Early Changes in Interferon Gene Expression and Antibody Responses Following Influenza Vaccination in Pregnant Women.

BACKGROUND: Influenza immunization during pregnancy provides protection to the mother and the infant. Studies in adults and children with inactivated influenza vaccine have identified changes in immune gene expression that were correlated with antibody responses. The current study was performed to define baseline blood transcriptional profiles and changes induced by inactivated influenza vaccine in pregnant women and to identify correlates with antibody responses. METHODS: Pregnant women were immunized with inactivated influenza vaccine during the 2013-2014 and 2014-2015 seasons. Blood samples were collected on day 0 (before vaccination) and on days 1 and 7 after vaccination for transcriptional profile analyses, and on days 0 and 30, along with delivery and cord blood samples, to measure antibody titers. RESULTS: Transcriptional analysis demonstrated overexpression of interferon-stimulated genes (ISGs) on day 1 and of plasma cell genes on day 7. Prevaccination ISG expression and ISGs overexpressed on day 1 were significantly correlated with increased H3N2, B Yamagata, and B Victoria antibody titers. Plasma cell gene expression on day 7 was correlated with increased B Yamagata and B Victoria antibody titers. Compared with women who were vaccinated during the previous influenza season, those who were not showed more frequent significant correlations between ISGs and antibody titers. CONCLUSIONS: Influenza vaccination in pregnant women resulted in enhanced expression of ISGs and plasma cell genes correlated with antibody responses. Brief summary: This study identified gene expression profiles of interferon-stimulated genes and plasma cells before vaccination and early after vaccination that were correlated with antibody responses in pregnant women vaccinated for influenza.

Secondhand smoke alters arachidonic acid metabolism and inflammation in infants and children with cystic fibrosis.

BACKGROUND: Mechanisms that facilitate early infection and inflammation in cystic fibrosis (CF) are unclear. We previously demonstrated that children with CF and parental-reported secondhand smoke exposure (SHSe) have increased susceptibility to bacterial infections. SHSe hinders arachidonic acid (AA) metabolites that mediate immune function in patients without CF, and may influence CF immune dysfunction. We aimed to define SHSe's impact on inflammation mediators and infection in children with CF. METHODS: Seventy-seven children with CF <10 years of age (35 infants <1 year; 42 children 1-10 years) were enrolled and hair nicotine concentrations measured as an objective surrogate of SHSe. AA signalling by serum and macrophage lipidomics, inflammation using blood transcriptional profiles and in vitro macrophage responses to bacterial infection after SHSe were assessed. RESULTS: Hair nicotine concentrations were elevated in 63% of patients. Of the AA metabolites measured by plasma lipidomics, prostaglandin D2 (PGD2) concentrations were decreased in children with CF exposed to SHSe, and associated with more frequent hospitalisations (p=0.007) and worsened weight z scores (p=0.008). Children with CF exposed to SHSe demonstrated decreased expression of the prostaglandin genes PTGES3 and PTGR2 and overexpression of inflammatory pathways. These findings were confirmed using an in vitro model, where SHSe was associated with a dose-dependent decrease in PGD2 and increased methicillin-resistant Staphylococcus aureus survival in human CF macrophages. CONCLUSIONS: Infants and young children with CF and SHSe have altered AA metabolism and dysregulated inflammatory gene expression resulting in impaired bacterial clearance. Our findings identified potential therapeutic targets to halt early disease progression associated with SHSe in the young population with CF.

Laser refrigeration of hydrothermal nanocrystals in physiological media.

