Impairment of insulin signaling in the brain has been linked to neurodegenerative diseases. To test the hypothesis that neuronal insulin resistance contributes to defects in neuronal function, we have performed a detailed analysis of brain͞neuron-specific insulin receptor knockout (NIRKO) mice. We find that NIRKO mice exhibit a complete loss of insulin-mediated activation of phosphatidylinositol 3-kinase and inhibition of neuronal apoptosis. In intact animals, this loss results in markedly reduced phosphorylation of Akt and GSK3␤, leading to substantially increased phosphorylation of the microtubule-associated protein Tau, a hallmark of neurodegenerative diseases. Nevertheless, these animals exhibit no alteration in neuronal proliferation͞survival, memory, or basal brain glucose metabolism. Thus, lack of insulin signaling in the brain may lead to changes in Akt and GSK3␤ activity and Tau hyperphosphorylation but must interact with other mechanisms for development of Alzheimer's disease.

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Massive skeletal defects are encountered in the setting of tumors necessitating excision, failed total hip arthroplasty with periprosthetic bone loss, periprosthetic fracture, complex trauma, multiple failed osteosynthesis and infection. Reconstruction of the segmental defects poses a tremendous challenge to the orthopaedic surgeons. The goal of osseous reconstruction of these defects is to restore the bone length and function. Currently the most commonly employed methods for reconstruction are either a megaprosthesis or an Allograft Prosthesis Composite (APC). Megaprosthesis, initially created for the treatment in neoplastic pathologies are being used for the non-neoplastic pathologies as well. The longevity of these implants is an issue as majority of the patients receiving them are the survivors of oncologic issue or elderly population, both in which the life expectancy is limited. However, the early complications like instability, infection, prosthetic breakage and fixation failure have been extensively reported in several literatures. Moreover, the megaprostheses are non-biological options preventing secure fixation of the soft tissue around the implant. The Allograft Prosthesis Composites were introduced to overcome the complications of megaprosthesis. APC is made of a revision-type prosthesis cemented into the skeletal allograft to which the remaining soft tissue sleeve can be biologically fixed. APCs are preferred in young and low risk patients. Though the incidence of instability is relatively low with the composites as compared to the megaprosthesis, apart from infection, the newer complications pertaining to APCs are inevitable that includes non-union, allograft resorption, periprosthetic fracture and potential risk of disease transmission. The current review aims to give an overview on the treatment outcomes, complications and survival of both the megaprostheses and APCs at different anatomic sites in both the upper and lower limbs.

The results of this multicentre study showed encouraging short- and mid-term results for the use of TM augments in the management of Paprosky grade IIIA and IIIB defects. Cite this article: Bone Joint J 2018;100-B:903-8.