Gene expression in gastric biopsies from patients infected with Helicobacter pylori.

BACKGROUND: Helicobacter pylori infection has protean effects on gene expression in the host gastric mucosa, which have been investigated by gene chip analysis in vitro. In this study the effects of H. pylori infection on host gene expression in the gastric antral mucosa in patients were examined. METHODS: One gastric antral biopsy was obtained from a total of 18 untreated patients undergoing routine endoscopic evaluation of chronic abdominal complaints. Nine patients had histologic evidence of H. pylori infection and 9 age- and sex-matched patients had no histologic evidence of H. pylori infection. A microarray analysis was performed using a gene chip containing 35,000 human expressed sequence tags on RNA extracted from endoscopic, gastric antral biopsies, and average gene expression among infected and uninfected patients was compared. RESULTS: Underexpressed genes in infected patients' mucosa included gastric intrinsic factor and several metallothionein isoforms. Overexpressed genes in infected patients' mucosa comprised MHC Class II molecules, immunoglobulin and B-cell activation genes, as well as genes known to induce apoptosis. Changes in expression were confirmed for a subset of genes by SYBR green real-time PCR. CONCLUSIONS: Microarray analysis of antral biopsies from patients with and without H. pylori infection revealed differential expression of metal regulatory, immunity and inflammation-related genes.

Psychophysical estimates of cochlear phase response: masking by harmonic complexes.

Harmonic complexes with identical component frequencies and amplitudes but different phase spectra may be differentially effective as maskers. Such harmonic waveforms, constructed with positive or negative Schroeder phases, have similar envelopes and identical long-term power spectra, but the positive Schroeder-phase waveform is typically a less effective masker than the negative Schroeder-phase waveform. These masking differences have been attributed to an interaction between the masker phase spectrum and the phase characteristic of the basilar membrane. To explore this relationship, the gradient of stimulus phase change across masker bandwidth was varied by systematically altering the Schroeder-phase algorithm. Observers detected a signal tone added in-phase to a single component of a masker whose frequencies ranged from 200 to 5000 Hz, with a fundamental frequency of 100 Hz. For signal frequencies of 1000-4000 Hz, differences in masking across the harmonic complexes could be as large as 5-10 dB for phase gradients changing by only 10%. The phase gradient that resulted in a minimum amount of masking varied with signal frequency, with low frequencies masked least effectively by stimuli with rapidly changing component phases and high frequencies masked by stimuli with more shallow phase gradients. A gammachirp filter was implemented to model these results, predicting the qualitative changes in curvature of the phase-byfrequency function estimated from the empirical data: In some cases, small modifications to the gammachirp filter produced better quantitative predictions of curvature changes across frequency, but this filter, as implemented here, was unable to accurately represent all the data.

Different auditory filter bandwidth estimates based on profile analysis, notched noise, and hybrid tasks.

Auditory filter bandwidths were estimated in three experiments. The first experiment was a profile-analysis experiment. The stimuli were composed of sinusoidal components ranging in frequency from 200 to 5000 Hz. The standard stimulus was the sum of equal-amplitude tones, and the signal stimulus had a power spectrum that varied up-down ... up-down. The number of components ranged from four to 60. Interval-by-interval level randomization prevented the change in level of a single component from reliably indicating the change from standard to signal. The second experiment was a notched-noise experiment in which the 1000-Hz tone to be detected was added to a noise with a notch arithmetically centered at 1000 Hz. Detection thresholds were estimated both in the presence of and in the absence of level randomization. In the third, hybrid, experiment a 1000-Hz tone was to be detected, and the masker was composed of equal-amplitude sinusoidal components ranging in frequency from 200 to 5000 Hz. For this experiment, thresholds were estimated both in the presence and absence of level variation. For both the notched-noise and hybrid experiments, only modest effects of level randomization were obtained. A variant of Durlach et al.'s channel model ["Towards a model for discrimination of broadband signals," J. Acoust. Soc. Am. 80, 63-72 (1986)] was used to estimate auditory filter bandwidths for all three experiments. When a two-parameter roex(p,r) filter weighting function was used to fit the data, bandwidth estimates were approximately two to three times as large for the two detection tasks than for the profile-analysis task.

Donor polymorphism of tumor necrosis factor gene: relationship with variable severity of hepatitis C recurrence after liver transplantation.

