Anti-cytomegalovirus antibody levels stratify human immune profiles across the lifespan.

Human cytomegalovirus (hCMV) is a ubiquitous latent persistent herpesvirus infecting 60-90% of the population worldwide. hCMV carriage in immunocompetent people is asymptomatic; thus, hCMV can be considered a component of normative aging. However, hCMV powerfully modulates many features of the immune, and likely other, systems and organs. Questions remain as to how hCMV carriage affects the human host. We used anti-CMV antibody titers as a stratifying criterion to examine the impact of "intensity" of hCMV infection as a potential biomarker of aging, inflammation, and immune homeostasis in a cohort of 247 participants stratified into younger (21-40 years) and older (> 65 years of age) groups. We showed that anti-CMV antibody titers increased with age and directly correlated to increased levels of soluble tumor necrosis factor (sTNFR) I in younger but not older participants. CD8 + cell numbers were reduced in the older group due to the loss in CD8 + T naïve (Tn) cells. In CMV carriers and, in particular, in anti-CMV Ab-high participants, this loss was mitigated or reversed by an increase in the numbers of CD8 + T effector memory (Tem) and T effector memory reexpressing CD45RA (Temra) cells. Analysis of CD38, HLA-DR, and CD57 expression revealed subset (CD4 or CD8)-specific changes that correlated with anti-CMV Ab levels. In addition, anti-CMV Ab levels predicted anti-CMV CD8 T cell responsiveness to different CMV open reading frames (ORFs) selectively in older participants, which correlated to the transcriptional order of expression of specific CMV ORFs. Implications of these results for the potential predictive value of anti-CMV Ab titers during aging are discussed.

Preimplant Hearing Aid Fittings and Aided Audibility for Pediatric Cochlear Implant Recipients.

BACKGROUND: Audibility of speech for children with hearing loss (HL) depends on the degree of HL and the fitting of the hearing aids (HAs) themselves. Many studies on cochlear implant (CI) users have demonstrated that preimplant hearing is associated with postimplant outcomes, but there have been very few reports on the fitting of HAs before surgery. PURPOSE: The aims of this study were to characterize HA fittings and aided audibility of speech for pediatric HA users with severe to profound HL and to examine the relation between preimplant aided audibility and postimplant speech perception. RESEARCH DESIGN: A descriptive/observational and correlational study. Audiologic records of pediatric CI participants involved in a larger study examining the effects of early acoustic hearing were analyzed retrospectively; when available, these records included HA verification and speech recognition performance. STUDY SAMPLE: The CI participants were enrolled in audiology centers and oral schools for the deaf across the United States. DATA COLLECTION AND ANALYSIS: To determine whether deviations from prescribed DSL target were significantly greater than zero, 95% confidence intervals of the mean deviation were calculated for each frequency (250, 500, 1000, 2000, and 4000 Hz). Correlational analyses were used to examine the relationship between preimplant aided Speech Intelligibility Indices (SIIs) and postimplant speech perception in noise. Correlational analyses were also used to explore the relationship between preimplant aided SIIs and demographic data. T-tests were used to compare preimplant-aided SIIs of HAs of listeners who later became users of either sequential CIs, simultaneous CIs, or bimodal devices. RESULTS: Preimplant fittings of HAs were generally very close to prescriptive targets, except at 4000 Hz for those HAs with active frequency-lowering processing, and preimplant SIIs, albeit low, were correlated with postimplant speech recognition performance in noise. These results suggest that aided audibility should be maximized throughout the HA trial for later speech recognition purposes. CONCLUSIONS: It is recommended that HA fittings be optimized to support speech audibility even when considering implantation. In addition to the age at which HA use begins, the aided audibility itself is important in determining CI candidacy and decisions regarding bimodal HA use.

Effects of Exposure and Vowel Space Distribution on Phonetic Drift: Evidence from American English Learners of French.

