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Cochlear synaptopathy can result from various insults, including acoustic trauma, aging, ototoxicity, or chronic conductive hearing loss. For example, moderate noise exposure in mice can destroy up to ∼50% of synapses between auditory nerve fibers (ANFs) and inner hair cells (IHCs) without affecting outer hair cells (OHCs) or thresholds, because the synaptopathy occurs first in high-threshold ANFs. However, the fiber loss likely impairs temporal processing and hearing-in-noise, a classic complaint of those with sensorineural hearing loss. Non-human primates appear to be less vulnerable to noise-induced hair-cell loss than rodents, but their susceptibility to synaptopathy has not been studied. Because establishing a non-human primate model may be important in the development of diagnostics and therapeutics, we examined cochlear innervation and the damaging effects of acoustic overexposure in young adult rhesus macaques. Anesthetized animals were exposed bilaterally to narrow-band noise centered at 2 kHz at various sound-pressure levels for 4 h. Cochlear function was assayed for up to 8 weeks following exposure via auditory brainstem responses (ABRs) and otoacoustic emissions (OAEs). A moderate loss of synaptic connections (mean of 12-27% in the basal half of the cochlea) followed temporary threshold shifts (TTS), despite minimal hair-cell loss. A dramatic loss of synapses (mean of 50-75% in the basal half of the cochlea) was seen on IHCs surviving noise exposures that produced permanent threshold shifts (PTS) and widespread hair-cell loss. Higher noise levels were required to produce PTS in macaques compared to rodents, suggesting that primates are less vulnerable to hair-cell loss. However, the phenomenon of noise-induced cochlear synaptopathy in primates is similar to that seen in rodents.
Copyright © 2017 Elsevier B.V. All rights reserved.

BACKGROUND - Mobility limitation is highly prevalent among older adults and is central to the loss of functional independence. Dynamic isokinetic muscle fatigue testing may reveal increased vulnerability to disability and mortality beyond strength testing.
METHODS - We studied community-dwelling older adults enrolled in the Health Aging and Body Composition study (age range: 71-82) free of mobility disability and who underwent isokinetic muscle fatigue testing in 1999-2000 (n = 1,963). Isokinetic quadriceps work and fatigue index was determined over 30 repetitions and compared with isometric quadriceps maximum torque. Work was normalized to leg lean mass accounting for gender-specific differences (specific work). The primary outcome was incident persistent severe lower extremity limitation (PSLL), defined as two consecutive reports of either having a lot of difficulty or being unable to walk 1/4 mile or climb 10 steps without resting. The secondary outcome was all-cause mortality.
RESULTS - There were 608 (31%) occurrences of incident PSLL and 488 (25%) deaths during median follow-up of 9.3 years. After adjustment, lower isokinetic work was associated with significantly greater risks of PSLL and mortality across the full measured range. Hazard ratios per standard deviation lower specific isokinetic work were 1.22 (95% CI 1.12, 1.33) for PSLL and 1.21 (95% CI 1.13, 1.30) for mortality, respectively. Lower isometric strength was associated with PSLL, but not mortality. Fatigue index was not associated with PSLL or mortality.
CONCLUSIONS - Muscle endurance, estimated by isokinetic work, is an indicator of muscle health associated with mobility limitation and mortality providing important insight beyond strength testing.
© The Author 2016. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

BACKGROUND - Fibromyalgia is a common chronic pain condition that has a significant impact on quality of life and often leads to disability. To date, there have been few well-controlled trials assessing the utility of nonpharmacological treatment modalities such as transcutaneous electrical nerve stimulation (TENS) in the management of pain and improvement in function in individuals with fibromyalgia.
OBJECTIVES - The purpose of this study will be to complete a long-term, multicenter study to assess the effects of TENS in women with fibromyalgia.
DESIGN - This will be a phase II randomized, double-blind, placebo-controlled, multicenter clinical trial.
PARTICIPANTS - Three hundred forty-three participants with fibromyalgia will be recruited for this study.
INTERVENTION - Participants will be randomly assigned to 1 of 3 groups: the intervention (TENS), placebo, or no treatment. After completing the randomized period, all participants will receive the intervention for 1 month. The participants will be asked to use TENS at the highest tolerable level for at least 2 hours daily during physical activity.
MEASUREMENTS - The primary outcome will be pain with movement, with secondary outcomes assessing functional abilities, patient-reported outcomes, and quantitative sensory testing.
LIMITATIONS - Because having participants refrain from their typical medications is not practical, their usage and any change in medication use will be recorded.
CONCLUSIONS - The results of this study will provide some of the first evidence from a large-scale, double-blind, placebo-controlled trial on the effectiveness of TENS on pain control and quality-of-life changes in patients with fibromyalgia.
© 2015 American Physical Therapy Association.

