Effect of altered sensory conditions on multivariate descriptors of human postural sway

Multivariate descriptors of sway were used to test whether altered sensory conditions result not only in changes in amount of sway but also in postural coordination. Eigenvalues and directions of eigenvectors of the covariance of shnk and hip angles were used as a set of multivariate descriptors. These quantities were measured in 14 healthy adult subjects performing the Sensory Organization test, which disrupts visual and somatosensory information used for spatial orientation. Multivariate analysis of variance and discriminant analysis showed that resulting sway changes were at least bivariate in character, with visual and somatosensory conditions producing distinct changes in postural coordination. The most significant changes were found when somatosensory information was disrupted by sway-referencing of the support surface ( P =3.2·10 −10 ). The resulting covariance measurements showed that subjects not only swayed more but also used increased hip motion analogous to the hip strategy. Disruption of vision, by either closing the eyes or sway-referencing the visual surround, also resulted in altered sway ( P =1.7·10 −10 ), with proportionately more motion of the center of mass than with platform sway-referencing. As shown by discriminant analysis, an optimal univariate measure could explain at most 90% of the behavior due to altered sensory conditions. The remaining 10%, while smaller, are highly significant changes in posture control that depend on sensory conditions. The results imply that normal postural coordination of the trunk and legs requires both somatosensory and visual information and that each sensory modality makes a unique contribution to posture control. Descending postural commands are multivariate in nature, and the motion at each joint is affected uniquely by input from multiple sensors.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/42010/1/221-122-2-185_81220185.pd

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Visual, vestibular, and somatosensory contributions to postural control during altered sensory conditions: A study of the separate effects of spaceflight, aging and balance system pathology.

Adequate postural control depends on the spatial and temporal integration of vestibular, visual, and somatosensory information about the active and passive motion of the head and body. Individuals who are unable to quickly select the most reliable source of sensory information from those available are at risk for falling whenever the sensory environment changes suddenly. Changes in maintenance of stance are multifactorial, involving the processing of multiple sensory inputs and the selection and weighting of these inputs for an appropriate postural response. We hypothesized that reorganization of postural control relying on these multiple inputs, due to exposure to microgravity, healthy aging, or balance system pathology, would result in not only greater amounts of sway, but also changes in interjoint coordination. We tested this hypothesis by examining the multivariate characteristics of postural sway and comparing the postural control gains used for maintenance of upright stance during the altered sensory conditions of the Sensory Organization Test (EquiTest, NeuroCom International). We improved the sensitivity of the Sensory Organization Test with the use of direct kinematic measurements for assessment of postural sway as well as to provide a more direct feedback signal for sway-referencing of the balance platform or visual surround. We used the covariance of hip and ankle kinematics as a measure of joint motion and interjoint coordination, and then utilized discriminant analysis to further examine these sway characteristics. Our results suggest that after spaceflight, astronauts exhibit significant multivariate changes in multijoint coordination, of which increased sway is only one component. Similarly, our results suggest that the contributions of visual vestibular and somatosensory information for postural control are altered with healthy aging. These coordinative changes are partially explained by diminished sensory perception of spatial orientation, as well as a change in the feedback response to altered sensory inputs. Such changes are consistent with reweighting of vestibular inputs and changes in control strategy in a multivariable control system. Additionally, the use of hip and shank kinematics with shank angle sway-referencing can provide new clinical information regarding the postural control of balance disorder patients as well as further classification of functional compensation.Ph.D.Applied SciencesBiological SciencesBiomedical engineeringNeurosciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/131795/2/9929959.pd