Recent work by Chang has shown that even at the very earliest stages of second language (L2) acquisition, the phonetic implementation of speakers' native English phoneme categories is slightly modified by contact with L2 Korean, which is referred to as "phonetic drift." This study investigates whether rapid phonetic drift generalizes to another pairing of languages. We examined naïve American English learners of French, who were recorded producing both American English and French vowels after one and six weeks of a study abroad program in Paris. In addition, the Study Abroad group is compared with proficient American English L1 speakers of French who have been residents of Paris for at least five years, to investigate the impact of long-term use of an L2 on the vowel categories of L1. Whereas the Study Abroad group showed no evidence of phonetic drift after six weeks, the Paris Residents' American English vowel space shifted along F1 and several English vowels demonstrated clear movement toward French monolingual norms. A closer look at the high vowels provides insight into how phonetic categories are influenced both by drift and by a pressure to keep vowel categories distinct between the languages. The results are also discussed with respect to potential effects of the size of the vowel inventory and the amount of input required to cause phonetic drift.

Alcohol and other substance use among a sample of young people in the Solomon Islands.

OBJECTIVE: Investigate alcohol and other substance use, with a focus on harmful alcohol use patterns, among young people in the Solomon Islands. METHODS: A structured, interviewer-administered questionnaire was administered to respondents aged 15-24 years across four of the country's provinces in late 2015. RESULTS: Four hundred young people completed the questionnaire across urban, peri-urban and rural communities. The most common substances ever used by participants were betel nut (94%), licit/store-bought and/or illicit alcohol (79%) and tobacco (76%). Lifetime and recent substance use was particularly common among male respondents; e.g. 89% of male participants reported ever using any alcohol versus 54% of females (p<0.001). Harmful alcohol use patterns were common. CONCLUSIONS: Our sample generally reported higher levels of substance use compared to previous research in the Solomon Islands, including in relation to the country's relatively recent (2012/13) Household Income and Expenditure Survey. Implications for public health: Our study made considerable advances in addressing key knowledge gaps regarding alcohol and other substance use among young people in the Solomon Islands. Evidence-based initiatives to address early initiation of alcohol and other substance use and the progression to more problematic use patterns among young people in the Solomon Islands need to be explored.

Cystic fibrosis CFBE41o- cells contain TLR1 SNP I602S and fail to respond to Mycobacterium abscessus.

BACKGROUND: Mycobacterium abscessus causes lung infection in patients with cystic fibrosis. M. abscessus stimulates the host innate immune response via TLR2 on respiratory epithelial cells. Signaling through TLR2 requires the formation of TLR2/TLR1 heterodimers on the cell surface. METHODS: The ability of M. abscessus to stimulate the innate immune response of cystic fibrosis CFBE41o- respiratory epithelial cells was measured as expression of HßD2 by RT PCR, and release of IL-8 by ELISA. Genotyping of CFBE41o- TLR polymorphisms was carried out. RESULTS: CFBE41o- cells are hyporesponsive to M. abscessus. They are homozygous for the TLR1 SNP I602S which has been demonstrated to cause diminished cellular responses to TLR2 agonists. CONCLUSIONS: Homozygosity for I602S is prevalent in Western Europeans and North American Caucasians, the same demographic in which the ΔF508 mutation is present. This SNP may play a role in the pathogenesis of M. abscessus lung infection in patients with cystic fibrosis.

Exaggerated neutrophil-mediated reperfusion injury after ischemic stroke in a rodent model of type 2 diabetes.

OBJECTIVE: We tested the hypothesis that both chronic and acute inflammatory processes contribute to worse reperfusion injury and stroke outcome in an experimental model of T2DM. MATERIALS AND METHODS: Twelve- to thirteen-week-old male Zucker Diabetic Fatty (ZDF) rats vs. Zucker Lean Controls (ZLC) rats were tested at baseline and after middle cerebral artery occlusion (ischemia) and reperfusion (I-R). Neutrophil adhesion to the cerebral microcirculation, neutrophil expression of CD11b, infarction size, edema, neurologic function, sICAM, and cerebral expression of neutrophil-endothelial inflammatory genes were measured. RESULTS: At baseline, CD11b and sICAM were significantly increased in ZDF vs. ZLC animals (p < 0.05). After I-R, significantly more neutrophil adhesion and cell aggregates were observed in ZDF vs. ZLC (p < 0.05); infarction size, edema, and neurologic function were significantly worse in ZDF vs. ZLC (p < 0.05). CD11b and sICAM-1 remained significantly increased in ZDFs (p < 0.05), and cerebral expression of IL-1ß, GRO/KC, E-selectin, and sICAM were significantly induced in ZDF, but not ZLC groups (p < 0.05) after 2.5 hours of reperfusion. CONCLUSION: Both sides of the neutrophil-endothelial interface appear to be primed prior to I-R, and remain significantly more activated during I-R in an experimental model of T2DM. Consequently, reperfusion injury appears to play a significant role in poor stroke outcome in T2DM.

