The cortical (auditory and prefrontal) and/or subcortical (thalamic and hippocampal) generators of abnormal electrophysiological responses during sensory gating remain actively debated in the schizophrenia literature. Functional magnetic resonance imaging has the spatial resolution for disambiguating deep or simultaneous sources but has been relatively under-utilized to investigate generators of the gating response. Thirty patients with chronic schizophrenia (SP) and 30 matched controls participated in the current experiment. Hemodynamic response functions (HRFs) for single (S1) and pairs (S1 + S2) of identical ("gating-out" redundant information) or nonidentical ("gating-in" novel information) tones were generated through deconvolution. Increased or prolonged activation for patients in conjunction with deactivation for controls was observed within auditory cortex, prefrontal cortex, and thalamus in response to single tones during the late hemodynamic response, and these group differences were not associated with clinical or cognitive symptomatology. Although patient hyperactivation to paired-tones conditions was present in several regions of interest, the effects were not statistically significant for either the gating-out or gating-in conditions. Finally, abnormalities in the postundershoot of the auditory HRF were also observed for both single and paired-tones conditions in patients. In conclusion, the amalgamation of the entire electrophysiological response to both S1 and S2 stimuli may limit hemodynamic sensitivity to paired tones during sensory gating, which may be more readily overcome by paradigms that use multiple stimuli rather than pairs. Patient hyperactivation following single tones is suggestive of deficits in basic inhibition, neurovascular abnormalities, or a combination of both factors.

1. The auditory cortex in the superior temporal region of the alert rhesus monkey was explored for neuronal responses to pure and harmonic complex tones and noise. The monkeys had been previously trained to recognize the similarity between harmonic complex tones with and without fundamentals. Because this suggested that they could preceive the pitch of the lacking fundamental similarly to humans, we searched for neuronal responses relevant to this perception. 2. Combination-sensitive neurons that might explain pitch perception were not found in the surveyed cortical regions. Such neurons would exhibit similar responses to stimuli with similar periodicities but differing spectral compositions. The fact that no neuron with responses to a fundamental frequency responded also to a corresponding harmonic complex missing the fundamental indicates that cochlear distortion products at the fundamental may not have been responsible for missing fundamental-pitch perception in these monkeys. 3. Neuronal responses can be expressed as relatively simple filter functions. Neurons with excitatory response areas (tuning curves) displayed various inhibitory sidebands at lower and/or higher frequencies. Thus responses varied along a continuum of combined excitatory and inhibitory filter functions. 4. Five elementary response classes along this continuum are presented to illustrate the range of response patterns. 5. "Filter (F) neurons" had little or no inhibitory sidebands and responded well when any component of a complex tone entered its pure-tone receptive field. Bandwidths increased with intensity. Filter functions of these neurons were thus similar to cochlear nerve-fiber tuning curves. 6. "High-resolution filter (HRF) neurons" displayed narrow tuning curves with narrowband widths that displayed little growth with intensity. Such cells were able to resolve up to the lowest seven components of harmonic complex tones as distinct responses. They also responded well to wideband stimuli. 7. "Fundamental (F0) neurons" displayed similar tuning bandwidths for pure tones and corresponding fundamentals of harmonic complexes. This response pattern was due to lower harmonic complexes. This response pattern was due to lower inhibitory sidebands. Thus these cells cannot respond to missing fundamentals of harmonic complexes. Only physically present components in the pure-tone receptive field would excite such neurons. 8. Cells with no or very weak responses to pure tones or other narrowband stimuli responded well to harmonic complexes or wideband noise.(ABSTRACT TRUNCATED AT 400 WORDS)

OBJECTIVE

In two studies, the reliability of 3 balance, 2 flexibility, and 4 muscular strength tests proposed as test items were investigated in a health-related fitness (HRF) test battery for adults.

METHODS

Methodological study.

METHODS

A health promotion research institute.

METHODS

In study A, volunteers (n=42) from two worksites participated. In study B, a population sample (n=510) of 37-to 57-year-old men and women was selected.

