Distortion-product emissions and auditory sensitivity in human ears with normal hearing and cochlear hearing loss.

Distortion product emissions (DPEs) at 2f1-f2 frequencies were measured in 53 human ears; 21 of them exhibited cochlear hearing loss. DPEs were obtained as a function of stimulus level (DPE growth curves) at seven frequency regions between 707 Hz and 5656 Hz. Several distinctly different shapes or patterns of DPE growth curves were observed. These included single-segment monotonic growth curves with and without saturation at moderate and high stimulus levels, diphasic growth curves with nulls at moderate stimulus levels, and non-monotonic growth curves with negative slopes at high stimulus levels. Low-level, irregularly shaped segments were more frequent in normal-hearing ears, suggestive of normal low-level active nonlinearities from the outer-hair-cell subsystem. High-level, steeply sloped segments were frequent in hearing-impaired ears, suggestive of residual nonlinearities from a cochlear partition without functional outer hair cells. The stimulus level at which the DPE could just be distinguished from the noise floor, the DPE detection threshold, demonstrated moderate positive correlations (r's from 0.50 to 0.81) with auditory thresholds when all ears, both normal and impaired, were considered together. Those correlations were not strong enough to quantitatively predict auditory thresholds with any great accuracy. However, DPE thresholds were able to predict abnormal auditory sensitivity with some precision. DPE thresholds correctly predicted abnormal auditory sensitivity 79% of the time in the present study, and up to 96% of the time in previous studies. These results suggest that DPE thresholds may prove useful for hearing screening in cases where cooperation from the subject is limited or where corroboration of cochlear hearing loss is required. Different patterns of DPE growth curves suggest underlying micro-mechanical differences between ears, but the differential diagnostic value of those patterns remains to be determined.     

Rapidly changing perspectives about mast cells at mucosal surfaces

Summary: Mast cells (MCs) are major effector cells of immunoglobulin E (IgE)‐mediated allergic inflammation. However, it has become increasingly clear that they also play important roles in diverse physiological and pathological processes. Recent advances have focused on the importance of MCs in both innate and adaptive immune responses and have fostered studies of MCs beyond the myopic focus on allergic reactions. MCs possess a variety of surface receptors and may be activated by inflammatory mediators, IgE, IgG, light chains, complement fragments, proteases, hormones, neuropeptides, and microbial products. Following activation, they produce a plethora of pro‐inflammatory mediators and participate in inflammatory reactions in many organs. This review focuses on the role of MCs in inflammatory reactions in mucosal surfaces with particular emphasis on their role in respiratory and gastrointestinal inflammatory conditions.     

Anti-inflammatory effect of β2-agonists: Inhibition of TNF-α release from human mast cells

β₂-Agonists inhibit the release of preformed mediators such as histamine and newly synthesized mediators such as prostaglandin D₂ from mast cells. However, although mast cells have been identified as an important source of several cytokines including tumor necrosis factor-α (TNF-α), there is no information about their regulation by β₂-agonists. Thus given the importance of TNF-α in inflammation and the widespread use of β₂-agonists, we investigated the effect of long-acting (salmeterol) and short-acting (salbutamol) β₂-agonists on the secretion of TNF-α from human skin mast cells. Treatment of mast cells with salmeterol or salbutamol (100 nmol/L) inhibited the IgE-dependent release of TNF-α (82% and 74%, respectively). Moreover, 2-hour treatment with salmeterol, isoproterenol, or salbutamol inhibited mast cell cytotoxicity against a TNF-α–sensitive cell line, WEHI-164, with an IC₅₀ of 71, 50, and 29 nmol/L, respectively. Specificity for β-adrenergic receptors was shown with propranolol. The inhibitory effect of β₂-agonists was observed after only 20 minutes of treatment but was lost by 24 hours after removal of salbutamol and isoproterenol (7% and 11% inhibition remaining, respectively). In contrast, the inhibition of TNF-α release was increased 1 hour after removal of salmeterol and remained significant 24 hours later. Furthermore, β₂-agonists did not show tachyphylaxis for the inhibition of TNF-α release. Thus selective β₂-agonists demonstrate anti-inflammatory activity by inhibiting the release of TNF-α from mast cells stimulated through their IgE receptor or by a tumor target cell. This inhibitory effect of β-agonists may be important in their mode of action in the treatment of allergic diseases. (J Allergy Clin Immunol 1997;100:825-31.)     