BACKGROUND: Hepatitis C-related liver failure is the leading indication for liver transplantation worldwide. Although histologic recurrence is identified in the majority of patients, the spectrum of allograft injury is wide. To date, most studies have focused on the contribution of immunosuppression and viral factors. We hypothesized that the allograft plays a significant role in determining timing and severity of hepatitis C virus (HCV) recurrence. The purpose of this analysis was to determine if genetic polymorphisms of the tumor necrosis factor (TNF) locus were associated with the highly variable severity of HCV recurrence. METHODS: Thirty-one HCV-seropositive liver transplant recipients with long-term follow-up were studied. Genomic DNA was extracted from archived donor spleens which corresponded to each patient. We performed polymerase chain reaction amplification, followed by sequencing for two promoter TNF-alpha variants (at positions -238 and -308), and restriction fragment length analysis for four polymorphic loci within the TNF-beta gene (NcoI, TNFc, aa13, and aa26). RESULTS: The relative prevalence of polymorphisms corresponded to distributions previously reported in normal control populations. Twenty-two of 31 (71%) patients received a donor liver homozygous for the wild type allele (TNF1) at the -308 TNF-alpha promoter region. The interval to histologic recurrence was significantly shorter and severity of HCV allograft hepatitis was significantly greater in patients with one or two TNF308.2 alleles. At last follow-up biopsy, 5 of 9 (56%) patients with a TNF308.2 donor liver had evidence of severe histological activity index as compared to 2 of 22 (9%) of patients receiving a donor liver homozygous for the TNF1 allele (P = 0.01). There was no correlation between rejection rates and the presence of any TNF-alpha or TNF-beta alleles. TNF-beta polymorphisms within the donor liver did not correlate with severity of HCV recurrence. CONCLUSIONS: The donor TNF-alpha promoter genotype may influence the inflammatory response to HCV reinfection of the graft and contribute to accelerated graft injury. If the association between this genetic marker (TNF308.2) and disease progression is confirmed, it could improve our understanding of HCV pathogenesis and influence donor selection and patient management.

Sensitivity to changes in level and envelope patterns across frequency.

In the first experiment, two measurements were compared--sensitivity to across-frequency changes in level and sensitivity to across-frequency changes in the modulation phase of SAM tones. For the level task, multi-tone stimuli composed of 2-80 tones ranging in frequency from 200 to 5000 Hz were used. For the phase task, the same frequency range was used, and 2-80 SAM tones were tested. For the level task, observers discriminated between a multi-tone, equal-amplitude standard and one of two signals--a one-step or an up-down signal. The one-step signal had higher levels at low frequencies and lower levels at high frequencies. The up-down signal had components with levels that varied high-low-high-low. For the phase task, the standard was the sum of SAM tones with identical modulator phases across frequency. The one-step signal had a common modulator phase at low frequencies and a different common modulator phase at high frequencies. The up-down signal had modulator phases that varied lag-lead-lag-lead. The results suggest that sensitivity to across-frequency changes in level and modulation phase reflect similar initial processing stages. In a second experiment, SAM tones were used, and psychometric functions were measured for the level task, the phase task, and a condition in which changes in level and modulator phase were both present. The standard was "flat," and an up-down signal was to be detected. For one observer, the data suggest that level and phase information are independently represented. For the other two observers, interactions between the two features of the stimuli are apparent. A multiple-looks model was moderately successful in accounting for the data.

The effects of amplitude perturbation and increasing numbers of components in profile analysis.

In a profile-analysis task, the effect of randomly perturbing the amplitudes of the components of multi-tone stimuli was studied in two experiments. In the first experiment, thresholds for a signal added in-phase to the central component of a standard were measured for different numbers of components in two conditions. In one condition thresholds were measured in blocks for six different "jagged" standards, and in another, thresholds were measured when one of the six standards was chosen randomly on a presentation-by-presentation basis. Regardless of condition, thresholds did not depend on the numbers of components and increased magnitude of perturbation increased thresholds. Moreover, the slope relating thresholds to number of components did not increase with increasing magnitude of perturbation. In the second experiment, the signal consisted of an increase in amplitude of the central components and a decrease in amplitude of the outer components of the standard (a stimulus type which has been shown to maximize the change in threshold with increasing number of components). The amplitudes of component tones were selected randomly on a presentation-by-presentation basis. Thresholds fell with increases in the number of components, but the slope relating thresholds to numbers of components did not change as the magnitude of perturbation increased. The latter result contrasts with that reported by Kidd et al. [J. Acoust. Soc. Am. 90, 1340-1354 (1991)].

Sensitivity to changes in overall level and spectral shape: an evaluation of a channel model.

Two experiments involving level and spectral shape discrimination which test an optimal channel model developed by Durlach et al. [J. Acoust. Soc Am. 80, 63-72 (1986)] are described. The model specifies how the auditory system compares and/or combines intensity information in different frequency channels. In the first experiment, psychometric functions were obtained for the discrimination of changes in level and discrimination of changes in spectral shape for an eight-tone complex sound. A variety of different base spectral shapes were tested. In some conditions, level randomization was introduced to reduce the reliability of across-interval changes in level. Increasing the amount of level variation degraded performance for the level discrimination task but had no effect on the shape discrimination task. In all conditions, sensitivity to changes in spectral shape was superior to sensitivity to changes in level. Consequently, two models of central noise are evaluated in an attempt to explain these results; one in which central noise acts prior to the formation of the likelihood ratio and one in which central noise degrades the likelihood ratio. The former model is more successful in accounting for the data. In a second experiment, the detectability of a level increment to one component of a multitone complex was measured. The frequency content of the complex was varied by systematically removing six components from a 23-component complex. Thresholds were measured for increments at three different signal frequencies. A common trend in the data was that when there was a spectral gap directly above the signal frequency, thresholds were lowest. This result differs from the predictions of a simple channel model, and contrasts with results presented by Green and Berg [Q. J. Exp. Psychol. 43A, 449-458 (1991)].