Functional Trajectories in the Year Before Hospice

PURPOSEWe undertook a study to identify distinct functional trajectories in the year before hospice, to determine how patients with these trajectories differ according to demographic characteristics and hospice diagnosis, and to evaluate the association between these trajectories and subsequent outcomes.METHODSFrom an ongoing cohort study of 754 community-living persons aged 70 years or older, we evaluated data on 213 persons who were subsequently enrolled in hospice from March 1998 to December 2011. Disability in 13 basic, instrumental, and mobility activities was assessed during monthly telephone interviews through June 2012.RESULTSIn the year before hospice, we identified 5 clinically distinct functional trajectories, representing worsening cumulative burden of disability: late decline (10.8%), accelerated (10.8%), moderate (21.1%), progressively severe (24.9%), and persistently severe (32.4%). Participants with a cancer diagnosis (34.7%) had the most favorable functional trajectories (ie, lowest burden of disability), whereas those with neurodegenerative disease (21.1%) had the worst. Median survival in hospice was only 14 days and did not differ significantly by functional trajectory. Compared with participants in the persistently severe trajectory, those in the moderate trajectory had the highest likelihood of surviving and being independent in at least 1 activity in the month after hospice admission (adjusted odds ratio = 5.5; 95% CI, 1.9–35.9).CONCLUSIONSThe course of disability in the year before hospice differs greatly among older persons but is particularly poor among those with neurodegenerative disease. Late admission to hospice (as shown by the short survival), coupled with high levels of severe disability before hospice, highlight potential unmet palliative care needs for many older persons at the end of life.     

The impact of chemokine receptor CX3CR1 deficiency during respiratory infections with Mycobacterium tuberculosis or Francisella tularensis

Recruitment of immune cells to infection sites is a critical component of the host response to pathogens. This process is facilitated partly through interactions of chemokines with cognate receptors. Here, we examine the importance of fractalkine (CX3CL1) receptor, CX3CR1, which regulates function and trafficking of macrophages and dendritic cells, in the host''s ability to control respiratory infections with Mycobacterium tuberculosis or Francisella tularensis. Following low-dose aerosol challenge with M. tuberculosis, CX3CR1^−/− mice were no more susceptible to infection than wild-type C57BL/6 mice as measured by organ burden and survival time. Similarly, following inhalation of F. tularensis, CX3CR1^−/− mice displayed similar organ burdens to wild-type mice. CX3CR1^−/− mice had increased recruitment of monocytes and neutrophils in the lung; however, this did not result in increased abundance of infected monocytes or neutrophils. We conclude that CX3CR1-deficiency affects immune-cell recruitment; however, loss of CX3CR1 alone does not render the host more susceptible to M. tuberculosis or F. tularensis.     

Characterization of isolated liver sinusoidal endothelial cells for liver bioengineering

Background

The liver sinusoidal capillaries play a pivotal role in liver regeneration, suggesting they may be beneficial in liver bioengineering. This study isolated mouse liver sinusoidal endothelial cells (LSECs) and determined their ability to form capillary networks in vitro and in vivo for liver tissue engineering purposes.

Methods and results

In vitro LSECs were isolated from adult C57BL/6 mouse livers. Immunofluorescence labelling indicated they were LYVE-1⁺/CD32b⁺/FactorVIII⁺/CD31^?. Scanning electron microscopy of LSECs revealed the presence of characteristic sieve plates at 2 days. LSECs formed tubes and sprouts in the tubulogenesis assay, similar to human microvascular endothelial cells (HMEC); and formed capillaries with lumens when implanted in a porous collagen scaffold in vitro. LSECs were able to form spheroids, and in the spheroid gel sandwich assay produced significantly increased numbers (p?=?0.0011) of capillary-like sprouts at 24 h compared to HMEC spheroids. Supernatant from LSEC spheroids demonstrated significantly greater levels of vascular endothelial growth factor-A and C (VEGF-A, VEGF-C) and hepatocyte growth factor (HGF) compared to LSEC monolayers (p?=?0.0167; p?=?0.0017; and p?<?0.0001, respectively), at 2 days, which was maintained to 4 days for HGF (p?=?0.0017) and VEGF-A (p?=?0.0051). In vivo isolated mouse LSECs were prepared as single cell suspensions of 500,000 cells, or as spheroids of 5000 cells (100 spheroids) and implanted in SCID mouse bilateral vascularized tissue engineering chambers for 2 weeks. Immunohistochemistry identified implanted LSECs forming LYVE-1⁺/CD31^? vessels. In LSEC implanted constructs, overall lymphatic vessel growth was increased (not significantly), whilst host-derived CD31⁺ blood vessel growth increased significantly (p?=?0.0127) compared to non-implanted controls. LSEC labelled with the fluorescent tag DiI prior to implantation formed capillaries in vivo and maintained LYVE-1 and CD32b markers to 2 weeks.

Conclusion

Isolated mouse LSECs express a panel of vascular-related cell markers and demonstrate substantial vascular capillary-forming ability in vitro and in vivo. Their production of liver growth factors VEGF-A, VEGF-C and HGF enable these cells to exert a growth stimulus post-transplantation on the in vivo host-derived capillary bed, reinforcing their pro-regenerative capabilities for liver tissue engineering studies.