Immunization reverses memory deficits without reducing brain Abeta burden in Alzheimer's disease model

We have previously shown that chronic treatment with the monoclonal antibody m266, which is specific for amyloid beta-peptide (Abeta), increases plasma concentrations of Abeta and reduces Abeta burden in the PDAPP transgenic mouse model of Alzheimer's disease (AD). We now report that administration of m266 to PDAPP mice can rapidly reverse memory deficits in both an object recognition task and a holeboard learning and memory task, but without altering brain Abeta burden. We also found that an Abeta/antibody complex was present in both the plasma and the cerebrospinal fluid of m266-treated mice. Our data indicate that passive immunization with this anti-Abeta monoclonal antibody can very rapidly reverse memory impairment in certain learning and memory tasks in the PDAPP mouse model of AD, owing perhaps to enhanced peripheral clearance and (or) sequestration of a soluble brain Abeta species.     

Subpopulations of motor and sensory neurons respond differently to brain-derived neurotrophic factor depending on the presence of the skeletal muscle.

The aim of our study was to assess the ability of brain-derived neurotrophic factor (BDNF) to rescue motor and sensory neurons from programmed cell death. It is clearly demonstrated that the administration of a single injection of a putative neurotrophic factor to mouse embryos in utero on embryonic day (E) 14.5 is sufficient to significantly reduce the death of motor neurons when assessed on E18.5. However, the trophic requirements of somatic neurons have not been unequivocally determined in a mammalian species in vivo. Indeed, the unexpectedly high numbers of surviving neurons observed in neurotrophin and tyrosine kinase receptor knockout mice are probably the consequence of functional redundancy between the neurotrophins and their receptors. We studied spinal cord and facial motor nucleus neurons and proprioceptive neurons in the dorsal root ganglion and mesencephalic nucleus. The action of BDNF was assessed in wild-type fetuses to gain insight into its ability to rescue neurons from naturally occurring programmed cell death. In addition, we used Myf5(-/-):MyoD(-/-) embryos, which completely lack skeletal musculature, to assess the ability of BDNF to rescue neurons from excessively occurring programmed cell death. We found that BDNF differentially rescued neurons from naturally vs. excessively occurring cell death and that its ability to do so varied among neuronal subpopulations.     

Founder mutations in <Emphasis Type="Italic">BRCA1/2</Emphasis> are not frequent in Canadian Ashkenazi Jewish men with prostate cancer

Background  

Relatives of BRCA1 and BRCA2 mutation carriers have long been proposed by epidemiological studies to have an increased risk of developing prostate cancer. In the Ashkenazi Jewish (AJ) population, the existence of 3 frequent founder mutations, 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2 greatly facilitates screening for carriers.     

Human Diversity of Killer Cell Immunoglobulin-Like Receptors and Human Leukocyte Antigen Class I Alleles and Ebola Virus Disease Outcomes

We investigated the genetic profiles of killer cell immunoglobulin-like receptors (KIRs) in Ebola virus–infected patients. We studied the relationship between KIR–human leukocyte antigen (HLA) combinations and the clinical outcomes of patients with Ebola virus disease (EVD). We genotyped KIRs and HLA class I alleles using DNA from uninfected controls, EVD survivors, and persons who died of EVD. The activating 2DS4–003 and inhibitory 2DL5 genes were significantly more common among persons who died of EVD; 2DL2 was more common among survivors. We used logistic regression analysis and Bayesian modeling to identify 2DL2, 2DL5, 2DS4–003, HLA-B-Bw4-Thr, and HLA-B-Bw4-Ile as probably having a significant relationship with disease outcome. Our findings highlight the importance of innate immune response against Ebola virus and show the association between KIRs and the clinical outcome of EVD.