METHODS

Intraclass correlation coefficient of repeated measures was used to assess inter-rater reliability. The degree of measurement error was expressed as the standard error of measurement. The mean difference with 95% confidence intervals between the testing days or test trials was used to assess test-retest or trial-to-trial reproducibility. The coefficient of variation(CV=[SD/mean] x 100%) from day to day was also calculated.

RESULTS

The following tests appeared to provide acceptable reliability as methods for field assessment of HRF: standing on one leg with eyes open for balance, side-bending of the trunk for spinal flexibility, modified push-ups for upper body muscular function, and jump and reach and one leg squat for leg muscular function.

CONCLUSIONS

This reliability assessment provided useful information on the characteristics of potential test items in a HRF test battery for adults and on the limitations of its practical use. Testers must be properly trained to ensure reliable assessment of HRF of adults.

In multiple sclerosis, infiltrating T lymphocytes and perivascular microglia may initiate demyelinating lesions, but a role for antibody and complement in the ensuing inflammatory damage to myelin and oligodendrocytes is likely. In most tissues, ubiquitously expressed complement regulatory proteins prevent autologous destruction, protecting host cells from the powerful cytolytic activity of activated complement. We have studied the surface expression of a comprehensive range of complement regulatory proteins by live adult human oligodendrocytes in vitro. Only DAF of the activation pathway regulators was expressed, not CR1 or MCP. Of the membrane attack pathway regulatory proteins, HRF was not expressed, while substantial heterogeneity of CD59 expression by oligodendrocytes was found. Clusterin expression was not found. A relative deficiency of protective complement regulatory proteins on human oligodendrocytes may contribute to their selective damage in multiple sclerosis.

The 65 kD homologous restriction factor (HRF) was isolated from normal human erythrocytes (E) by immunoadsorption using rabbit anti-human HRF. The protein was radiolabeled and incorporated into the membrane of sheep erythrocytes (Es). Es bearing HRF exhibited a markedly reduced susceptibility to reactive lysis by C5b-9. Es-HRF with 1,000-3,000 HRF molecules per cell and sensitized with rabbit IgG anti-Es also were less susceptible to lysis by human large granular lymphocytes (LGL) than untreated Es sensitized with IgG antibody. Similarly, human E of a patient with paroxysmal nocturnal hemoglobinuria (PNH), lacking HRF and sensitized with IgG antibody underwent lysis by human LGL. Lysis was abrogated by incorporation of isolated human HRF. Incorporation of human decay-accelerating factor (DAF) into sensitized Es had no effect on antibody-dependent, cell-mediated cytotoxicity. Furthermore, lysis of Es by the isolated cytolytic C9-related protein (C9RP) of human cytotoxic lymphocytes could be inhibited by cell bound human HRF. These results suggest that HRF inhibits channel formation not only by C5b-9, but also by cytotoxic lymphocytes.

To further understand the biological function of translationally controlled tumor protein (TCTP), also known as IgE-dependent histamine-releasing factor (HRF), the yeast two-hybrid system was used to screen interacting molecules. We isolated cDNA clones coding for TCTP/HRF, suggesting that it may have a self-interacting property. Domain mapping of the interaction revealed that the C-terminal region of residue 126-172 is involved in self-interaction. The self-interacting property of TCTP/HRF was further supported by FPLC gel-filtration chromatography and coimmunoprecipitation analysis from transfected COS-7 cells. Our data suggests that TCTP/HRF may have a potential to self-interact through the C-terminal region, and the self-interaction property may be related to its biological function.

