Verbal Learning and Memory After Cochlear Implantation in Postlingually Deaf Adults: Some New Findings with the CVLT-II

OBJECTIVES: Despite the importance of verbal learning and memory in speech and language processing, this domain of cognitive functioning has been virtually ignored in clinical studies of hearing loss and cochlear implants in both adults and children. In this article, we report the results of two studies that used a newly developed visually based version of the California Verbal Learning Test-Second Edition (CVLT-II), a well-known normed neuropsychological measure of verbal learning and memory. DESIGN: The first study established the validity and feasibility of a computer-controlled visual version of the CVLT-II, which eliminates the effects of audibility of spoken stimuli, in groups of young normal-hearing and older normal-hearing (ONH) adults. A second study was then carried out using the visual CVLT-II format with a group of older postlingually deaf experienced cochlear implant (ECI) users (N = 25) and a group of ONH controls (N = 25) who were matched to ECI users for age, socioeconomic status, and nonverbal IQ. In addition to the visual CVLT-II, subjects provided data on demographics, hearing history, nonverbal IQ, reading fluency, vocabulary, and short-term memory span for visually presented digits. ECI participants were also tested for speech recognition in quiet. RESULTS: The ECI and ONH groups did not differ on most measures of verbal learning and memory obtained with the visual CVLT-II, but deficits were identified in ECI participants that were related to recency recall, the buildup of proactive interference, and retrieval-induced forgetting. Within the ECI group, nonverbal fluid IQ, reading fluency, and resistance to the buildup of proactive interference from the CVLT-II consistently predicted better speech recognition outcomes. CONCLUSIONS: Results from this study suggest that several underlying foundational neurocognitive abilities are related to core speech perception outcomes after implantation in older adults. Implications of these findings for explaining individual differences and variability and predicting speech recognition outcomes after implantation are discussed

RAMP3 determines rapid recycling of atypical chemokine receptor-3 for guided angiogenesis.

Receptor-activity-modifying proteins (RAMPs) are single transmembrane-spanning proteins which serve as molecular chaperones and allosteric modulators of G-protein-coupled receptors (GPCRs) and their signaling pathways. Although RAMPs have been previously studied in the context of their effects on Family B GPCRs, the coevolution of RAMPs with many GPCR families suggests an expanded repertoire of potential interactions. Using bioluminescence resonance energy transfer-based and cell-surface expression approaches, we comprehensively screen for RAMP interactions within the chemokine receptor family and identify robust interactions between RAMPs and nearly all chemokine receptors. Most notably, we identify robust RAMP interaction with atypical chemokine receptors (ACKRs), which function to establish chemotactic gradients for directed cell migration. Specifically, RAMP3 association with atypical chemokine receptor 3 (ACKR3) diminishes adrenomedullin (AM) ligand availability without changing G-protein coupling. Instead, RAMP3 is required for the rapid recycling of ACKR3 to the plasma membrane through Rab4-positive vesicles following either AM or SDF-1/CXCL12 binding, thereby enabling formation of dynamic spatiotemporal chemotactic gradients. Consequently, genetic deletion of either ACKR3 or RAMP3 in mice abolishes directed cell migration of retinal angiogenesis. Thus, RAMP association with chemokine receptor family members represents a molecular interaction to control receptor signaling and trafficking properties.This work was supported by NIH Grants RO1-DK099156, RO1-HD060860, and RO1-HL129086 (to K.M.C.); American Heart Association Innovator Award 16IRG27260077 (to K.M.C.); NIH Grant F32-HL134279 (to D.I.M.); American Heart Association Grant 15POST25270006 (to R.B.D.); NIH Grant F31-HL143836 (to N.R.N.); Biotechnology and Biological Sciences Research Council (BBSRC) Grant BB/M00015X/2 (to G.L.); and BBSRC Doctoral Training Partnership Grant BB/JO14540/1 (to M.H.)

The rsmS (ybaM) mutation causes bypass suppression of the RsmAB post-transcriptional virulence regulation system in enterobacterial phytopathogens.

Plant cell wall degrading enzymes (PCWDEs) are the primary virulence determinants of soft rotting bacteria such as the potato pathogen, Pectobacterium atrosepticum. The regulation of secondary metabolite (Rsm) system controls production of PCWDEs in response to changing nutrient conditions. This work identified a new suppressor of an rsmB mutation - ECA1172 or rsmS (rsmB suppressor). Mutants defective in rsmB (encoding a small regulatory RNA), show reduced elaboration of the quorum sensing molecule (N-3-oxohexanoyl-homoserine lactone; OHHL) and PCWDEs. However, OHHL and PCWDE production were partially restored in an rsmB, rsmS double mutant. Single rsmS mutants, overproduced PCWDEs and OHHL relative to wild type P. atrosepticum and exhibited hypervirulence in potato. RsmS overproduction also resulted in increased PCWDEs and OHHL. Homology searches revealed rsmS conservation across pathogens such as Escherichia coli (ybaM), Dickeya solani, Klebsiella pneumoniae and Shigella flexneri. An rsmS mutant of Pectobacterium carotovorum ATCC39048 showed bypass of rsmB-dependent repression of PCWDEs and OHHL production. P. carotovorum ATCC39048 produces the β-lactam antibiotic, 1-carbapen-2-em-3-carboxylic acid (a carbapenem). Production of the antibiotic was repressed in an rsmB mutant but partially restored in an rsmB, rsmS double mutant. This work highlights the importance of RsmS, as a conserved pleiotropic regulator of virulence and antibiotic biosynthesis.James Hutton Institut

A digital pathology tool for quantification of color features in histologic specimens.

