Point-of-Care Glucose and Lipid Profile Measures Using a Human Point-of-Care Device in Mouse Models of Type 2 Diabetes Mellitus, Aging, and Alzheimer Disease.

A point-of-care (POC) device to measure mouse glucose and lipid profiles is an important unmet need for cost-effective, immediate decision making in research. We compared metabolic analyte profiles obtained using a human clinical POC device with those from a veterinary laboratory chemical analyzer (LCA). Unfasted terminal blood samples were obtained by cardiac puncture from C57Bl/6J mice used in a diet-induced obesity model of type 2 diabetes mellitus; age-matched C57Bl/6J controls; a transgenic mouse model of Alzheimer's disease on a C57BL/6J background (16 wk old); and aged C57BL/6J mice (24 to 60 wk old). Aliquots of the blood were immediately assayed onsite using the POC device. Corresponding serum aliquots were sent analyzed by LCA. Measures from the POC and LCA devices were compared by using the Bland-Altman and Passing-Bablok methods. Of a total of 40 aliquots, LCA results were within reported reference ranges for each model. POC results that fell beyond the device range were excluded from the analyses. The coefficient of determination and Passing-Bablok analysis demonstrated that POC glucose and HDL had the best agreement with LCA. The Bland-Altman analysis found no value-dependent bias in glucose and no significant bias in HDL. The remaining lipid analytes (cholesterol and triglyceride) showed significant bias. Until an improved, validated mouse POC device with lipid profile capability is available, the POC device that we tested appears adequate for screening glucose and HDL in mouse blood. Disadvantages of this clinical POC device are the narrow human ranges relative to ranges found in mice and its limited precision as compared with the LCA. This study demonstrates that when the samples are within the device range limits, this human POC device can accurately track metabolic syndrome and be used to compare patterns in glucose and HDL.

Pericyte abnormalities precede strial capillary basement membrane thickening in Alport mice.

In 129 Sv autosomal Alport mice, the strial capillary basement membranes (SCBMs) progressively thicken between 5 and 9 weeks of age resulting in a hypoxic microenvironment with metabolic stress and induction of pro-inflammatory cytokines and chemokines. These events occur concomitant with a drop in endocochlear potential and a susceptibility to noise-induced hearing loss under conditions that do not permanently affect age/strain-matched littermates. Here we aimed to gain an understanding of events that occur before the onset of SCBM thickening. Alport stria has normal thickness and shows levels of extracellular matrix (ECM) molecules in the SCBMs commensurate with wild-type mice. Hearing thresholds in the 3-week Alport mice do not differ from those of wild-type mice. We performed RNAseq analysis using RNA from stria vascularis isolated from 3-week Alport mice and wild type littermates. Data was processed using Ingenuity Pathway Analysis software and further distilled using manual procedures. RNAseq analysis revealed significant dysregulation of genes involved in cell adhesion, cell migration, formation of protrusions, and both actin and tubulin cytoskeletal dynamics. Overall, the data suggested changes in the cellular architecture of the stria might be apparent. To test this notion, we performed dual immunofluorescence analysis on whole mounts of the stria vascularis from these same animals stained with anti-isolectin gs-ib4 (endothelial cell marker) and anti-desmin (pericyte marker) antibodies. The results showed evidence of pericyte detachment and migration as well as the formation of membrane ruffling on pericytes in z-stacked confocal images from Alport mice compared to wild type littermates. This was confirmed by TEM analysis. Earlier work from our lab showed that endothelin A receptor blockade prevents SCBM thickening and ECM accumulation in the SCBMs. Treating cultured pericytes with endothelin-1 induced actin cytoskeletal rearrangement, increasing the ratio of filamentous to globular actin. Collectively, these findings suggest that the change in type IV collagen composition in the Alport SCBMs results in cellular insult to the pericyte compartment, activating detachment and altered cytoskeletal dynamics. These events precede SCBM thickening and hearing loss in Alport mice, and thus constitute the earliest event so far recognized in Alport strial pathology.

Effects of interaural time and level differences on the binaural interaction component of the 80 Hz auditory steady-state response.