Coherent laser radiation has enabled many scientific and technological breakthroughs including Bose-Einstein condensates, ultrafast spectroscopy, superresolution optical microscopy, photothermal therapy, and long-distance telecommunications. However, it has remained a challenge to refrigerate liquid media (including physiological buffers) during laser illumination due to significant background solvent absorption and the rapid (∼ ps) nonradiative vibrational relaxation of molecular electronic excited states. Here we demonstrate that single-beam laser trapping can be used to induce and quantify the local refrigeration of physiological media by >10 °C following the emission of photoluminescence from upconverting yttrium lithium fluoride (YLF) nanocrystals. A simple, low-cost hydrothermal approach is used to synthesize polycrystalline particles with sizes ranging from <200 nm to >1 µm. A tunable, near-infrared continuous-wave laser is used to optically trap individual YLF crystals with an irradiance on the order of 1 MW/cm(2). Heat is transported out of the crystal lattice (across the solid-liquid interface) by anti-Stokes (blue-shifted) photons following upconversion of Yb(3+) electronic excited states mediated by the absorption of optical phonons. Temperatures are quantified through analysis of the cold Brownian dynamics of individual nanocrystals in an inhomogeneous temperature field via forward light scattering in the back focal plane. The cold Brownian motion (CBM) analysis of individual YLF crystals indicates local cooling by >21 °C below ambient conditions in D2O, suggesting a range of potential future applications including single-molecule biophysics and integrated photonic, electronic, and microfluidic devices.

Nasopharyngeal Microbiota, Host Transcriptome, and Disease Severity in Children with Respiratory Syncytial Virus Infection.

RATIONALE: Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infections and hospitalizations in infants worldwide. Known risk factors, however, incompletely explain the variability of RSV disease severity, especially among healthy children. We postulate that the severity of RSV infection is influenced by modulation of the host immune response by the local bacterial ecosystem. OBJECTIVES: To assess whether specific nasopharyngeal microbiota (clusters) are associated with distinct host transcriptome profiles and disease severity in children less than 2 years of age with RSV infection. METHODS: We characterized the nasopharyngeal microbiota profiles of young children with mild and severe RSV disease and healthy children by 16S-rRNA sequencing. In parallel, using multivariable models, we analyzed whole-blood transcriptome profiles to study the relationship between microbial community composition, the RSV-induced host transcriptional response, and clinical disease severity. MEASUREMENTS AND MAIN RESULTS: We identified five nasopharyngeal microbiota clusters characterized by enrichment of either Haemophilus influenzae, Streptococcus, Corynebacterium, Moraxella, or Staphylococcus aureus. RSV infection and RSV hospitalization were positively associated with H. influenzae and Streptococcus and negatively associated with S. aureus abundance, independent of age. Children with RSV showed overexpression of IFN-related genes, independent of the microbiota cluster. In addition, transcriptome profiles of children with RSV infection and H. influenzae- and Streptococcus-dominated microbiota were characterized by greater overexpression of genes linked to Toll-like receptor and by neutrophil and macrophage activation and signaling. CONCLUSIONS: Our data suggest that interactions between RSV and nasopharyngeal microbiota might modulate the host immune response, potentially affecting clinical disease severity.

Association of RNA Biosignatures With Bacterial Infections in Febrile Infants Aged 60 Days or Younger.

IMPORTANCE: Young febrile infants are at substantial risk of serious bacterial infections; however, the current culture-based diagnosis has limitations. Analysis of host expression patterns ("RNA biosignatures") in response to infections may provide an alternative diagnostic approach. OBJECTIVE: To assess whether RNA biosignatures can distinguish febrile infants aged 60 days or younger with and without serious bacterial infections. DESIGN, SETTING, AND PARTICIPANTS: Prospective observational study involving a convenience sample of febrile infants 60 days or younger evaluated for fever (temperature >38° C) in 22 emergency departments from December 2008 to December 2010 who underwent laboratory evaluations including blood cultures. A random sample of infants with and without bacterial infections was selected for RNA biosignature analysis. Afebrile healthy infants served as controls. Blood samples were collected for cultures and RNA biosignatures. Bioinformatics tools were applied to define RNA biosignatures to classify febrile infants by infection type. EXPOSURE: RNA biosignatures compared with cultures for discriminating febrile infants with and without bacterial infections and infants with bacteremia from those without bacterial infections. MAIN OUTCOMES AND MEASURES: Bacterial infection confirmed by culture. Performance of RNA biosignatures was compared with routine laboratory screening tests and Yale Observation Scale (YOS) scores. RESULTS: Of 1883 febrile infants (median age, 37 days; 55.7% boys), RNA biosignatures were measured in 279 randomly selected infants (89 with bacterial infections-including 32 with bacteremia and 15 with urinary tract infections-and 190 without bacterial infections), and 19 afebrile healthy infants. Sixty-six classifier genes were identified that distinguished infants with and without bacterial infections in the test set with 87% (95% CI, 73%-95%) sensitivity and 89% (95% CI, 81%-93%) specificity. Ten classifier genes distinguished infants with bacteremia from those without bacterial infections in the test set with 94% (95% CI, 70%-100%) sensitivity and 95% (95% CI, 88%-98%) specificity. The incremental C statistic for the RNA biosignatures over the YOS score was 0.37 (95% CI, 0.30-0.43). CONCLUSIONS AND RELEVANCE: In this preliminary study, RNA biosignatures were defined to distinguish febrile infants aged 60 days or younger with vs without bacterial infections. Further research with larger populations is needed to refine and validate the estimates of test accuracy and to assess the clinical utility of RNA biosignatures in practice.

