Sepsis is primarily a disease of the aged, with increased incidence and mortality occurring in aged hosts. Heat shock protein (HSP) 70 plays an important role in both healthy aging and the stress response to injury. The purpose of this study was to determine the role of HSP70 in mediating mortality and the host inflammatory response in aged septic hosts. Sepsis was induced in both young (6- to 12-wk-old) and aged (16- to 17-mo-old) HSP70−/− and wild-type (WT) mice to determine whether HSP70 modulated outcome in an age-dependent fashion. Young HSP70−/− and WT mice subjected to cecal ligation and puncture, Pseudomonas aeruginosa pneumonia, or Streptococcus pneumoniae pneumonia had no differences in mortality, suggesting HSP70 does not mediate survival in young septic hosts. In contrast, mortality was higher in aged HSP70−/− mice than aged WT mice subjected to cecal ligation and puncture (p = 0.01), suggesting HSP70 mediates mortality in sepsis in an age-dependent fashion. Compared with WT mice, aged septic HSP70−/− mice had increased gut epithelial apoptosis and pulmonary inflammation. In addition, HSP70−/− mice had increased systemic levels of TNF-α, IL-6, IL-10, and IL-1β compared with WT mice. These data demonstrate that HSP70 is a key determinant of mortality in aged, but not young hosts in sepsis. HSP70 may play a protective role in an age-dependent response to sepsis by preventing excessive gut apoptosis and both pulmonary and systemic inflammation.

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Integration of cues from multiple sensory channels improves our ability to sense and respond to stimuli. Cues arising from a single event may arrive at the brain asynchronously, requiring them to be "bound" in time. The perceptual asynchrony between vestibular and auditory stimuli has been reported to be several times greater than other stimulus pairs. However, these data were collected using electrically evoked vestibular stimuli, which may not provide similar results to those obtained using actual head rotations. Here, we tested whether auditory stimuli and vestibular stimuli consisting of physiologically relevant mechanical rotations are perceived with asynchronies consistent with other sensory systems. We rotated 14 normal subjects about the earth-vertical axis over a raised-cosine trajectory (0.5 Hz, peak velocity 10 deg/s) while isolated from external noise and light. This trajectory minimized any input from extravestibular sources such as proprioception. An 800-Hz, 10-ms auditory tone was presented at stimulus onset asynchronies ranging from 200 ms before to 700 ms after the onset of motion. After each trial, subjects reported whether the stimuli were "simultaneous" or "not simultaneous." The experiment was repeated, with subjects reporting whether the tone or rotation came first. After correction for the time the rotational stimulus took to reach vestibular perceptual threshold, asynchronies spanned from -41 ms (auditory stimulus leading vestibular) to 91 ms (vestibular stimulus leading auditory). These values are significantly lower than those previously reported for stimulus pairs involving electrically evoked vestibular stimuli and are more consistent with timing relationships between pairs of non-vestibular stimuli.

Recent evidence has shown that auditory information may be used to improve postural stability, spatial orientation, navigation, and gait, suggesting an auditory component of self-motion perception. To determine how auditory and other sensory cues integrate for self-motion perception, we measured motion perception during yaw rotations of the body and the auditory environment. Psychophysical thresholds in humans were measured over a range of frequencies (0.1–1.0 Hz) during self-rotation without spatial auditory stimuli, rotation of a sound source around a stationary listener, and self-rotation in the presence of an earth-fixed sound source. Unisensory perceptual thresholds and the combined multisensory thresholds were found to be frequency dependent. Auditory thresholds were better at lower frequencies, and vestibular thresholds were better at higher frequencies. Expressed in terms of peak angular velocity, multisensory vestibular and auditory thresholds ranged from 0.39°/s at 0.1 Hz to 0.95°/s at 1.0 Hz and were significantly better over low frequencies than either the auditory-only (0.54°/s to 2.42°/s at 0.1 and 1.0 Hz, respectively) or vestibular-only (2.00°/s to 0.75°/s at 0.1 and 1.0 Hz, respectively) unisensory conditions. Monaurally presented auditory cues were less effective than binaural cues in lowering multisensory thresholds. Frequency-independent thresholds were derived, assuming that vestibular thresholds depended on a weighted combination of velocity and acceleration cues, whereas auditory thresholds depended on displacement and velocity cues. These results elucidate fundamental mechanisms for the contribution of audition to balance and help explain previous findings, indicating its significance in tasks requiring self-orientation. NEW & NOTEWORTHY Auditory information can be integrated with visual, proprioceptive, and vestibular signals to improve balance, orientation, and gait, but this process is poorly understood. Here, we show that auditory cues significantly improve sensitivity to self-motion perception below 0.5 Hz, whereas vestibular cues contribute more at higher frequencies. Motion thresholds are determined by a weighted combination of displacement, velocity, and acceleration information. These findings may help understand and treat imbalance, particularly in people with sensory deficits.

Objective Integration of balance-related cues from the vestibular and other sensory systems requires that they be perceived simultaneously despite arriving asynchronously at the central nervous system. Failure to perform temporal integration of multiple sensory signals represents a novel mechanism to explain symptoms in patients with imbalance. This study tested the ability of normal observers to compensate for sensory asynchronies between vestibular and auditory inputs. Study Design Double-blinded experimental design. Methods We performed whole-body rotations about the earth-vertical axis following a raised-cosine trajectory at 0.5 and 1.0 Hz to several peak velocities up to a maximum of 180 deg/sec in five normal subjects. Headphones were used to present a diotic auditory stimulus at various times relative to the onset of the rotation. Subjects were required to indicate which cue occurred first. Results The vestibular stimulus needed to be presented 61 ms before the auditory stimulus (at a stimulus frequency of 0.5 Hz) and 19 ms (at 1.0 Hz). Stimuli presented within a window of 300 ms (at 0.5 Hz) and 200 ms (at 1.0 Hz) were judged to be simultaneous. Conclusion The central nervous system must accommodate for delays in perception of vestibular and other sensory cues. Inaccurate temporal integration of these inputs represents a novel explanation for symptoms of imbalance. Level of Evidence 4