Deletion of the mmpL4b gene in the Mycobacterium abscessus glycopeptidolipid biosynthetic pathway results in loss of surface colonization capability, but enhanced ability to replicate in human macrophages and stimulate their innate immune response.

Mycobacterium abscessus is considered to be the most virulent of the rapidly growing mycobacteria. Generation of bacterial gene knockout mutants has been a useful tool for studying factors that contribute to virulence of pathogenic bacteria. Until recently, the optimal genetic approach to generation of M. abscessus gene knockout mutants was not clear. Based on the recent identification of genetic recombineering as the preferred approach, a M. abscessus mutant was generated in which the gene mmpL4b, critical to glycopeptidolipid synthesis, was deleted. Compared to the previously well-characterized parental strain 390S, the mmpL4B deletion mutant had lost sliding motility and the ability to form biofilm, but acquired the ability to replicate in human macrophages and stimulate macrophage Toll-like receptor 2. This study demonstrates that deletion of a gene associated with expression of a cell-wall lipid can result in acquisition of an immunostimulatory, invasive bacterial phenotype and has important implications for the study of M. abscessus pathogenesis at the cellular level.

Mycobacterium abscessus glycopeptidolipid prevents respiratory epithelial TLR2 signaling as measured by HßD2 gene expression and IL-8 release.

Mycobacterium abscessus has emerged as an important cause of lung infection, particularly in patients with bronchiectasis. Innate immune responses must be highly effective at preventing infection with M. abscessus because it is a ubiquitous environmental saprophyte and normal hosts are not commonly infected. M. abscessus exists as either a glycopeptidolipid (GPL) expressing variant (smooth phenotype) in which GPL masks underlying bioactive cell wall lipids, or as a variant lacking GPL which is immunostimulatory and invasive in macrophage infection models. Respiratory epithelium has been increasingly recognized as playing an important role in the innate immune response to pulmonary pathogens. Respiratory epithelial cells express toll-like receptors (TLRs) which mediate the innate immune response to pulmonary pathogens. Both interleukin-8 (IL-8) and human ß-defensin 2 (HßD2) are expressed by respiratory epithelial cells in response to toll-like receptor 2 (TLR2) receptor stimulation. In this study, we demonstrate that respiratory epithelial cells respond to M. abscessus variants lacking GPL with expression of IL-8 and HßD2. Furthermore, we demonstrate that this interaction is mediated through TLR2. Conversely, M. abscessus expressing GPL does not stimulate expression of IL-8 or HßD2 by respiratory epithelial cells which is consistent with "masking" of underlying bioactive cell wall lipids by GPL. Because GPL-expressing smooth variants are the predominant phenotype existing in the environment, this provides an explanation whereby initial M. abscessus colonization of abnormal lung airways escapes detection by the innate immune system.

Risk factors for death after sepsis in patients immunosuppressed before the onset of sepsis.

Few studies have focused on sepsis in patients with pre-existing immunosuppression. Since the numbers and the incidence of sepsis are increasing, sepsis in immunosuppressed patients will increase in importance. We studied the epidemiology of sepsis and risk factors for 28-d mortality in patients immunosuppressed prior to the onset of sepsis using data from the Academic Medical Center Consortium's (AMCC) prospective observational cohort study of sepsis. We compared characteristics of immunosuppressed (n =412) and immunocompetent (n =754) patients. Immunosuppressed patients were younger and more likely to have underlying liver or lung disease, and nosocomial infection or bloodstream infection of unknown source when presenting with sepsis. They were also more likely to die within 28 d compared to immunocompetent patients (adjusted relative risk 1.62, 95% CI 1.38 - 1.91). Septic shock, hypothermia, cancer and invasive fungal infections were associated with increased mortality in immunosuppressed patients. Black race and the presence of rigors were independent predictors of survival in immunosuppressed patients. We conclude that sepsis among patients immunosuppressed prior to the onset of sepsis was associated with higher mortality than in immunocompetent patients. As the numbers of immunosuppressed patients continue to grow, more studies on the epidemiology of sepsis in this group will become increasingly important.