The auditory steady-state evoked response (ASSR) is a scalp-recorded potential elicited by modulated sounds or repetitive transient sounds presented at a high rate. The binaural interaction component (BIC) of the ASSR equals the difference between the response to binaural stimuli and the sum of the responses to a monaural stimulus presented to the left ear and the right ear. This study examined the effect of the interaural time (ITD) and level (ILD) difference on the BIC of the 80 Hz ASSR. Sixteen human participants with normal hearing were tested. The ITD and ILD were varied from -1.6 to +1.6 msec and from 0 to +12 dB, respectively. The ITD function of the BIC showed a "V" shape, with a 0 value of BIC at ITD 0 msec and a positive BIC at ITD +0.8 to +1.6 msec. For ILD conditions, the BIC displayed negative values, and its amplitude became more negative as the ILD was increased. The results indicate that the ITD and ILD may be processed by different groups of binaural neurons in different pathways. It is suggested that the 80 Hz ASSR provides an objective means for evaluating binaural functions in patients such as those with central auditory processing disorders.

Contralateral suppression of distortion product otoacoustic emissions: effect of the primary frequency in Dpgrams.

The amplitude of the 2f1-f2 distortion product otoacoustic emission (DPOAE) can be suppressed by presenting contralateral acoustic stimulation. To test the hypothesis that DPOAE contralateral suppression is influenced by the primary frequency in DPgrams, DPgrams were recorded at resolutions of 1, 8, and 17 pts/octave, in the absence and presence of contralateral broadband noise (BBN). Participants were 20 normal-hearing human adults. In DPgrams with higher frequency resolutions, DPOAE suppression at amplitude peaks in DPgrams (8 pts/octave: Mean = - 0.92 dB, SD = 0.71 for BBN at 60 dB SPL; 17 pts/octave: Mean = - 0.25 to -1.44 dB, SD = 0.51 to 0.86 for BBN at 40 to 70 dB SPL, respectively) was larger than the suppression at the dips in DPgrams (8 pts/octave: Mean = - 0.13 dB, SD = 1.00; 17 pts/octave: Mean = - 0.03 to -0.73 dB, SD = 0.55 to 0.91). A larger intersubject variability in DPOAE contralateral suppression was observed at the dips. The results suggest that measuring DPOAE contralateral suppression at the primary frequencies corresponding to the peaks in DPgrams with higher frequency resolutions may improve the assessment of the efferent system function.

Auditory evoked-potential correlates of decrement detection.

Decrement detection is a commonly used psychophysical technique in which a subject is required to detect partially filled gaps in an ongoing sound. The paradigm provides information regarding both temporal resolution and intensity discrimination. The purpose of this project was to determine if an evoked-potential paradigm using decrements in an ongoing noise approximates psychophysical data. If so, the evoked-response paradigm would be useful in estimating decrement detection in laboratory animals, where training time for a psychophysical model of decrement detection might prove prohibitive. In this study, Mongolian gerbils aged 3-10 months were used as subjects. The stimulus was a broadband noise (low-pass filtered at 5 or 30 kHz, overall level of 70 dB SPL), interrupted for durations of 2-32 ms. Within each off period, a second, identically filtered noise at levels of 0-70 dB SPL was presented. In a manner qualitatively similar to previous human and animal psychophysical studies, the ABR threshold decreased as the duration of the decrement was increased. Latency and amplitudes changed as a function of decrement duration when the decrement depth was held constant, but minimal change as a function of decrement depth occurred when the decrement duration was held constant. The results suggest that ABR paradigm for decrement detection is a qualitative alternative to psychophysical techniques, but that amplitude and latency data may not provide more information on temporal and intensity coding than ABR measures of gap detection.

Behavioral and evoked-potential thresholds in young and old Mongolian gerbils (Meriones unguiculatus).