Young infants display heterogeneous serological responses and extensive but reversible transcriptional changes following initial immunizations.

Infants necessitate vaccinations to prevent life-threatening infections. Our understanding of the infant immune responses to routine vaccines remains limited. We analyzed two cohorts of 2-month-old infants before vaccination, one week, and one-month post-vaccination. We report remarkable heterogeneity but limited antibody responses to the different antigens. Whole-blood transcriptome analysis in an initial cohort showed marked overexpression of interferon-stimulated genes (ISGs) and to a lesser extent of inflammation-genes at day 7, which normalized one month post-vaccination. Single-cell RNA sequencing in peripheral blood mononuclear cells from a second cohort identified at baseline a predominantly naive immune landscape including ISGhi cells. On day 7, increased expression of interferon-, inflammation-, and cytotoxicity-related genes were observed in most immune cells, that reverted one month post-vaccination, when a CD8+ ISGhi and cytotoxic cluster and B cells expanded. Antibody responses were associated with baseline frequencies of plasma cells, B-cells, and monocytes, and induction of ISGs at day 7.

Modeling Noise-Related Timbre Semantic Categories of Orchestral Instrument Sounds With Audio Features, Pitch Register, and Instrument Family.

Audio features such as inharmonicity, noisiness, and spectral roll-off have been identified as correlates of "noisy" sounds. However, such features are likely involved in the experience of multiple semantic timbre categories of varied meaning and valence. This paper examines the relationships of stimulus properties and audio features with the semantic timbre categories raspy/grainy/rough, harsh/noisy, and airy/breathy. Participants (n = 153) rated a random subset of 52 stimuli from a set of 156 approximately 2-s orchestral instrument sounds representing varied instrument families (woodwinds, brass, strings, percussion), registers (octaves 2 through 6, where middle C is in octave 4), and both traditional and extended playing techniques (e.g., flutter-tonguing, bowing at the bridge). Stimuli were rated on the three semantic categories of interest, as well as on perceived playing exertion and emotional valence. Correlational analyses demonstrated a strong negative relationship between positive valence and perceived physical exertion. Exploratory linear mixed models revealed significant effects of extended technique and pitch register on valence, the perception of physical exertion, raspy/grainy/rough, and harsh/noisy. Instrument family was significantly related to ratings of airy/breathy. With an updated version of the Timbre Toolbox (R-2021 A), we used 44 summary audio features, extracted from the stimuli using spectral and harmonic representations, as input for various models built to predict mean semantic ratings for each sound on the three semantic categories, on perceived exertion, and on valence. Random Forest models predicting semantic ratings from audio features outperformed Partial Least-Squares Regression models, consistent with previous results suggesting that non-linear methods are advantageous in timbre semantic predictions using audio features. Relative Variable Importance measures from the models among the three semantic categories demonstrate that although these related semantic categories are associated in part with overlapping features, they can be differentiated through individual patterns of audio feature relationships.

Infectivity acts as in vivo selection for maintenance of the chlamydial cryptic plasmid.

