Age-Related Changes in the Relationship Between Auditory Brainstem Responses and Envelope-Following Responses

Hearing thresholds and wave amplitudes measured using auditory brainstem responses (ABRs) to brief sounds are the predominantly used clinical measures to objectively assess auditory function. However, frequency-following responses (FFRs) to tonal carriers and to the modulation envelope (envelope-following responses or EFRs) to longer and spectro-temporally modulated stimuli are rapidly gaining prominence as a measure of complex sound processing in the brainstem and midbrain. In spite of numerous studies reporting changes in hearing thresholds, ABR wave amplitudes, and the FFRs and EFRs under neurodegenerative conditions, including aging, the relationships between these metrics are not clearly understood. In this study, the relationships between ABR thresholds, ABR wave amplitudes, and EFRs are explored in a rodent model of aging. ABRs to broadband click stimuli and EFRs to sinusoidally amplitude-modulated noise carriers were measured in young (3–6 months) and aged (22–25 months) Fischer-344 rats. ABR thresholds and amplitudes of the different waves as well as phase-locking amplitudes of EFRs were calculated. Age-related differences were observed in all these measures, primarily as increases in ABR thresholds and decreases in ABR wave amplitudes and EFR phase-locking capacity. There were no observed correlations between the ABR thresholds and the ABR wave amplitudes. Significant correlations between the EFR amplitudes and ABR wave amplitudes were observed across a range of modulation frequencies in the young. However, no such significant correlations were found in the aged. The aged click ABR amplitudes were found to be lower than would be predicted using a linear regression model of the young, suggesting altered gain mechanisms in the relationship between ABRs and FFRs with age. These results suggest that ABR thresholds, ABR wave amplitudes, and EFRs measure complementary aspects of overlapping neurophysiological processes and the relationships between these measurements changes asymmetrically with age. Hence, measuring all three metrics provides a more complete assessment of auditory function, especially under pathological conditions like aging.     

自分泌运动因子受体基因及其干扰RNA表达载体的构建

目的 构建AMFR基因的表达载体和AMFRsiRNA表达载体，观察AMFRsiRNA对AMFR基因表达的影响。方法 采用PCR技术，扩增AMFR基因，并将其插入到带FLAG标签的真核表达载体上；利用RNAi技术，设计并合成了两条针对AMFR基因的siRNA，将其克隆到pSliencer 2.1-U6 neo表达载体上。将构建的AMFR基因表达载体和AMFRsiRNA表达载体共转染人胚肾细胞293T，通过Western blot实验了解AMFRsiRNA对AMFR基因表达的影响。结果 通过双酶切和测序鉴定表明，构建的AMFR基因表达载体和AMFRsiRNA表达载体序列正确；通过Western blot实验证明，构建的AMFRsiRNA能有效抑制AMFR基因的表达。结论 成功构建了AMFR基因表达载体和AMFRsiRNA表达载体，且表达的AMFRsiRNA能有效地抑制AMFR基因的表达。     

Abschätzung der Hörschwelle mit stationären auditorischen evozierten Potentialen: Probleme der digitalen Signalverarbeitung

The evaluation of hearing thresholds in human subjects using steady-state auditory evoked potentials (AEP) requires an appropriate test procedure to detect the response at poor signal to noise ratios. Differences in signal processing between transient and steady-state AEP are discussed and optimal conditions for recording of steady-state AEP in the frequency domain are established. 40-Hz-Click-AEP (5 subjects) und 40 Hz-AMFR (Amplitude Modulation Following Response, 11 subjects) were recorded in normal hearing subjects at stimulus levels ranging from 10 to 80 dB (nHL). An estimate of residual background noise for a narrow frequency band (30 … 50 Hz) was plotted as a function of the number of signal periods analysed. Differences in response amplitudes and signal to noise ratios between 40-Hz-Click-AEP and 40 Hz-AMFR were discussed.     

