Introduction: Frequent falls and risk of injury are evident in individuals with Parkinson's disease (PD) as the disease progresses. There have been no reports of any interventions that reduce the incidence of falls in idiopathic PD. Purpose: Assess the benefit of gait and step perturbation training in individuals with PD. Design: Randomized, controlled trial. Setting: Outpatient research, education and clinical center in a tertiary care Veterans Affairs Medical Center. Outcome measures: Gait parameters, 5-step test, report of falls Subjects: Eighteen men with idiopathic PD in stage 2 or 3 of the Hoehn and Yahr staging Methods: Subjects were randomly assigned to a trained or control group. They were asked about any falls 2 weeks prior to and after an 8 week period. Gait speed, cadence, and step length were tested on an instrumented walkway. Subjects were timed while stepping onto and back down from an 8.8 cm step for 5 consecutive steps. Gait training consisted of walking on a treadmill at a speed greater than over ground walking speed while walking in 4 directions and while supported in a harness for safety. Step training consisted of suddenly turning the treadmill on and off while the subject stood in the safety harness facing either forwards, backwards, or sideways. Training occurred 1 hour per day, three times per week for 8 weeks. A two-factor (time and group) analysis of variance with repeated measures was used to compare the groups. Results: Substantial reduction occurred in falls in the trained group, but not in the control group. Gait speed increased in the trained group from 1.28 ± 0.33 meters/sec to 1.45 ± 0.37 meters/sec, but not in the control group (from 1.26 to 1.27 m/s). The cadence increased for both groups: from 112.8 to 120.3 steps/min for the trained group and 117.7 to 124.3 steps/min for the control group. Stride lengths increased for the trained group, but not the control group. The 5-step test speed increased in the trained group from 0.40 ± 0.08 steps/sec to 0.51 ± 0.12 steps/sec, and in the control group (0.36 ± 0.11 steps/sec to 0.42 ± 0.11 steps/sec). Conclusion: Gait and step perturbation training resulted in a reduction in falls and improvements in gait and dynamic balance. This is a promising approach to reduce falls for patients with PD.

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Expression quantitative trait loci (eQTL) studies illuminate the genetics of gene expression and, in disease research, can be particularly illuminating when using the tissues directly impacted by the condition. In nephrology, there is a paucity of eQTL studies of human kidney. Here, we used whole-genome sequencing (WGS) and microdissected glomerular (GLOM) and tubulointerstitial (TI) transcriptomes from 187 individuals with nephrotic syndrome (NS) to describe the eQTL landscape in these functionally distinct kidney structures. Using MatrixEQTL, we performed cis-eQTL analysis on GLOM (n = 136) and TI (n = 166). We used the Bayesian "Deterministic Approximation of Posteriors" (DAP) to fine-map these signals, eQTLBMA to discover GLOM- or TI-specific eQTLs, and single-cell RNA-seq data of control kidney tissue to identify the cell type specificity of significant eQTLs. We integrated eQTL data with an IgA Nephropathy (IgAN) GWAS to perform a transcriptome-wide association study (TWAS). We discovered 894 GLOM eQTLs and 1,767 TI eQTLs at FDR < 0.05. 14% and 19% of GLOM and TI eQTLs, respectively, had >1 independent signal associated with its expression. 12% and 26% of eQTLs were GLOM specific and TI specific, respectively. GLOM eQTLs were most significantly enriched in podocyte transcripts and TI eQTLs in proximal tubules. The IgAN TWAS identified significant GLOM and TI genes, primarily at the HLA region. In this study, we discovered GLOM and TI eQTLs, identified those that were tissue specific, deconvoluted them into cell-specific signals, and used them to characterize known GWAS alleles. These data are available for browsing and download via our eQTL browser, "nephQTL."

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Successful engraftment of organ transplants has traditionally relied on preventing the activation of recipient (host) T cells. Once T-cell activation has occurred, however, stalling the rejection process becomes increasingly difficult, leading to graft failure. Here we demonstrate that graft-infiltrating, recipient (host) dendritic cells (DCs) play a key role in driving the rejection of transplanted organs by activated (effector) T cells. We show that donor DCs that accompany heart or kidney grafts are rapidly replaced by recipient DCs. The DCs originate from non-classical monocytes and form stable, cognate interactions with effector T cells in the graft. Eliminating recipient DCs reduces the proliferation and survival of graft-infiltrating T cells and abrogates ongoing rejection or rejection mediated by transferred effector T cells. Therefore, host DCs that infiltrate transplanted organs sustain the alloimmune response after T-cell activation has already occurred. Targeting these cells provides a means for preventing or treating rejection.

The migration of effector or memory T cells to the graft is a critical event in the rejection of transplanted organs. The prevailing view is that the key steps involved in T cell migration -integrin-mediated firm adhesion followed by transendothelial migration -are dependent on the activation of Gα i -coupled chemokine receptors on T cells. In contrast to this view, we demonstrated in vivo that cognate antigen was necessary for the firm adhesion and transendothelial migration of CD8 + effector T cells specific to graft antigens and that both steps occurred independent of Gα i signaling. Presentation of cognate antigen by either graft endothelial cells or bone marrow-derived APCs that extend into the capillary lumen was sufficient for T cell migration. The adhesion and transmigration of antigen-nonspecific (bystander) effector T cells, on the other hand, remained dependent on Gα i , but required the presence of antigen-specific effector T cells. These findings underscore the primary role of cognate antigen presented by either endothelial cells or bone marrow-derived APCs in the migration of T cells across endothelial barriers and have important implications for the prevention and treatment of graft rejection.

Mice devoid of T, B, and NK cells distinguish between self and allogeneic non-self despite the absence of an adaptive immune system. When challenged with an allograft they mount an innate response characterized by accumulation of mature, monocyte-derived dendritic cells (DCs) that produce IL-12 and initiate graft rejection. The molecular mechanisms, however, by which the innate immune system detects allogeneic non-self to generate these DCs are not known. To address this question, we studied the innate response of Rag2−/−γc−/− mice, which lack T, B, NK cells, to grafts from allogeneic donors. We identified by positional cloning that donor polymorphism in the gene encoding signal regulatory protein alpha (SIRPα) is a key modulator of the recipient’s innate allorecognition response. Donors that differed from the recipient in one or both Sirpa alleles elicited an innate alloresponse. The response was mediated by binding of donor SIRPα to recipient CD47 and was modulated by the strength of the SIRPα-CD47 interaction. Therefore, sensing SIRPα polymorphism by CD47 provides a molecular mechanism by which the innate immune system distinguishes between self and allogeneic non-self independently of T, B, and NK cells.