Chlamydia trachomatis contains a conserved ∼7.5-kb plasmid. Loss of the plasmid results in reduced glycogen accumulation, failure to activate TLR2, and reduced infectivity. We hypothesized that reduced infectivity functions as a means of selection for plasmid maintenance. We directly examined the biological significance of the reduced infectivity associated with plasmid deficiency by determining the relative fitness of plasmid-deficient CM972 versus that of wild-type C. muridarum Nigg in mixed inocula in vitro and in vivo. C. muridarum Nigg rapidly out-competed its plasmid-cured derivative CM972 in vitro but was not competitive with CM3.1, a derivative of CM972 that has reverted to a normal infectivity phenotype. C. muridarum Nigg also effectively competed with CM972 during lower and upper genital tract infection in the mouse, demonstrating that strong selective pressure for plasmid maintenance occurs during infection. The severity of oviduct inflammation and dilatation resulting from these mixed infections correlated directly with the amount of C. muridarum Nigg in the initial inoculum, confirming the role of the plasmid in virulence. Genetic characterization of CM972 and CM3.1 revealed no additional mutations (other than loss of the plasmid) to account for the reduced infectivity of CM972 and detected a single base substitution in TC_0236 in CM3.1 that may be responsible for its restored infectivity. These data demonstrate that a chlamydial strain that differs genetically from its wild-type parent only with respect to the lack of the chlamydial plasmid is unable to compete in vitro and in vivo, likely explaining the rarity of plasmid-deficient isolates in nature.

Toll-like receptor 2 activation by Chlamydia trachomatis is plasmid dependent, and plasmid-responsive chromosomal loci are coordinately regulated in response to glucose limitation by C. trachomatis but not by C. muridarum.

We previously demonstrated that plasmid-deficient Chlamydia muridarum retains the ability to infect the murine genital tract but does not elicit oviduct pathology because it fails to activate Toll-like receptor 2 (TLR2). We derived a plasmid-cured derivative of the human genital isolate Chlamydia trachomatis D/UW-3/Cx, strain CTD153, which also fails to activate TLR2, indicating this virulence phenotype is associated with plasmid loss in both C. trachomatis and C. muridarum. As observed with plasmid-deficient C. muridarum, CTD153 displayed impaired accumulation of glycogen within inclusions. Transcriptional profiling of the plasmid-deficient strains by using custom microarrays identified a conserved group of chromosomal loci, the expression of which was similarly controlled in plasmid-deficient C. muridarum strains CM972 and CM3.1 and plasmid-deficient C. trachomatis CTD153. However, although expression of glycogen synthase, encoded by glgA, was greatly reduced in CTD153, it was unaltered in plasmid-deficient C. muridarum strains. Thus, additional plasmid-associated factors are required for glycogen accumulation by this chlamydial species. Furthermore, in C. trachomatis, glgA and other plasmid-responsive chromosomal loci (PRCLs) were transcriptionally responsive to glucose limitation, indicating that additional regulatory elements may be involved in the coordinated expression of these candidate virulence effectors. Glucose-limited C. trachomatis displayed reduced TLR2 stimulation in an in vitro assay. During human chlamydial infection, glucose limitation may decrease chlamydial virulence through its effects on plasmid-responsive chromosomal genes.

Sex Differences in Blood Transcriptional Profiles and Clinical Phenotypes in Pediatric Patients with Eosinophilic Esophagitis.