Analysis of cerebral hemodynamics reveals a wide spectrum of oscillations ranging from 0.0095 to 2 Hz. While most of these oscillations can be filtered out during analysis of functional near-infrared spectroscopy (fNIRS) signals when estimating stimulus evoked hemodynamic responses, oscillations around 0.1 Hz are an exception. This is due to the fact that they share a common spectral range with typical stimulus evoked hemodynamic responses from the brain. Here we investigate the effect of hemodynamic oscillations around 0.1 Hz on the estimation of hemodynamic response functions from fNIRS data. Our results show that for an expected response of ~1 µM in oxygenated hemoglobin concentration (HbO), Mayer wave oscillations with an amplitude>> ~1 µM at 0.1 Hz reduce the accuracy of the estimated response as quantified by a 3 fold increase in the mean squared error and decrease in correlation (R(2) below 0.78) when compared to the true HRF. These results indicate that the amplitude of oscillations at 0.1 Hz can serve as an objective metric of the expected HRF estimation accuracy. In addition, we investigated the effect of short separation regression on the recovered HRF, and found that this improves the recovered HRF when large amplitude 0.1 Hz oscillations are present in fNIRS data. We suspect that the development of other filtering strategies may provide even further improvement.

BACKGROUND

Translationally Controlled Tumor Protein (TCTP) found in nasal lavage fluids of allergic patients was named IgE-dependent histamine-releasing factor (HRF). Human recombinant HRF (HrHRF) has been recently reported to be much less effective than HRF produced from activated mononuclear cells (HRFmn).

RESULTS

We found that only NH(2)-terminal truncated, but not C-terminal truncated, TCTP shows cytokine releasing activity compared to full-length TCTP. Interestingly, only NH(2)-terminal truncated TCTP, unlike full-length TCTP, forms dimers through intermolecular disulfide bonds. We tested the activity of dimerized full-length TCTP generated by fusing it to rabbit Fc region. The untruncated-full length protein (Fc-HrTCTP) was more active than HrTCTP in BEAS-2B cells, suggesting that dimerization of TCTP, rather than truncation, is essential for the activation of TCTP in allergic responses. We used confocal microscopy to evaluate the affinity of TCTPs to its putative receptor. We detected stronger fluorescence in the plasma membrane of BEAS-2B cells incubated with Del-N11TCTP than those incubated with rat recombinant TCTP (RrTCTP). Allergenic activity of Del-N11TCTP prompted us to see whether the NH(2)-terminal truncated TCTP can induce allergic airway inflammation in vivo. While RrTCTP had no influence on airway inflammation, Del-N11TCTP increased goblet cell hyperplasia in both lung and rhinal cavity. The dimerized protein was found in sera from allergic patients, and bronchoalveolar lavage fluids from airway inflamed mice.

CONCLUSIONS

Dimerization of TCTP seems to be essential for its cytokine-like activity. Our study has potential to enhance the understanding of pathogenesis of allergic disease and provide a target for allergic drug development.

One of the most consistent electrophysiological deficits reported in the schizophrenia literature is the failure to inhibit, or properly gate, the neuronal response to the second stimulus of an identical pair (i.e., sensory gating). Although animal and invasive human studies have consistently implicated the auditory cortex, prefrontal cortex and hippocampus in mediating the sensory gating response, localized activation in these structures has not always been reported during non-invasive imaging modalities. In the current experiment, event-related FMRI and a variant of the traditional gating paradigm were utilized to examine how the gating network differentially responded to the processing of pairs of identical and non-identical tones. Two single-tone conditions were also presented so that they could be used to estimate the HRF for paired stimuli, reconstructed based on actual hemodynamic responses, to serve as a control non-gating condition. Results supported an emerging theory that the gating response for both paired-tone conditions was primarily mediated by auditory and prefrontal cortex, with potential contributions from the thalamus. Results also indicated that the left auditory cortex may play a preferential role in determining the stimuli that should be inhibited (gated) or receive further processing due to novelty of information. In contrast, there was no evidence of hippocampal involvement, suggesting that future work is needed to determine what role it may play in the gating response.

