Changes in spontaneous movement in response to silent gaps are not robust enough to indicate the perception of tinnitus in mice

Approaches to identify the perception of tinnitus in various animal models have been difficult to apply to mouse. As a result, mice have been underutilized to investigate the cellular, molecular, and genetic mechanisms underlying tinnitus. A recent study in guinea pigs identified a novel spontaneous behavior (unconditioned response), changes in movement during silent gaps, that identified a subgroup of animals presumably with tinnitus. Guinea pigs identified with tinnitus failed to ''freeze'' in response to silent gaps in sound. In the hope of developing a rapid and reliable assay for mice, we used a similar approach. C57BL/6J mice underwent three trials in which spontaneous movement was video recorded in the presence of white noise interrupted with six silent gaps. Movement metrics included velocity and body movement. Before the third trial, mice underwent either sham or noise exposure to induce hearing loss and tinnitus. Auditory brainstem responses before and after noise trauma confirmed normal hearing in sham-treated animals and hearing loss in the noise-exposed cohort. No differences in the various movement metrics were detected during the silent gaps either before or after sham/noise exposure. Variability in spontaneous movement both before and after sham/noise exposure was substantially greater in mice compared to guinea pigs. Thus, this assay is not sufficiently statistically powerful to identify changes in movement that might indicate tinnitus perception in mice. Previous observations also reported increased movement overall in guinea pigs identified as suffering tinnitus. In contrast, mice showed no statistically significant differences in movement between the three trials. Despite our results, other unconditioned (as well as conditioned) behaviors should be examined in mice to test their utility to detect changes that indicate the perception of tinnitus. Such assays are essential to accelerate the use of mouse models in tinnitus research

Declining NAD+ Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication during Aging

SummaryEver since eukaryotes subsumed the bacterial ancestor of mitochondria, the nuclear and mitochondrial genomes have had to closely coordinate their activities, as each encode different subunits of the oxidative phosphorylation (OXPHOS) system. Mitochondrial dysfunction is a hallmark of aging, but its causes are debated. We show that, during aging, there is a specific loss of mitochondrial, but not nuclear, encoded OXPHOS subunits. We trace the cause to an alternate PGC-1α/β-independent pathway of nuclear-mitochondrial communication that is induced by a decline in nuclear NAD+ and the accumulation of HIF-1α under normoxic conditions, with parallels to Warburg reprogramming. Deleting SIRT1 accelerates this process, whereas raising NAD+ levels in old mice restores mitochondrial function to that of a young mouse in a SIRT1-dependent manner. Thus, a pseudohypoxic state that disrupts PGC-1α/β-independent nuclear-mitochondrial communication contributes to the decline in mitochondrial function with age, a process that is apparently reversible

Exposure–response relationship of AMG 386 in combination with weekly paclitaxel in recurrent ovarian cancer and its implication for dose selection

To characterize exposure-response relationships of AMG 386 in a phase 2 study in advanced ovarian cancer for the facilitation of dose selection in future studies.A population pharmacokinetic model of AMG 386 (N = 141) was developed and applied in an exposure-response analysis using data from patients (N = 160) with recurrent ovarian cancer who received paclitaxel plus AMG 386 (3 or 10 mg/kg once weekly) or placebo. Reduction in the risk of progression or death with increasing exposure (steady-state area under the concentration-versus-time curve [AUC(ss)]) was assessed using Cox regression analyses. Confounding factors were tested in multivariate analysis. Alternative AMG 386 doses were explored with Monte Carlo simulations using population pharmacokinetic and parametric survival models.There was a trend toward increased PFS with increased AUC(ss) (hazard ratio [HR] for each one-unit increment in AUC(ss), 0.97; P = 0.097), suggesting that the maximum effect on prolonging PFS was not achieved at the highest dose tested (10 mg/kg). Among patients with AUC(ss) ≥ 9.6 mg h/mL, PFS was 8.1 months versus 5.7 months for AUC(ss) < 9.6 mg h/mL and 4.6 months for placebo. No relationship between AUC(ss) and grade ≥ 3 adverse events was observed. Simulations predicted that AMG 386 15 mg/kg once weekly would result in an AUC(ss) ≥ 9.6 mg h/mL in > 90% of patients with median PFS of 8.2 months versus 5.0 months for placebo (HR [15 mg/kg vs. placebo], 0.56).Increased exposure to AMG 386 was associated with improved clinical outcomes in recurrent ovarian cancer, supporting the evaluation of a higher dose in future studies

Paediatric schistosomiasis:What we know and what we need to know

Schistosomiasis affects over 200 million people worldwide, most of whom are children. Research and control strategies directed at preschool-aged children (PSAC), i.e., ≤5 years old, have lagged behind those in older children and adults. With the recent WHO revision of the schistosomiasis treatment guidelines to include PSAC, and the recognition of gaps in our current knowledge on the disease and its treatment in this age group, there is now a concerted effort to address these shortcomings. Global and national schistosome control strategies are yet to include PSAC in treatment schedules. Maximum impact of schistosome treatment programmes will be realised through effective treatment of PSAC. In this review, we (i) discuss the current knowledge on the dynamics and consequences of paediatric schistosomiasis and (ii) identify knowledge and policy gaps relevant to these areas and to the successful control of schistosome infection and disease in this age group. Herein, we highlight risk factors, immune mechanisms, pathology, and optimal timing for screening, diagnosis, and treatment of paediatric schistosomiasis. We also discuss the tools required for treating schistosomiasis in PSAC and strategies for accessing them for treatment