AMP-activated protein kinase (AMPK) is a sensor of cellular energy status that plays a central role in skeletal muscle metabolism. We used skeletal muscle-specific AMPKα1α2 double-knockout (mdKO) mice to provide direct genetic evidence of the physiological importance of AMPK in regulating muscle exercise capacity, mitochondrial function, and contraction-stimulated glucose uptake. Exercise performance was significantly reduced in the mdKO mice, with a reduction in maximal force production and fatigue resistance. An increase in the proportion of myofibers with centralized nuclei was noted, as well as an elevated expression of interleukin 6 (IL-6) mRNA, possibly consistent with mild skeletal muscle injury. Notably, we found that AMPKα1 and AMPKα2 isoforms are dispensable for contraction-induced skeletal muscle glucose transport, except for male soleus muscle. However, the lack of skeletal muscle AMPK diminished maximal ADP-stimulated mitochondrial respiration, showing an impairment at complex I. This effect was not accompanied by changes in mitochondrial number, indicating that AMPK regulates muscle metabolic adaptation through the regulation of muscle mitochondrial oxidative capacity and mitochondrial substrate utilization but not baseline mitochondrial muscle content. Together, these results demonstrate that skeletal muscle AMPK has an unexpected role in the regulation of mitochondrial oxidative phosphorylation that contributes to the energy demands of the exercising muscle.-Lantier, L., Fentz, J., Mounier, R., Leclerc, J., Treebak, J. T., Pehmøller, C., Sanz, N., Sakakibara, I., Saint-Amand, E., Rimbaud, S., Maire, P., Marette, A., Ventura-Clapier, R., Ferry, A., Wojtaszewski, J. F. P., Foretz, M., Viollet, B. AMPK controls exercise endurance, mitochondrial oxidative capacity, and skeletal muscle integrity.
© FASEB.

BACKGROUND - Many patients on maintenance dialysis experience significant sleepiness and fatigue. However, the influence of the hemodialysis (HD) day and circadian rhythms on patients' symptoms have not been well characterized. We sought to use ecological momentary assessment to evaluate day-to-day and diurnal variability of fatigue, sleepiness, exhaustion and related symptoms in thrice-weekly maintenance HD patients.
METHODS - Subjects used a modified cellular phone to access an interactive voice response system that administered the Daytime Insomnia Symptom Scale (DISS). The DISS assessed subjective vitality, mood, and alertness through 19 questions using 7- point Likert scales. Subjects completed the DISS 4 times daily for 7 consecutive days. Factor analysis was conducted and a mean composite score of fatigue-sleepiness-exhaustion was created. Linear mixed regression models (LMM) were used to examine the association of time of day, dialysis day and fatigue, sleepiness, and exhaustion composite scores.
RESULTS - The 55 participants completed 1,252 of 1,540 (81%) possible assessments over the 7 day period. Multiple symptoms related to mood (e.g., feeling sad, feeling tense), cognition (e.g., difficulty concentrating), and fatigue (e.g., exhaustion, feeling sleepy) demonstrated significant daily and diurnal variation, with higher overall symptom scores noted on hemodialysis days and later in the day. In factor analysis, 4 factors explained the majority of the observed variance for DISS symptoms. Fatigue, sleepiness, and exhaustion loaded onto the same factor and were highly intercorrelated. In LMM, mean composite fatigue-sleepiness-exhaustion scores were associated with dialysis day (coefficient and 95% confidence interval [CI] 0.21 [0.02 - 0.39]) and time of day (coefficient and 95% CI 0.33 [0.25 - 0.41]. Observed associations were minimally affected by adjustment for demographics and common confounders.
CONCLUSIONS - Maintenance HD patients experience fatigue-sleepiness-exhaustion symptoms that demonstrate significant daily and diurnal variation. The variability in symptoms may contribute to poor symptom awareness by providers and greater misclassification bias of fatigue related symptoms in clinical studies.

