Simultaneous Activation of Complement and Coagulation by MBL-Associated Serine Protease 2

The complement system is an important immune mechanism mediating both recognition and elimination of foreign bodies. The lectin pathway is one pathway of three by which the complement system is activated. The characteristic protease of this pathway is Mannan-binding lectin (MBL)-associated serine protease 2 (MASP2), which cleaves complement proteins C2 and C4. We present a novel and alternative role of MASP2 in the innate immune system. We have shown that MASP2 is capable of promoting fibrinogen turnover by cleavage of prothrombin, generating thrombin. By using a truncated active form of MASP2 as well as full-length MASP2 in complex with MBL, we have shown that the thrombin generated is active and can cleave both factor XIII and fibrinogen, forming cross-linked fibrin. To explore the biological significance of these findings we showed that fibrin was covalently bound on a bacterial surface to which MBL/MASP2 complexes were bound. These findings suggest that, as has been proposed for invertebrates, limited clotting may contribute to the innate immune response

27-Hydroxycholesterol increases α-synuclein protein levels through proteasomal inhibition in human dopaminergic neurons

Abstract Background Accumulation of the α-synuclein (α-syn) protein is a hallmark of a group of brain disorders collectively known as synucleinopathies. The mechanisms responsible for α-syn accumulation are not well understood. Several studies suggest a link between synucleinopathies and the cholesterol metabolite 27-hydroxycholesterol (27-OHC). 27-OHC is the major cholesterol metabolite in the blood that crosses the blood brain barrier, and its levels can increase following hypercholesterolemia, aging, and oxidative stress, which are all factors for increased synucleinopathy risk. In this study, we determined the extent to which 27-OHC regulates α-syn levels in human dopaminergic neurons, the cell type in which α-syn accumulates in PD, a major synucleinopathy disorder. Results Our results show that 27-OHC significantly increases the protein levels, not the mRNA expression of α-syn. The effects of 27-OHC appear to be independent of an action through liver X receptors (LXR), its cognate receptors, as the LXR agonist, GW3965, or the LXR antagonist ECHS did not affect α-syn protein or mRNA levels. Furthermore, our data strongly suggest that the 27-OHC-induced increase in α-syn protein levels emanates from inhibition of the proteasomal degradation of this protein and a decrease in the heat shock protein 70 (HSP70). Conclusions Identifying 27-OHC as a factor that can increase α-syn levels and the inhibition of the proteasomal function and reduction in HSP70 levels as potential cellular mechanisms involved in regulation of α-syn. This may help in targeting the correct degradation of α-syn as a potential avenue to preclude α-syn accumulation

Decisions about transferring nursing home residents to hospital : highlighting the roles of advance care planning and support from local hospital and community health services

The aim of this study was to explore current practice and opportunities to improve practice in decision-making about transfer of nursing home residents to hospital. Nursing home staff are often faced with the decision of whether to send a resident to hospital for medical treatment. While many residents will benefit from going to hospital, there are also several risks associated with this. This study sought to add to the existing body of research on this issue by seeking the views of nursing home managers, who are the persons most frequently involved in making these decisions. Qualitative interviews were conducted with 41 nursing home managers from south-western Sydney, Australia. Factors affecting the decision to transfer a resident to hospital include acuteness of their condition; level and style of medical care available; role of family members; numbers, qualifications and skills mix of staff; and concern about criticism for not transferring to hospital. Two factors that have not featured as strongly in previous research are the roles of advance care planning and support from local hospital and community health services. While transferring a nursing home resident to hospital is often necessary, there are many situations where they could be cared for in the nursing home; therefore, avoid complications associated with being in hospital. Apart from a range of factors already identified in the literature, this study has highlighted the important role that advance care planning and support from local health services can play in reducing unnecessary transfers to hospital. There are several strategies that nursing homes and local health authorities can adopt to promote advance care planning and build better support systems between the two sectors, thereby reducing the numbers of residents who need to be transferred to hospital for their health care