Embryonic Mutant Huntingtin Aggregate Formation in Mouse Models of Huntington’s Disease

The role of aggregate formation in the pathophysiology of Huntington’s disease (HD) remains uncertain. However, the temporal appearance of aggregates tends to correlate with the onset of symptoms and the numbers of neuropil aggregates correlate with the progression of clinical disease. Using highly sensitive immunohistochemical methods we have detected the appearance of diffuse aggregates during embryonic development in the R6/2 and YAC128 mouse models of HD. These are initially seen in developing axonal tracts and appear to spread throughout the cerebrum in the early neonate

Treatment with THI, an inhibitor of sphingosine-1-phosphate lyase, modulates glycosphingolipid metabolism and results therapeutically effective in experimental models of Huntington's disease

Huntington's disease (HD) is a fatal neurodegenerative disorder with no effective cure currently available. Over the past few years our research has shown that alterations in sphingolipid metabolism represent a critical determinant in HD pathogenesis. In particular, aberrant metabolism of sphingosine-1-phosphate (S1P) has been reported in multiple disease settings, including human postmortem brains from HD patients. In this study, we investigate the potential therapeutic effect of the inhibition of S1P degradative enzyme SGPL1, by the chronic administration of the 2-acetyl-5-tetrahydroxybutyl imidazole (THI) inhibitor. We show that THI mitigated motor dysfunctions in both mouse and fly models of HD. The compound evoked the activation of pro-survival pathways, normalized levels of brain-derived neurotrophic factor, preserved white matter integrity, and stimulated synaptic functions in HD mice. Metabolically, THI restored normal levels of hexosylceramides and stimulated the autophagic and lysosomal machinery, facilitating the reduction of nuclear inclusions of both wild-type and mutant huntingtin proteins

Surgical cannulation: Indication, Technique and Complications

The establishment of ECMO support could be achieved through intrathoracic or extrathoracic cannulation strategies. Central cannulation requires a surgical approach, a sternotomy, and the cannulation of the right atrium and the ascending aorta. The features listed above make the central cannulation the best approach for patients with postcardiotomy complications. Such a cannulation strategy allows the best venous drainage and an anterograde blood flow in ascending aorta; it is though related to important complications such as bleeding and mediastinitis. In case of peripheral cannulation, it is necessary to choose among several sites: femoral vessels, axillary vessels, and cervical vessels are the most used ones. Peripheral vessel cannulation could be achieved either by percutaneous procedures or surgical incisions through an open approach with different techniques (direct cannulation or cannulation with side graft), a semi-Seldinger, or a full Seldinger method. The surgical approach allows the visualization of the vessels, the direct placement of the cannulas, and the control of possible complications. Therefore, it is recommended if immediate support is needed or if a peripheral vascular disease is suspected. Also a mixed central/peripheral cannulation approach is possible. The best cannulation technique should be chosen on the basis of patients and the clinical settings. Moreover, it is necessary to assess benefits and risks of the selected options to pick the best site and strategy of the cannulation