BACKGROUND: Eosinophilic esophagitis (EoE) is an increasingly recognized, chronic inflammatory disease. Recent reports suggest clinical differences between males and females. OBJECTIVE: To define the relevant molecular pathways that could be related to clinical phenotypes in children with EoE. METHODS: We performed blood RNA expression analysis in children with newly diagnosed EoE and matched, healthy controls, and applied bioinformatics tools to define EoE host immune biosignatures. Questionnaires and medical records were used to characterize symptoms, esophagogastroduodenoscopy results, and treatment response. RESULTS: Forty-one subjects (aged 2-17 years) were enrolled; the cohort consisted of 27 males and 14 females. Patients were randomly divided into a discovery cohort (21 EoE patients and 12 controls) that identified 544 significant differentially expressed transcripts (P ≤ .01; 1.25-fold change). Those 544 transcripts correctly classified most EoE patients in the validation cohort (n = 20) from healthy controls. Global transcriptional perturbation relative to healthy controls, Molecular Distance to Health scores were greater in EoE patients than controls (P = .003). When we analyzed subjects based on age and sex, males 13 years of age and older were more likely to have food impactions (P = .033) and to have higher endoscopic severity scores (P = .036). Separate group comparisons according to sex identified 294 differentially expressed transcripts in males and 643 transcripts in female EoE patients. Of those, 37 genes were shared and similarly expressed irrespective of sex. CONCLUSIONS: Whole blood transcriptional analysis represents a promising noninvasive tool to assess activity of the immune/inflammatory response in children with EoE. Male and female EoE patients showed robust differences in gene expression suggesting distinct pathogenic endotypes.

Immune profiles provide insights into respiratory syncytial virus disease severity in young children.

Respiratory syncytial virus (RSV) is associated with major morbidity in infants, although most cases result in mild disease. The pathogenesis of the disease is incompletely understood, especially the determining factors of disease severity. A better characterization of these factors may help with development of RSV vaccines and antivirals. Hence, identification of a "safe and protective" immunoprofile induced by natural RSV infection could be used as a as a surrogate of ideal vaccine-elicited responses in future clinical trials. In this study, we integrated blood transcriptional and cell immune profiling, RSV loads, and clinical data to identify factors associated with a mild disease phenotype in a cohort of 190 children <2 years of age. Children with mild disease (outpatients) showed higher RSV loads, greater induction of interferon (IFN) and plasma cell genes, and decreased expression of inflammation and neutrophil genes versus children with severe disease (inpatients). Additionally, only infants with severe disease had increased numbers of HLA-DRlow monocytes, not present in outpatients. Multivariable analyses confirmed that IFN overexpression was associated with decreased odds of hospitalization, whereas increased numbers of HLA-DRlow monocytes were associated with increased risk of hospitalization. These findings suggest that robust innate immune responses are associated with mild RSV infection in infants.

Interface-Dependent Radiative Lifetimes of Yb3+, Er3+ Co-doped Single NaYF4 Upconversion Nanowires.

The development of upconversion nanomaterials for many photonic applications requires a detailed understanding of their radiative lifetimes that in turn depend critically on local environmental conditions. In this work, hexagonal (ß-phase) sodium-yttrium-fluoride (NaYF4) nanowires (NWs) were synthesized and substitutionally co-doped with a luminescent solid solution of trivalent erbium and ytterbium ions. A single-beam laser trapping instrument was used in tandem with a piezo-controlled, variable-temperature stage to precisely vary the nanowire's distance from the substrate. The spontaneous photoluminescence lifetime of the 4S3/2 → 4I15/2 transition from Er3+ ions was observed to change by >60% depending on the ions' separation distance from a planar (water/glass) dielectric interface. The 4S3/2 state lifetime is observed to increase by a factor of 1.62 ± 0.01 as the distance from the quartz coverslip increases from ∼0 nm to ∼40 µm. Less significant changes in the luminescence lifetime (≤10%) were observed over a temperature range between 25 and 50 °C. The distance dependence of the lifetime is interpreted quantitatively in the context of classical electromagnetic coupling between Er3+ ions within the nanowire and the adjacent dielectric interface. We also demonstrate potential applications of the NaYF4 NWs for both controlling and probing temperatures at nanometer scales by integrating them within a poly(dimethylsiloxane) composite matrix.

Whole blood transcriptional profiles as a prognostic tool in complete and incomplete Kawasaki Disease.