Hydroxyl Radical Footprinting (HRF) is a tried-and-tested method for analysis of the tertiary structure of RNA and for identification of protein footprints on RNA. The hydroxyl radical reaction breaks accessible parts of the RNA backbone, thereby allowing ribose accessibility to be determined by detection of reverse transcriptase termination sites. Current methods for HRF rely on reverse transcription of a single primer and detection by fluorescent fragments by capillary electrophoresis. Here, we describe an accurate and efficient massive parallel-sequencing-based method for probing RNA accessibility with hydroxyl radicals, called HRF-Seq. Using random priming and a novel barcoding scheme, we show that HRF-Seq dramatically increases the throughput of HRF experiments and facilitates the parallel analysis of multiple RNAs or experimental conditions. Moreover, we demonstrate that HRF-Seq data for the Escherichia coli 16S rRNA correlates well with the ribose accessible surface area as determined by X-ray crystallography and have a resolution that readily allows the difference in accessibility caused by exposure of one side of RNA helices to be observed.

Nucleated cells can resist attack by C by exocytosis or endocytosis of the terminal C components C5b-9 (membrane attack complex) (MAC), but it is generally accepted that formation of a single MAC channel on E leads to lysis (one-hit theory). We find that human and guinea pig E, but not SRBC, can eliminate the MAC from the membrane in the form of microvesicles and escape destruction. When guinea pig or human E are incubated with C5b-9, vesiculation proceeds without a lag and is detected at nonlytic doses of C9. Continuous Ca2+ influx is required for vesiculation. The amount of released vesicles is in direct relation to Ca2+ concentration, and the increase in vesiculation is associated with a parallel decrease in lysis. SRBC, which do not vesiculate when Ca2+ loaded, are lysed by C5b-9 with the same efficiency in the presence or absence of Ca2+. Vesicles released from guinea pig RBC under C5b-9 attack are enriched in C9 by a factor of 10, compared with the unlysed cells, and by a factor of 3 to 4, compared with ghosts. We conclude that E are protected from lysis not only by CD59 and C8bp/HRF, which prevent MAC assembly, but also by selective elimination of the MAC.

We analyzed the influence of acute and chronic ionizing radiation (IR) on plant genome stability and global genome expression. Plants from the "chronic" group were grown for 21 days on (137)Cs-artificially contaminated soil, and received a cumulative dose of 1Gy. The "acute" plant group was exposed to an equal dose of radiation delivered as a single pulse. Analysis of homologous recombination (HR) events revealed a significantly higher increase in HR frequency (HRF) in the "chronic" group as compared to "acute" group. To understand the observed difference we performed global genome expression analysis. RNA profiling at 2h and 24h after acute irradiation showed two-third of up- and down-regulated genes to be similarly regulated at both time points. In contrast, less than 10% of the genes up- or down-regulated at 2h or 24h post-acute irradiation were similarly changed after chronic exposure. Promoter analysis revealed substantial differences in the specific regulatory elements found in acute and chronic transcriptomes. Further comparison of the data with existing profiles for several stresses, including UVC and heavy metals, showed substantial transcriptome similarities with the acute but not the chronic transcriptome. Plants exposed to chronic but not acute radiation showed early flowering; transcriptome analysis also revealed induction of flowering genes in "chronic" group.

The ferritin H-chain gene promoter regulation was analyzed in heme-treated Friend leukemia cells (FLCs) and during monocyte-to-macrophage differentiation. In the majority of cell lines studied, the regulation of ferritin expression was exerted mostly at the translational level. However, in differentiating erythroid cells, which must incorporate high levels of iron to sustain hemoglobin synthesis, and in macrophages, which are involved in iron storage, transcriptional regulation seemed to be a relevant mechanism. We show here that the minimum region of the ferritin H-gene promoter that is able to confer transcriptional regulation by heme in FLCs to a reporter gene is 77 nucleotides upstream of the TATA box. This cis element binds a protein complex referred to as HRF (heme-responsive factor), which is greatly enhanced both in heme-treated FLCs and during monocyte-to-macrophage differentiation. The CCAAT element present in reverse orientation in this promoter region of the ferritin H-chain gene is necessary for binding and for gene activity, since a single point mutation is able to abolish the binding of HRF and the transcriptional activity in transfected cells. By competition experiments and supershift assays, we identified the induced HRF as containing at least the ubiquitous transcription factor NF-Y. NF-Y is formed by three subunits, A, B, and C, all of which are necessary for DNA binding. Cotransfection with a transdominant negative mutant of the NF-YA subunit abolishes the transcriptional activation by heme, indicating that NF-Y plays an essential role in this activation. We have also observed a differential expression of the NF-YA subunit in heme-treated and control FLCs and during monocyte-to-macrophage differentiation.