Overexpression of vascular endothelial growth factor in renal cell carcinoma (RCC) leads to angiogenesis, tumor progression, and inhibition of immune function. We conducted the first phase II study to estimate the efficacy and safety of bevacizumab with high-dose interleukin-2 (IL-2) therapy in patients with metastatic RCC. Eligible patients had predominantly clear cell metastatic RCC, measurable disease, a Karnofsky Performance Status of ≥80%, and adequate end-organ function. IL-2 (600,000 IU/kg) was infused intravenously every 8 hours (maximum 28 doses) during two 5-day cycles on days 1 and 15 of each 84-day course. Bevacizumab (10 mg/kg) was infused intravenously every 2 weeks beginning 2 weeks before initiating IL-2. Fifty of 51 eligible patients from 8 centers were enrolled. Median progression-free survival (PFS) was 11.2 months (90% confidence interval, 5.7-17.7), and 2-year PFS was 18% (90% confidence interval, 8%-27%). Responses included 4 complete (8%) and 11 partial (22%) responses. Toxicities did not exceed those expected from each agent alone. Combining IL-2 plus bevacizumab is feasible, with a response rate and PFS at least as high as reported previously for the single agents. The regimen did not appear to enhance the rate of durable major responses over that of IL-2 alone.

PURPOSE - This is a pilot study investigating the effect of healing touch (HT) on fatigue in breast cancer patients undergoing radiation therapy (RT).
METHODS/DESIGN - This study presents the results of a within-subjects design randomized clinical trial where the treatment group was treated with HT, whereas the control group experienced sham therapy. The setting was a university RT clinic. The participants were breast cancer patients treated with lumpectomy or mastectomy, 21 to 75 years old with an Eastern Cooperative Oncology Group (ECOG) score of 0 to 2. The intervention was a 45-minute session of HT or sham therapy once a week during RT. Outcome measures included fatigue, quality of life (QOL), and anxiety/depression.
RESULT - A total of 70 patients were approached, with 41 completing the study. At completion, the HT participants tended to report higher levels of fatigue, statistically significant for interference ( : = .010) and usual fatigue ( : = .024). The control group tended to report greater reductions in fatigue relative to their own means than the HT group (Cohen's : = 0.30 to 0.49 vs 0.06 to 0.18, respectively). There were no statistically significant differences between the groups for QOL.
CONCLUSION - Our enrollment and retention indicate that HT is feasible for women during RT. Our pilot findings do not support a beneficial effect of HT on fatigue or QOL. Future research may explore increasing dose and teasing out therapist effect.

OBJECTIVE - To collect and analyze quality-of-life (QOL) data from PROvenge Treatment and Early Cancer Treatment trial (PROTECT, NCT00779402), a phase III, randomized controlled trial of sipuleucel-T in patients with asymptomatic androgen-dependent prostate cancer.
METHODS - Patients experiencing prostate-specific antigen relapse after radical prostatectomy entered a 3- to 4-month run-in phase of androgen-deprivation therapy (ADT), followed by 2:1 randomization to sipuleucel-T or control. QOL was assessed throughout the run-in and 26-week post-randomization phases using the Brief Fatigue Inventory (BFI), Linear Analog Self-Assessment (LASA) scale, Global Rating of Change (GRoC) scale, and an elicited symptoms list.
RESULTS - One hundred seventy-six patients were randomized into 2 groups, the sipuleucel-T group (n = 117) or the control group (n = 59). The sample provided 80% power to detect a difference in fatigue interference score between treatment arms of 0.9 points. QOL declined predictably during ADT. At week 26, 26.2% of sipuleucel-T-treated patients and 21.6% of control-treated patients (P = .68) reported fatigue in the previous week, and the mean score for fatigue interference in the past 24 hours was 0.9 for both arms (P = .88). Results were comparable for usual fatigue (P = .91) and worst fatigue (P >.99). Mean LASA scores decreased in both groups (P = .26). The proportion of patients reporting better overall QOL on GRoC was similar (P = .62).
CONCLUSION - There is no clinically significant negative impact on QOL after sipuleucel-T treatment compared with control after a period of ADT in patients with asymptomatic androgen-dependent prostate cancer.
Copyright © 2013 Elsevier Inc. All rights reserved.

