Nā Hīmeni Hawai‘i: Transcending Kū‘ē, Promoting Kūpa‘a.

M.A. Thesis. University of Hawaiʻi at Mānoa 2017

Auditory and tactile gap discrimination by observers with normal and impaired hearing

Temporal processing ability for the senses of hearing and touch was examined through the measurement of gap-duration discrimination thresholds (GDDTs) employing the same low-frequency sinusoidal stimuli in both modalities. GDDTs were measured in three groups of observers (normal-hearing, hearing-impaired, and normal-hearing with simulated hearing loss) covering an age range of 21–69 yr. GDDTs for a baseline gap of 6 ms were measured for four different combinations of 100-ms leading and trailing markers (250–250, 250–400, 400–250, and 400–400 Hz). Auditory measurements were obtained for monaural presentation over headphones and tactile measurements were obtained using sinusoidal vibrations presented to the left middle finger. The auditory GDDTs of the hearing-impaired listeners, which were larger than those of the normal-hearing observers, were well-reproduced in the listeners with simulated loss. The magnitude of the GDDT was generally independent of modality and showed effects of age in both modalities. The use of different-frequency compared to same-frequency markers led to a greater deterioration in auditory GDDTs compared to tactile GDDTs and may reflect differences in bandwidth properties between the two sensory systems.National Institute on Deafness and Other Communication Disorders (U.S.) (Grant R01 DC000117

HIV-1 Inhibits Autophagy in Bystander Macrophage/Monocytic Cells through Src-Akt and STAT3

Autophagy is a homeostatic mechanism of lysosomal degradation. Defective autophagy has been linked to various disorders such as impaired control of pathogens and neurodegeneration. Autophagy is regulated by a complex array of signaling pathways that act upstream of autophagy proteins. Little is known about the role of altered regulatory signaling in disorders associated with defective autophagy. In particular, it is not known if pathogens inhibit autophagy by modulation of upstream regulatory pathways. Cells infected with HIV-1 blocked rapamycin-induced autophagy and CD40-induced autophagic killing of Toxoplasma gondii in bystander (non-HIV-1 infected) macrophage/monocytic cells. Blockade of autophagy was dependent on Src-Akt and STAT3 triggered by HIV-1 Tat and IL-10. Neutralization of the upstream receptors VEGFR, β-integrin or CXCR4, as well as of HIV-1 Tat or IL-10 restored autophagy in macrophage/monocytic cells exposed to HIV-1-infected cells. Defective autophagic killing of T. gondii was detected in monocyte-derived macrophages from a subset of HIV-1+ patients. This defect was also reverted by neutralization of Tat or IL-10. These studies revealed that a pathogen can impair autophagy in non-infected cells by activating counter-regulatory pathways. The fact that pharmacologic manipulation of cell signaling restored autophagy in cells exposed to HIV-1-infected cells raises the possibility of therapeutic manipulation of cell signaling to restore autophagy in HIV-1 infection

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

Survival of the native hip after spinopelvic fusion

Studies describe progression of adjacent joint arthritis after hip fusion but not vise versa. We investigated the relationship after spinopelvic fusion and total hip arthroplasty. 383 patients undergoing spinopelvic were investigated. Perioperative demographics were recorded. A matched 2:1 cohort was used to detect risk factors for THA progression. 10 patients (2.6%) underwent THA after spinopelvic fusion. Average time from surgery to THA was 24.4 months. After spinopelvic fusion, patients progressed to THA 24.4 months on average. Due to small numbers, we couldn't find differences between the two groups regarding comorbidities nor risk factors for THA. Further studies are needed

Effects of fondaparinux on wound drainage after total hip and knee arthroplasty

BackgroundThe purpose of this investigation was to determine the effects of fondaparinux on postoperative wound drainage, length of hospital stay (LOS) and rate of surgical site infection in total joint patients.Methods117 patients undergoing total joint arthroplasty treated with fondaparinux for venous thromboembolism (VTE) prophylaxis were prospectively studied.ResultsThe average time to a dry wound was 3.4 days, with an average LOS of 3.77 days. Perioperative complications included 2 cases each of superficial cellulitis, deep vein thrombosis, and pulmonary embolism; there were no cases of deep infection. Multi-variate analysis showed increased patient BMI increased LOS (p = 0.0169).ConclusionFondaparinux is an effective drug for VTE prophylaxis in total joint arthroplasty with wound drainage and LOS comparable to historical controls of enoxaparin, warfarin, and rivaroxaban

Speech reception by listeners with real and simulated hearing impairment: Effects of continuous and interrupted noise

The effects of audibility and age on masking for sentences in continuous and interrupted noise were examined in listeners with real and simulated hearing loss. The absolute thresholds of each of ten listeners with sensorineural hearing loss were simulated in normal-hearing listeners through a combination of spectrally-shaped threshold noise and multi-band expansion for octave bands with center frequencies from 0.25–8 kHz. Each individual hearing loss was simulated in two groups of three normal-hearing listeners (an age-matched and a non-age-matched group). The speech-to-noise ratio (S∕N) for 50%-correct identification of hearing in noise test (HINT) sentences was measured in backgrounds of continuous and temporally-modulated (10 Hz square-wave) noise at two overall levels for unprocessed speech and for speech that was amplified with the NAL-RP prescription. The S∕N in both continuous and interrupted noise of the hearing-impaired listeners was relatively well-simulated in both groups of normal-hearing listeners. Thus, release from masking (the difference in S∕N obtained in continuous versus interrupted noise) appears to be determined primarily by audibility. Minimal age effects were observed in this small sample. Observed values of masking release were compared to predictions derived from intelligibility curves generated using the extended speech intelligibility index (ESII) [Rhebergen et al. (2006). J. Acoust. Soc. Am. 120, 3988–3997]