Evaluation of a revised indication for determining adult cochlear implant candidacy.

OBJECTIVE: To evaluate the use of monosyllabic word recognition versus sentence recognition to determine candidacy and long-term benefit for cochlear implantation. STUDY DESIGN: Prospective multi-center single-subject design. METHODS: A total of 21 adults aged 18 years and older with bilateral moderate to profound sensorineural hearing loss and low monosyllabic word scores received unilateral cochlear implantation. The consonant-nucleus-consonant (CNC) word test was the central measure of pre- and postoperative performance. Additional speech understanding tests included the Hearing in Noise Test sentences in quiet and AzBio sentences in +5 dB signal-to-noise ratio (SNR). Quality of life (QoL) was measured using the Abbreviated Profile of Hearing Aid Benefit and Health Utilities Index. RESULTS: Performance on sentence recognition reached the ceiling of the test after only 3 months of implant use. In contrast, none of the participants in this study reached a score of 80% on CNC word recognition, even at the 12-month postoperative test interval. Measures of QoL related to hearing were also significantly improved following implantation. CONCLUSION: Results of this study demonstrate that monosyllabic words are appropriate for determining preoperative candidate and measuring long-term postoperative speech recognition performance. LEVEL OF EVIDENCE: 2c. Laryngoscope, 127:2368-2374, 2017.

MicroRNA expression profile in human macrophages in response to Leishmania major infection.

BACKGROUND: Leishmania (L.) are intracellular protozoan parasites able to survive and replicate in the hostile phagolysosomal environment of infected macrophages. They cause leishmaniasis, a heterogeneous group of worldwide-distributed affections, representing a paradigm of neglected diseases that are mainly embedded in impoverished populations. To establish successful infection and ensure their own survival, Leishmania have developed sophisticated strategies to subvert the host macrophage responses. Despite a wealth of gained crucial information, these strategies still remain poorly understood. MicroRNAs (miRNAs), an evolutionarily conserved class of endogenous 22-nucleotide non-coding RNAs, are described to participate in the regulation of almost every cellular process investigated so far. They regulate the expression of target genes both at the levels of mRNA stability and translation; changes in their expression have a profound effect on their target transcripts. METHODOLOGY/PRINCIPAL FINDINGS: We report in this study a comprehensive analysis of miRNA expression profiles in L. major-infected human primary macrophages of three healthy donors assessed at different time-points post-infection (three to 24 h). We show that expression of 64 out of 365 analyzed miRNAs was consistently deregulated upon infection with the same trends in all donors. Among these, several are known to be induced by TLR-dependent responses. GO enrichment analysis of experimentally validated miRNA-targeted genes revealed that several pathways and molecular functions were disturbed upon parasite infection. Finally, following parasite infection, miR-210 abundance was enhanced in HIF-1α-dependent manner, though it did not contribute to inhibiting anti-apoptotic pathways through pro-apoptotic caspase-3 regulation. CONCLUSIONS/SIGNIFICANCE: Our data suggest that alteration in miRNA levels likely plays an important role in regulating macrophage functions following L. major infection. These results could contribute to better understanding of the dynamics of gene expression in host cells during leishmaniasis.

LPA modulates monocyte migration directly and via LPA-stimulated endothelial cells.