Age-dependent hearing loss has been well documented in gerbils exceeding 2 years of age using physiological methods (e.g. [Mills et al. (1990) Hear. Res. 46, 201-210]). We determined behavioral thresholds for broad-band noise and pure-tone pulses in gerbils as a function of age. Contrary to expectations based on previously published physiological data, we found no significant (broad-band noise and 10 kHz) or only a very small hearing loss (7 dB at 2 kHz) in 30-36-month-old animals. In animals over 3 years of age we observed an increased spread of thresholds and threshold shifts exceeding 20 dB in some individuals. Behavioral thresholds of old gerbils from two breeding colonies (University of Regensburg and Medical University of South Carolina) were similar. Data from individual animals where thresholds were determined physiologically and behaviorally indicate that results from auditory brainstem response measurements show no shift at 18 months while subsequent measurements at 28-29 months revealed age-dependent threshold shifts of 10-15 dB. In contrast, thresholds determined by behavioral methods in these same individuals at 31-33 months of age remained stable.

The frequency-modulation following response in young and aged human subjects.

The frequency-modulation following response (FMFR) is a steady-state evoked response which may be a neural correlate of frequency discrimination. Aged subjects with normal hearing have abnormal frequency discrimination for low carrier frequencies and thus it might be predicted that aged individuals would have reduced FMFR amplitudes compared to young subjects. In this study, FMFR amplitudes were measured for frequency-modulated sinusoids with a carrier frequency of 0.5 kHz (80 dB SPL). In Experiment 1, the modulation depth was held constant (80%) and the modulation rate was varied (4-38 Hz), whereas in Experiment 2 the modulation rate was held constant (38 Hz) and the modulation depth was varied (0-80%). Aged subjects had significantly larger FMFR amplitudes than young subjects for certain stimulus parameters, although individual variability was large. Such results would not be predicted given previous data regarding frequency discrimination, but are consistent with several reports of larger-than-normal amplitudes of middle latency and late responses in aged subjects.

Presbyacusis and the auditory brainstem response.

Age-related hearing loss (ARHL or presbyacusis) is an increasingly common form of sensorineural hearing loss (SNHL) as a result of changing demographics, and the auditory brainstem response (ABR) is a common experimental and clinical tool in audiology and neurology. Some of the changes that occur in the aging auditory system may significantly influence the interpretation of the ABR in comparison to the ABRs of younger adults. The approach of this review will be to integrate physiological and histopathological data from human and animal studies to provide a better understanding of the array of age-related changes in the ABR and to determine how age-related changes in the auditory system may influence how the ABR should be interpreted in presbyacusis. Data will be described in terms of thresholds, latencies, and amplitudes, as well as more complex auditory functions such as masking and temporal processing. Included in the review of data will be an attempt to differentiate between age-related effects that may strictly be due to threshold elevation from those that may be due to the aging process.

Susceptibility to acoustic trauma in young and aged gerbils.

The effect of age on susceptibility to noise-induced hearing loss (NIHL), the effect of gender on the interaction of age-related hearing loss (ARHL) and NIHL, and the relative contributions of ARHL and NIHL to total hearing loss are poorly understood. The issues are difficult to resolve empirically in human subjects because of lack of control over extrinsic variables and for ethical reasons. Accordingly, these issues were examined in a well-studied animal model of both ARHL and NIHL, the Mongolian gerbil. Animals were exposed to an intense tone (3.5 kHz, 113 dB SPL, 1 h) either as young adults (6-8 months) or near the end of the average lifespan of the species (34-38 months). Hearing thresholds were determined with the auditory brainstem response (ABR). ARHL was approximately 5-10 dB, with slightly more observed in males at 16 kHz (p<0.05). NIHL of approximately 15-20 dB was similar for the young and old groups, suggesting no differences in susceptibility as a function of age. There were no gender differences in NIHL. The relative contributions of ARHL and NIHL to total hearing loss in aged, noise-exposed gerbils were predicted by an addition of ARHL and NIHL in dB, similar to an international standard on hearing loss allocation, ISO-1999 [Determination of Occupational Noise Exposure and Estimation of Noise-Induced Hearing Impairment (1990)]. Previous evaluations of ISO-1999 using the gerbil animal model concluded that addition of ARHL and NIHL in dB overpredicts total hearing loss. However, in these studies, ARHL was large and nearly equal to NIHL. In the current study, where ARHL was much less than NIHL, addition of the two factors in dB, as recommended by ISO-1999, results in fairly accurate predictions of total hearing loss.