OBJECTIVE - To identify muscle physiologic properties that may contribute to postexertional fatigue and malaise in women with fibromyalgia (FM).
METHODS - Healthy postmenopausal women with (n = 11) and without (n = 11) FM, ages 51-70 years, participated in this study. Physical characteristics and responses to self-reported questionnaires were evaluated. Strength loss and tissue oxygenation in response to a fatiguing exercise protocol were used to quantify fatigability and the local muscle hemodynamic profile. Muscle biopsies were performed to assess between-group differences in baseline muscle properties using histochemical, immunohistochemical, and electron microscopic analyses.
RESULTS - There was no significant difference between healthy controls and FM patients in muscle fatigue in response to exercise. However, self-reported fatigue and pain were correlated with prolonged loss of strength following 12 minutes of recovery in patients with FM. Although there was no difference in percent succinate dehydrogenase (SDH)-positive (type I) and SDH-negative (type II) fibers or in mean fiber cross-sectional area between groups, FM patients exhibited greater variability in fiber size and altered fiber size distribution. In healthy controls only, fatigue resistance was strongly correlated with the size of SDH-positive fibers and hemoglobin oxygenation. In contrast, FM patients with the highest percentage of SDH-positive fibers recovered strength most effectively, and this was correlated with capillary density. However, overall, capillary density was lower in the FM group.
CONCLUSION - Peripheral mechanisms, i.e., altered muscle fiber size distribution and decreased capillary density, may contribute to postexertional fatigue in FM. Understanding of these defects in fibromyalgic muscle may provide valuable insight with regard to treatment.
Copyright © 2013 by the American College of Rheumatology.

INTRODUCTION - Women with fibromyalgia (FM) have symptoms of increased muscular fatigue and reduced exercise tolerance, which may be associated with alterations in muscle microcirculation and oxygen metabolism. This study used near-infrared diffuse optical spectroscopies to noninvasively evaluate muscle blood flow, blood oxygenation and oxygen metabolism during leg fatiguing exercise and during arm arterial cuff occlusion in post-menopausal women with and without FM.
METHODS - Fourteen women with FM and twenty-three well-matched healthy controls participated in this study. For the fatiguing exercise protocol, the subject was instructed to perform 6 sets of 12 isometric contractions of knee extensor muscles with intensity steadily increasing from 20 to 70% maximal voluntary isometric contraction (MVIC). For the cuff occlusion protocol, forearm arterial blood flow was occluded via a tourniquet on the upper arm for 3 minutes. Leg or arm muscle hemodynamics, including relative blood flow (rBF), oxy- and deoxy-hemoglobin concentration ([HbO2] and [Hb]), total hemoglobin concentration (THC) and blood oxygen saturation (StO2), were continuously monitored throughout protocols using a custom-built hybrid diffuse optical instrument that combined a commercial near-infrared oximeter for tissue oxygenation measurements and a custom-designed diffuse correlation spectroscopy (DCS) flowmeter for tissue blood flow measurements. Relative oxygen extraction fraction (rOEF) and oxygen consumption rate (rVO2) were calculated from the measured blood flow and oxygenation data. Post-manipulation (fatiguing exercise or cuff occlusion) recovery in muscle hemodynamics was characterized by the recovery half-time, a time interval from the end of manipulation to the time that tissue hemodynamics reached a half-maximal value.
RESULTS - Subjects with FM had similar hemodynamic and metabolic response/recovery patterns as healthy controls during exercise and during arterial occlusion. However, tissue rOEF during exercise in subjects with FM was significantly lower than in healthy controls, and the half-times of oxygenation recovery (Δ[HbO2] and Δ[Hb]) were significantly longer following fatiguing exercise and cuff occlusion.
CONCLUSIONS - Our results suggest an alteration of muscle oxygen utilization in the FM population. This study demonstrates the potential of using combined diffuse optical spectroscopies (i.e., NIRS/DCS) to comprehensively evaluate tissue oxygen and flow kinetics in skeletal muscle.