自分泌运动因子在乳腺癌中表达情况及与预后关系

目的研究自分泌运动因子（AMFR）在乳腺癌中的表达情况及其与预后的关系。方法使用实时荧光定量PCR和免疫组化的方法对AMFR在乳腺癌中的表达情况进行研究，并进行统计分析。结果在乳腺癌和癌旁正常组织中，AMFR表达在mRNA和蛋白水平表达均有差异。免疫组化分析发现AMFR表达水平与乳腺癌肿块大小、T期、N期和M期有关，而与年龄无关。生存分析发现AMFR表达高的患者预后差，可以作为一个预后指标。结论AMFR在乳腺癌中表达升高，其可能成为一个肿瘤治疗的新靶点和预后新指标。     

干扰和过表达自分泌运动因子受体对A172细胞侵袭力的影响

目的：在人胶质瘤A172细胞系中干扰和过表达自分泌运动因子受体（ autocrine motility factor re-ceptor， AMFR）后，研究AMFR对其侵袭力的影响。方法应用体外连接法将外源AMFR的DNA连接到带GFP的外源干扰（ shRNA）和过表达（ cDNA）腺病毒基因组HK293中，运用荧光定量PCR （ QPCR）法得出其扩增曲线检验二种病毒的滴度，然后运用RT-PCR和Western印迹法来检测二种病毒是否成功干扰和过表达，和只带GFP标签正常的A172（ con A172）相比较，用MTT的方法来检测A172细胞增殖能力，应用伤口愈合实验（ wound healing assay）检测A172的细胞迁移能力， Transwell实验来检测细胞侵袭能力，从而研究AMFR与胶质瘤细胞的迁移能力的相关性。结果成功干扰A172细胞系（ shRNAA172）和过表达细胞系（ cDNAA172）中的AMFR，和正常的A172细胞系比较， AMFR干扰的细胞增殖能力、迁移和侵袭能力降低，过表达的AMFR A172细胞增殖能力、迁移和侵袭能力增强。结论 AMFR的表达量与胶质瘤细胞迁移和侵袭能力呈正相关。     

自分泌运动因子及其受体在恶性肿瘤侵袭和转移中的作用

肿瘤细胞分泌的自分泌运动因子和受体,一种跨膜糖蛋白,结合后,经胞吞或者囊泡作用进入细胞内,在肿瘤的侵袭和转移方面发挥作用。主要作用：（1）上调肿瘤细胞整合素的表达和基质金属蛋白酶3的分泌,改变细胞-基质之间的黏附性以利于肿瘤细胞迁移。（2）下调E-钙黏蛋白的表达,使纤连蛋白和波形蛋白表达增加,促进上皮组织向间叶组织转化。（3）通过血管内皮生长因子受体Flt-1表达及血管内皮细胞的迁移,促进肿瘤新生血管的形成。自分泌运动因子及其受体通过多种途径参与肿瘤的侵袭和转移。     

Monitoring residual hearing during cochlear implantation by intra-operative brainstem audiometry

OBJECTIVE: Aim of this paper is to prove the applicability of intra-operative recordings of auditory brainstem responses during cochlear implantation. METHODS: The clinical practicability of intra-operative monitoring of hearing thresholds (Notched-Noise BERA, Amplitude Modulation Following Response [AMFR]) is presented in the respective case. The recordings were performed prior to the cochlear implantation and were compared with those obtained during and after cochlear implantation. RESULTS: It is demonstrated that the patient's cochlear function can be monitored; residual hearing is available after surgery. CONCLUSION: The possibility of monitoring of hearing thresholds may add some security to the concept of electric-acoustic stimulation.     

Cytochrome P450 endoplasmic reticulum-associated degradation (ERAD): therapeutic and pathophysiological implications

The hepatic endoplasmic reticulum (ER)-anchored cytochromes P450 (P450s) are mixed-function oxidases engaged in the biotransformation of physiologically relevant endobiotics as well as of myriad xenobiotics of therapeutic and environmental relevance. P450 ER-content and hence function is regulated by their coordinated hemoprotein syntheses and proteolytic turnover. Such P450 proteolytic turnover occurs through a process known as ER-associated degradation (ERAD) that involves ubiquitin-dependent proteasomal degradation (UPD) and/or autophagic-lysosomal degradation (ALD). Herein, on the basis of available literature reports and our own recent findings of in vitro as well as in vivo experimental studies, we discuss the therapeutic and pathophysiological implications of altered P450 ERAD and its plausible clinical relevance. We specifically (i) describe the P450 ERAD-machinery and how it may be repurposed for the generation of antigenic P450 peptides involved in P450 autoantibody pathogenesis in drug-induced acute hypersensitivity reactions and liver injury, or viral hepatitis; (ii) discuss the relevance of accelerated or disrupted P450-ERAD to the pharmacological and/or toxicological effects of clinically relevant P450 drug substrates; and (iii) detail the pathophysiological consequences of disrupted P450 ERAD, contributing to non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) under certain synergistic cellular conditions.