Short- and Long-Term Complications of Free Anterolateral Thigh Flap Reconstructions: A Single-Centre Experience of 92 Consecutive Cases.

Background: The anterolateral thigh (ALT) flap has been amongst the most versatile components of the reconstructive surgeon's armamentarium. The authors utilise these flaps for a variety of reconstructive procedures including lower limb reconstruction; postsarcoma excision; and open fractures. Few studies have discussed the extent of recipient site morbidity and subsequent revisional procedures. We will report our experience of the ALT flap in 92 consecutive reconstructions with focus on recipient site complications and revisional procedures. Methods: Retrospective data collection was done from 92 patients who underwent ALT flap reconstruction-for various large soft tissue defects-at our unit at the Royal Free Hospital, London. We evaluated primary recipient site complications and the requirements for secondary operations after flap transfer. Results: All flaps survived with the exception of 3 cases (97% survival rate) in which irreversible venous thrombosis was encountered. 16 of 92 patients (17%) required a second recipient site operation for the following: 7 patients experienced major recipient site complications that warranted early return to theatre and 9 patients required a secondary revision thinning procedure(s). 8 of the 16 patients (50%) requiring second operations had construction on their lower leg/ankle/feet (p value = 0.10). Conclusions: Our data demonstrated effective use of the ALT flap in the management of soft tissue reconstructive surgery. Partial flap necrosis was the main complication at the recipient site. In future work, secondary thinning procedures, particularly at the ankle/foot, should be separated from flap-specific complications. Furthermore, we demonstrate tailoring ALT thickness can be performed safely without compromising flap viability.

FTY720/fingolimod increases NPC1 and NPC2 expression and reduces cholesterol and sphingolipid accumulation in Niemann-Pick type C mutant fibroblasts.

Niemann-Pick type C (NPC) disease is a fatal neurodegenerative disorder caused by mutations in NPC1 or NPC2 with decreased functions leading to lysosomal accumulation of cholesterol and sphingolipids. FTY720/fingolimod, used for treatment of multiple sclerosis, is phosphorylated by nuclear sphingosine kinase 2, and its active phosphorylated form (FTY720-P) is an inhibitor of class I histone deacetylases. In this study, administration of clinically relevant doses of FTY720 to mice increased expression of NPC1 and -2 in brain and liver and decreased cholesterol in an SphK2-dependent manner. FTY720 greatly increased expression of NPC1 and -2 in human NPC1 mutant fibroblasts that correlated with formation of FTY720-P and significantly reduced the accumulation of cholesterol and glycosphingolipids. In agreement with this finding, FTY720 pretreatment of human NPC1 mutant fibroblasts restored transport of the cholera toxin B subunit, which binds ganglioside GM1, to the Golgi apparatus. Together, these findings suggest that FTY720 administration can ameliorate cholesterol and sphingolipid storage and trafficking defects in NPC1 mutant fibroblasts. Because neurodegeneration is the main clinical feature of NPC disease, and FTY720 accumulates in the CNS and has several advantages over available histone deacetylase inhibitors now in clinical trials, our work provides a potential opportunity for treatment of this incurable disease.-Newton, J., Hait, N. C., Maceyka, M., Colaco, A., Maczis, M., Wassif, C. A., Cougnoux, A., Porter, F. D., Milstien, S., Platt, N., Platt, F. M., Spiegel, S. FTY720/fingolimod increases NPC1 and NPC2 expression and reduces cholesterol and sphingolipid accumulation in Niemann-Pick type C mutant fibroblasts.

Invariant natural killer T cells are not affected by lysosomal storage in patients with Niemann-Pick disease type C.

Invariant natural killer T (iNKT) cells are a specialised subset of T cells that are restricted to the MHC class I like molecule, CD1d. The ligands for iNKT cells are lipids, with the canonical superagonist being α-galactosylceramide, a non-mammalian glycosphingolipid. Trafficking of CD1d through the lysosome is required for the development of murine iNKT cells. Niemann-Pick type C (NPC) disease is a lysosomal storage disorder caused by dysfunction in either of two lysosomal proteins, NPC1 or NPC2, resulting in the storage of multiple lipids, including glycosphingolipids. In the NPC1 mouse model, iNKT cells are virtually undetectable, which is likely due to the inability of CD1d to be loaded with the selecting ligand due to defective lysosomal function and/or CD1d trafficking. However, in this study we have found that in NPC1 patients iNKT cells are present at normal frequencies, with no phenotypic or functional differences. In addi-tion, antigen-presenting cells derived from NPC1 patients are functionally competent to present several different CD1d/iNKT-cell ligands. This further supports the hypothesis that there are different trafficking requirements for the development of murine and human iNKT cells, and a functional lysosomal/late-endosomal compartment is not required for human iNKT-cell development.