In preclinical research, histological analysis of tissue samples is often limited to qualitative or semiquantitative scoring assessments. The reliability of this analysis can be impaired by the subjectivity of these approaches, even when read by experienced pathologists. Furthermore, the laborious nature of manual image assessments often leads to the analysis being restricted to a relatively small number of images that may not accurately represent the whole sample. Thus, there is a clear need for automated image analysis tools that can provide robust and rapid quantification of histologic samples from paraffin-embedded or cryopreserved tissues. To address this need, we have developed a color image analysis algorithm (DigiPath) to quantify distinct color features in histologic sections. We demonstrate the utility of this tool across multiple types of tissue samples and pathologic features, and compare results from our program to other quantitative approaches such as color thresholding and hand tracing. We believe this tool will enable more thorough and reliable characterization of histological samples to facilitate better rigor and reproducibility in tissue-based analyses

A Phase I study evaluating the safety and immunogenicity of MVA85A, a candidate TB vaccine, in HIV-infected adults

Objectives Control of the tuberculosis (TB) epidemic is a global health priority and one that is likely to be achieved only through vaccination. The critical overlap with the HIV epidemic requires any effective TB vaccine regimen to be safe in individuals who are infected with HIV. The objectives of this clinical trial were to evaluate the safety and immunogenicity of a leading candidate TB vaccine, MVA85A, in healthy, HIV-infected adults. Design This was an open-label Phase I trial, performed in 20 healthy HIV-infected, antiretroviral-naïve subjects. Two different doses of MVA85A were each evaluated as a single immunisation in 10 subjects, with 24 weeks of follow-up. The safety of MVA85A was assessed by clinical and laboratory markers, including regular CD4 counts and HIV RNA load measurements. Vaccine immunogenicity was assessed by ex vivo interferon γ (IFN-γ) ELISpot assays and flow-cytometric analysis. Results MVA85A was safe in subjects with HIV infection, with an adverse-event profile comparable with historical data from previous trials in HIV-uninfected subjects. There were no clinically significant vaccine-related changes in CD4 count or HIV RNA load in any subjects, and no evidence from qPCR analyses to indicate that MVA85A vaccination leads to widespread preferential infection of vaccine-induced CD4 T cell populations. Both doses of MVA85A induced an antigen-specific IFN-γ response that was durable for 24 weeks, although of a lesser magnitude compared with historical data from HIV-uninfected subjects. The functional quality of the vaccine-induced T cell response in HIV-infected subjects was remarkably comparable with that observed in healthy HIV-uninfected controls, but less durable. Conclusion MVA85A is safe and immunogenic in healthy adults infected with HIV. Further safety and efficacy evaluation of this candidate vaccine in TB- and HIV-endemic areas is merited

Acquired flavor acceptance and intake facilitated by monosodium glutamate in humans

Monosodium glutamate (MSG) is known to enhance liking for the flavor of savory foods, but whether associations between flavors and effects of MSG lead to changes in subsequent liking and intake for the flavor alone is unclear. To test this, 32 volunteers evaluated and consumed a novel savory soup with no added MSG before and after four training sessions where the same soup was consumed either unchanged (Control) or with added MSG. The addition of MSG during training increased both pleasantness and savory character of the soup and resulted in a larger increase in rated pleasantness of the soup in the MSG-trained relative to control condition when the soup was re-evaluated Post-training without MSG. There was also a significant increase in voluntary soup intake Post-training after the soup had been paired with MSG but not in the Control condition, and rated hunger increased more after tasting the soup Post-training in the MSG-trained but not Control condition. These findings demonstrate that co-experience of a savory flavor and MSG can result in increased subsequent liking and intake for the flavor in the absence of MSG, and possible explanations for how MSG reinforces learning are discussed

Development of a Reliable Surgical Quality Assurance System for 2-stage Esophagectomy in Randomized Controlled Trials

Objective: The aim was to develop a reliable surgical quality assurance system for 2-stage esophagectomy. This development was conducted during the pilot phase of the multicenter ROMIO trial, collaborating with international experts. Summary of Background Data: There is evidence that the quality of surgical performance in randomized controlled trials influences clinical outcomes, quality of lymphadenectomy and loco-regional recurrence. Methods: Standardization of 2-stage esophagectomy was based on structured observations, semi-structured interviews, hierarchical task analysis, and a Delphi consensus process. This standardization provided the structure for the operation manual and video and photographic assessment tools. Reliability was examined using generalizability theory. Results: Hierarchical task analysis for 2-stage esophagectomy comprised fifty-four steps. Consensus (75%) agreement was reached on thirty-nine steps, whereas fifteen steps had a majority decision. An operation manual and record were created. A thirty five-item video assessment tool was developed that assessed the process (safety and efficiency) and quality of the end product (anatomy exposed and lymphadenectomy performed) of the operation. The quality of the end product section was used as a twenty seven-item photographic assessment tool. Thirty-one videos and fifty-three photographic series were submitted from the ROMIO pilot phase for assessment. The overall Gcoefficient for the video assessment tool was 0.744, and for the photographic assessment tool was 0.700. Conclusions: A reliable surgical quality assurance system for 2-stage esophagectomy has been developed for surgical oncology randomized controlled trials