, we propose that this interaction may be conserved and is an instructive part of planarian posterior regeneration.

The use of diathermy scissors in parotid gland surgery.

OBJECTIVE: To evaluate the benefits, as well as the possible complications, of the use of diathermy scissors in parotid gland surgery. DESIGN: Prospective study of the surgical procedures of the diathermy scissors and a retrospective comparison with a conventionally treated control group concerning cut-closure time. SETTING: Tertiary care referral academic center. PATIENTS: Prospective examination of 30 unselected patients undergoing superficial (n=23) or subtotal/total (n=10) parotidectomies performed with diathermy scissors. Indications were benign tumors (n=18), malignant tumors (n=12), and cystic lesions (n=3). In a control group (n=50), 36 superficial and 21 subtotal/total parotidectomies were performed. RESULTS: The use of diathermy scissors reduces the need to frequently change dissecting and coagulating surgical instruments. The scissors reduce intraoperative bleeding and therefore improve visualization and orientation in the surgical field. Postoperative bleeding or seroma and Frey syndrome were not observed. In 1 case, a salivary fistula was present for 3 weeks. Three cases of transient facial weakness occurred, all of which completely resolved by 6 months after surgery. In the control group, the cut-closure time ranged from 50 to 120 minutes (average, 87.6 minutes) during superficial parotidectomy; it ranged from 80 to 160 minutes (average, 130.0 minutes) during subtotal and total parotidectomy. In comparison, in the study group, the average time gain was 16 minutes during superficial parotidectomy when diathermy scissors were used, a statistically significant difference (P=.03). During subtotal and total parotidectomy with diathermy scissors, the average time gain was 19.3 minutes and was statistically not significant (P=.23). CONCLUSIONS: The results of the present study show that diathermy scissors are very well suited for most of the surgical steps in parotid gland surgery. They provide an elegant, safe, and fast surgical procedure, especially in the hands of an experienced surgeon.