BACKGROUND: Early identification of children with Kawasaki Disease (KD) is key for timely initiation of intravenous immunoglobulin (IVIG) therapy. However, the diagnosis of the disease remains challenging, especially in children with an incomplete presentation (inKD). Moreover, we currently lack objective tools for identification of non-response (NR) to IVIG. METHODS: Children with KD were enrolled and samples obtained before IVIG treatment and sequentially at 24 h and 4-6 weeks post-IVIG in a subset of patients. We also enrolled children with other febrile illnesses [adenovirus (AdV); group A streptococcus (GAS)] and healthy controls (HC) for comparative analyses. Blood transcriptional profiles were analyzed to define: a) the cKD and inKD biosignature, b) compare the KD signature with other febrile illnesses and, c) identify biomarkers predictive of clinical outcomes. RESULTS: We identified a cKD biosignature (n = 39; HC, n = 16) that was validated in two additional cohorts of children with cKD (n = 37; HC, n = 20) and inKD (n = 13; HC, n = 8) and was characterized by overexpression of inflammation, platelets, apoptosis and neutrophil genes, and underexpression of T and NK cell genes. Classifier genes discriminated KD from adenovirus with higher sensitivity and specificity (92% and 100%, respectively) than for GAS (75% and 87%, respectively). We identified a genomic score (MDTH) that was higher at baseline in IVIG-NR [median 12,290 vs. 5,572 in responders, p = 0.009] and independently predicted IVIG-NR. CONCLUSION: A reproducible biosignature from KD patients was identified, and was similar in children with cKD and inKD. A genomic score allowed early identification of children at higher risk for non-response to IVIG.

Interactive processing of timbre dimensions: a Garner interference study.

Timbre characterizes the identity of a sound source. Psychoacoustic studies have revealed that timbre is a multidimensional perceptual attribute with multiple underlying acoustic dimensions of both temporal and spectral types. Here we investigated the relations among the processing of three major timbre dimensions characterized acoustically by attack time, spectral centroid, and spectrum fine structure. All three pairs of these dimensions exhibited Garner interference: speeded categorization along one timbre dimension was affected by task-irrelevant variations along another timbre dimension. We also observed congruency effects: certain pairings of values along two different dimensions were categorized more rapidly than others. The exact profile of interactions varied across the three pairs of dimensions tested. The results are interpreted within the frame of a model postulating separate channels of processing for auditory attributes (pitch, loudness, timbre dimensions, etc.) with crosstalk between channels.

Laser Refrigeration of Ytterbium-Doped Sodium-Yttrium-Fluoride Nanowires.

Sodium yttrium fluoride (ß-NaYF4 ) nanowires (NWs) with a hexagonal crystal structure are synthesized using a low-cost hydrothermal process and are shown to undergo laser refrigeration based on an upconversion process leading to anti-Stokes (blueshifted) photoluminescence. Single-beam laser trapping combined with forward light scattering is used to investigate cryophotonic laser refrigeration of individual NWs through analysis of their local Brownian dynamics.

Deuteron irradiation of W and WO3 for production of high specific activity (186)Re: Challenges associated with thick target preparation.

This investigation evaluated target fabrication and beam parameters for scale-up production of high specific activity (186)Re using deuteron irradiation of enriched (186)W via the (186)W(d,2n)(186)Re reaction. Thick W and WO3 targets were prepared, characterized and evaluated in deuteron irradiations. Full-thickness targets, as determined using SRIM, were prepared by uniaxially pressing powdered natural abundance W and WO3, or 96.86% enriched (186)W, into Al target supports. Alternatively, thick targets were prepared by pressing (186)W between two layers of graphite powder or by placing pre-sintered (1105°C, 12h) natural abundance WO3 pellets into an Al target support. Assessments of structural integrity were made on each target prepared. Prior to irradiation, material composition analyses were conducted using SEM, XRD, and Raman spectroscopy. Within a minimum of 24h post irradiation, gamma-ray spectroscopy was performed on all targets to assess production yields and radionuclidic byproducts. Problems were encountered with the structural integrity of some pressed W and WO3 pellets before and during irradiation, and target material characterization results could be correlated with the structural integrity of the pressed target pellets. Under the conditions studied, the findings suggest that all WO3 targets prepared and studied were unacceptable. By contrast, (186)W metal was found to be a viable target material for (186)Re production. Thick targets prepared with powdered (186)W pressed between layers of graphite provided a particularly robust target configuration.