Lysophosphatidic acid (LPA) is a bioactive lysophospholipid ligand present in oxidized low-density lipoprotein. The effects of LPA were investigated, first separately on endothelial cells (EC) and monocytes. Using Ki16425 (an LPA(1) and LPA(3) receptor antagonist), GW9662 [a peroxisome proliferator-activator receptor (PPARgamma) antagonist], and pertussis toxin (that inhibits G(i/o)), we demonstrate that LPA enhances IL-8 and monocyte chemoattractant protein-1 expression through a LPA(1)-, LPA(3)-, G(i/o)- and PPARgamma-dependent manner in the EAhy926 cells. The effect of LPA on chemokine overexpression was confirmed in human umbilical vein endothelial cells. LPA was able to enhance monocyte migration at concentrations <1 microM and to inhibit their migration at LPA concentrations >1 microM, as demonstrated by using a chemotaxis assay. We then investigated the effects of LPA on the cross-talk between EC and monocytes by evaluating the chemotactic activity in the supernatants of LPA-treated EC. At 1 microM LPA, both cell types respond cooperatively, favoring monocyte migration. At higher LPA concentration (25 microM), the chemotactic response varies as a function of time. After 4 h, the chemotactic effect of the cytokines secreted by the EC is counteracted by the direct inhibitory effect of LPA on monocytes. For longer periods of time (24 h), we observe a monocyte migration, probably due to lowered concentrations of bioactive LPA, given the induction of lipid phosphate phosphatase-2 in monocytes that may inactivate LPA. These results suggest that LPA activates EC to secrete chemokines that in combination with LPA itself might favor or not favor interactions between endothelium and circulating monocytes.

Upregulation of pentraxin-3 in human endothelial cells after lysophosphatidic acid exposure.

OBJECTIVE: The earliest event in atherogenesis appears to be endothelium dysfunction. Lysophosphatidic acid (LPA), one of the major bioactive lipid components of oxidized low-density lipoproteins (oxLDL), can cause the activation of endothelial cells (ECs), which start to secrete multiple proinflammatory polypeptides/proteins. The purpose of this study was to better document the proatherogenic properties of LPA using a subproteomic approach focused on the secretome of LPA-treated ECs. METHODS AND RESULTS: The secretome of LPA-treated ECs was analyzed using the 2D-DIGE approach. Among the 20 spots displaying significant variations of abundance compared with the control cells, we identified pentraxin-3 by mass spectrometry. Pentraxin-3 upregulation was confirmed at the mRNA and protein level, both on immortalized and primary ECs. LPA- but also oxLDL-induced pentraxin-3 upregulation was reduced in the presence of an antagonist of the LPA-receptors and largely dependent on NFkappaB activation. Finally, we demonstrated, for the first time, the chemotactic activity of pentraxin-3 on human THP-1 monocytes by using a chemotaxis assay. CONCLUSIONS: Our findings favor the proatherogenic role of LPA, a bioactive lipid produced by activated platelets and present in oxLDL, because it enhances pentraxin-3 secretion that could contribute to the accumulation of monocytes in the atherosclerotic lesion.

Objective findings with malpositioning of a nucleus 24RE(CA) cochlear implant.

BACKGROUND: Proper intracochlear placement of cochlear implant electrode arrays is believed to be important for optimum speech perception results. However, objective tests of cochlear implant function typically provide little or no information about the intracochlear placement of the array. We report the results for a variety of objective tests, including averaged electrode voltage (AEV) measurements, in a patient where the electrode array had folded up on itself during insertion. PURPOSE: To determine whether any of the objective measures provided evidence of incorrect electrode placement. RESEARCH DESIGN: Objective test data are reported for a patient with an incorrectly positioned electrode array, prior to and following reimplantation, and compared to data obtained in 42 patients with normal insertions. STUDY SAMPLE: One patient with an incorrectly placed electrode array, prior to and following reimplantation, and a sample of 42 implant recipients with correct insertions. INTERVENTION: The patient with the malpositioned electrode array was explanted and reimplanted. The results for the first and the second implant, with regards to objective test results, are compared. The results are also compared to the data obtained on 42 implant recipients with normal insertions. DATA COLLECTION AND ANALYSIS: The objective test data (primarily AEV data) are compared with AEV results obtained in 42 patients with normal electrode insertions. RESULTS AND CONCLUSIONS: Although the electrode array had folded up on itself during insertion, intraoperative electrode impedances and VIII nerve responses, as well as postoperative electrically evoked auditory brainstem responses, were within normal limits. However, averaged electrode voltages, obtained with the Nucleus Crystal Integrity Test system, were abnormal and consistent with a low-impedance pathway between the apical and middle portions of the electrode array.