Importance of Early Inpatient Geriatric Rehabilitation on Outcomes in Individuals on Dialysis.

OBJECTIVE: To report short-term functional outcomes of patients incident to dialysis undergoing inpatient rehabilitation within 3 months of dialysis initiation. DESIGN: Retrospective observation study using prospectively collected data. SETTING: Single-center, hospital-based geriatric dialysis rehabilitation unit. All patients incident to hemodialysis admitted to the geriatric dialysis rehabilitation unit between May 2002 and April 2016 were identified using a retrospective observational design. Clinical and demographic data were collected prospectively and linked, using the unique hospital number and dates of admission and discharge, to FIM scores (used to assess functional recovery) at admission and discharge. PARTICIPANTS: Patients (N=449; mean age ± SD, 74±9y) newly started on hemodialysis (within 3mo). INTERVENTIONS: Inpatient rehabilitation care, short daily dialysis therapy with nephrologist support, and geriatrician assessment. MAIN OUTCOMES: Change in FIM score; discharge location. RESULTS: Patients were admitted within 3 months of hemodialysis initiation. The median length of stay in the rehabilitation program was 43 days (25th and 75th quartile, 33-55 days). Of those with complete data (n=370), 95% had improvement in FIM scores (median changes in total FIM score 25 [quartiles, 16, 33]; in motor FIM 23 [quartiles, 15, 32]; and in cognitive FIM 1 [quartiles, 0, 3], respectively). Most improvement was seen in transfer abilities, grooming, and mobility. A total of 324 patients (72%; 95% CI, 68%-76%) were discharged to a private home. An additional 11 were discharged to a seniors' residence. CONCLUSION: The data suggest that older patients incident to dialysis with functional decline respond well to specialized rehabilitation care and suggest this may be a novel approach to dialysis initiation.

Conformational determinants of phosphotyrosine peptides complexed with the Src SH2 domain.

The inhibition of specific SH2 domain mediated protein-protein interactions as an effective chemotherapeutic approach in the treatment of diseases remains a challenge. That different conformations of peptide-ligands are preferred by different SH2 domains is an underappreciated observation from the structural analysis of phosphotyrosine peptide binding to SH2 domains that may aid in future drug design. To explore the nature of ligand binding, we use simulated annealing (SA) to sample the conformational space of phosphotyrosine-containing peptides complexed with the Src SH2 domain. While in good agreement with the crystallographic and NMR studies of high-affinity phosphopeptide-SH2 domain complexes, the results suggest that the structural basis for phopsphopeptide- Src SH2 interactions is more complex than the "two-pronged plug two-hole socket" model. A systematic study of peptides of type pYEEX, where pY is phosphotyrosine and X is a hydrophobic residue, indicates that these peptides can assume two conformations, one extended and one helical, representing the balance between the interaction of residue X with the hydrophobic hole on the surface of the Src SH2 domain, and its contribution to the inherent tendency of the two glutamic acids to form an alpha-helix. In contrast, a beta-turn conformation, almost identical to that observed in the crystal structure of pYVNV bound to the Grb2 SH2 domain, predominates for pYXNX peptides, even in the presence of isoleucine at the third position. While peptide binding affinities, as measured by fluorescence polarization, correlate with the relative proportion of extended peptide conformation, these results suggest a model where all three residues C-terminal to the phosphotyrosine determine the conformation of the bound phosphopeptide. The information obtained in this work can be used in the design of specific SH2 domain inhibitors.

Structural and functional heterogeneity in the CD200R family of immunoregulatory molecules and their expression at the feto-maternal interface.

PROBLEM: We have shown that CD200Fc, a chimeric molecule including the extracellular domain of CD200 and a murine immunoglobulin (Ig)G2a Fc region, regulates immune responses and prevents T helper (Th)1 cytokine-triggered spontaneous abortions in mice. CD200 is expressed on a subpopulation of uterine decidua cells and on trophoblast, both in the mouse and human. The receptor(s) for CD200, CD200R(s), was not previously well-characterized. METHODS: 5'-rapid amplification of cDNA ends (RACE), cDNA and genomic DNA clone analysis were used to identify a family of CD200Rs on mouse chromosome 16, juxtaposed to the CD200 gene, named CD200R1, R2, R3, and R4. Northern blot and reverse transcriptase polymerase chain reaction (RT-PCR) analysis was used to detect expression of different CD200R subtypes in different organs. Rabbit polyclonal and rat monoclonal antibodies (mAbs) to CD200R isoforms was used for fluorescence-activated cell sorter (FACS) analysis, to test for immunomodulatory effects on allogeneic mixed-lymphocyte responses in vitro, and for immunohistochemistry. RESULTS: The CD200Fc was able to interact physically with each of the CD200Rs expressed on the cell surface. Northern blot and RT-PCR analyses indicated distinct patterns of CD200R isoform mRNA expression in different tissues and FACS analyses confirmed unique cell- and tissue-specific expression of the different CD200Rs. mAbs directed against the different isoforms modified the development of in vitro alloimmune responses. The addition of anti-CD200R1/R4 elicited immunomodulatory responses in vitro comparable to findings with CD200Fc, but different from the effects of anti-CD200R2-3. CONCLUSIONS: These data provide evidence for a family of CD200R molecules in the mouse genome and defines the existence of previously unrecognized diversity in the CD200/CD200R immunomodulatory gene member family. Although this gene member family is clustered in the genome, the different CD200Rs and CD200 exhibit distinct expression patterns and functional properties. Restricted CD200R isoform expression at the feto-maternal interface suggests CD200:CD200R interactions may serve important function(s) determining the successful outcome of pregnancy.