Accelerator-based production of the (99m)Tc-(186)Re diagnostic-therapeutic pair using metal disulfide targets (MoS2, WS2, OsS2).

Novel, natural abundance metal disulfide targets were irradiated for 1h with a 10µA proton beam in a small, medical cyclotron. Osmium disulfide was synthesized by simple distillation and precipitation methods while MoS2 and WS2 were commercially available. The targets dissolved under mild conditions and were analyzed by γ-spectroscopy. Production rates and potential applications are discussed, including target recovery and recycling schemes for OsS2 and WS2.

Nanoscale materials for hyperthermal theranostics.

Recently, the use of nanoscale materials has attracted considerable attention with the aim of designing personalized therapeutic approaches that can enhance both spatial and temporal control over drug release, permeability, and uptake. Potential benefits to patients include the reduction of overall drug dosages, enabling the parallel delivery of different pharmaceuticals, and the possibility of enabling additional functionalities such as hyperthermia or deep-tissue imaging (LIF, PET, etc.) that complement and extend the efficacy of traditional chemotherapy and surgery. This mini-review is focused on an emerging class of nanometer-scale materials that can be used both to heat malignant tissue to reduce angiogenesis and DNA-repair while simultaneously offering complementary imaging capabilities based on radioemission, optical fluorescence, magnetic resonance, and photoacoustic methods.

The neuroanatomical substrate of sound duration discrimination.

We investigated the neuroanatomical substrate of sound duration discrimination, using the same experimental design as in a previous study on sound intensity discrimination [J. Neurosci. 18 (16) (1998) 6388]. Seven normal subjects were trained to detect deviant sounds presented with a slightly longer duration than a 300 ms long standard harmonic sound, using a Go/No Go paradigm. Individual psychometric curves were assessed using a three-step psychoacoustic procedure. Subjects were then scanned while passively listening to the standard sound, and while discriminating changes in sound duration at four different performance levels (d'=1.5, 2.5, 3.5 and 4.5). Analysis of regional cerebral blood flow (rCBF) data outlined activation, during the discrimination conditions, of a right hemispheric fronto-parietal network very similar to the one previously observed for intensity discrimination, as well as additional activation in the right prefrontal cortex (Brodmann Area (BA) 10), bilateral basal ganglia and cerebellar hemispheres. These findings suggest that discrimination of sound duration, as for discrimination of sound intensity, involves two cerebral networks: a supramodal right fronto-parietal cortical network responsible for allocation of sensory attentional resources, and a network of regions such as the basal ganglia, cerebellum, and right prefrontal cortex, more specifically involved in the temporal aspects of the discrimination task.

Rare occurrence of heterotrophic bacteria with pathogenic potential in potable water.

Since the discovery of Legionella pneumophila, an opportunistic pathogen that is indigenous to water, microbiologists have speculated that there may be other opportunistic pathogens among the numerous heterotrophic bacteria found in potable water. The US Environmental Protection Agency (USEPA) developed a series of rapid in vitro assays to assess the virulence potential of large numbers of bacteria from potable water to possibly identify currently unknown pathogens. Results of surveys of potable water from several distribution systems using these tests showed that only 50 of the approximately 10,000 bacterial colonies expressed one or more virulence characteristics. In another study, 45 potable water isolates that expressed multiple virulence factors were tested for pathogenicity in immunocompromised mice. None of the isolates infected mice that were compromised either by treatment with carrageenan (CG), to induce susceptibility to facultative intracellular pathogens, or by cyclophosphamide (CY), to induce susceptibility to extracellular pathogens. These results indicate that there are very few potential pathogens in potable water and that the currently developed in vitro virulence screening tests give an overestimation of the numbers of heterotrophic bacteria that may be pathogens. Current efforts are focused on using the animal models to screen concentrated samples of waters known to contain large numbers of heterotrophic bacteria and newly discovered Legionella-like organisms that parasitize amoebae.