Certain phthalate esters (di-2-ethylhexyl; di-n-butyl and butyl benzyl) have profound effects on the developing male reproductive system when administered orally to pregnant experimental animals during a critical window of development. These esters produce a syndrome of adverse effects that are characteristic of a disturbance in androgen-mediated development and include a variety of reproductive tract malformations and effects on developmental phenotypic markers. A testicular dysgenesis syndrome has been proposed to explain the secular increases in a number of human male reproductive deficits, including decreased semen parameters, increased incidence of cryptorchidism and hypospadias (two of the most common human birth defects), and increased incidence of testicular (germ cell derived) cancer. The rodent phthalate data lend support to the hypothesis. This example illustrates a number of points in the use of the Human Relevance Framework. First, chemical agents may have more than one mode of action (MOA): for example, phthalate-induced peroxisome proliferation leading to hepatocarcinogensis, compared with the induction of developmental effects via effects on androgen signaling. Second, the case demonstrates the life-stage sensitivity of the response to these compounds. Third, because humans may be exposed to multiple phthalate esters producing adverse effects on reproductive development, these compounds may be useful in testing the utility of the Human Relevance Framework (HRF) approach for evaluating cumulative and aggregate risk.

This article presents results obtained from applying various tools from FSL (FMRIB Software Library) to data from the repetition priming experiment used for the HBM'05 Functional Image Analysis Contest. We present analyses from the model-based General Linear Model (GLM) tool (FEAT) and from the model-free independent component analysis tool (MELODIC). We also discuss the application of tools for the correction of image distortions prior to the statistical analysis and the utility of recent advances in functional magnetic resonance imaging (FMRI) time series modeling and inference such as the use of optimal constrained HRF basis function modeling and mixture modeling inference. The combination of hemodynamic response function (HRF) and mixture modeling, in particular, revealed that both sentence content and speaker voice priming effects occurred bilaterally along the length of the superior temporal sulcus (STS). These results suggest that both are processed in a single underlying system without any significant asymmetries for content vs. voice processing.

In the era of life-prolonging antiretroviral therapy, chronic fatigue is one of the most prevalent and disabling symptoms of people living with HIV/AIDS, yet its measurement remains challenging. No instruments have been developed specifically to describe HIV-related fatigue. We assessed the reliability and construct validity of the HIV-Related Fatigue Scale (HRFS), a 56-item self-report instrument developed through formative qualitative research and designed to measure the intensity and consequences of fatigue as well as the circumstances surrounding fatigue in people living with HIV. The HRFS has three main scales, which measure fatigue intensity, the responsiveness of fatigue to circumstances and fatigue-related impairment of functioning. The functioning scale can be further divided into subscales measuring impairment of activities of daily living, impairment of mental functioning and impairment of social functioning. Each scale demonstrated high internal consistency (Cronbach's alpha=0.93, 0.91 and 0.97 for the intensity, responsiveness and functioning scales, respectively). The HRFS scales also demonstrated satisfactory convergent validity when compared to other fatigue measures. HIV-Related Fatigue Scales were moderately correlated with quality of nighttime sleep (rho=0.46, 0.47 and 0.35) but showed only weak correlations with daytime sleepiness (rho=0.20, 0.33 and 0.18). The scales were also moderately correlated with general mental and physical health as measured by the SF-36 Health Survey (rho ranged from 0.30 to 0.68 across the 8 SF-36 subscales with most >0.40). The HRFS is a promising tool to help facilitate research on the prevalence, etiology and consequences of fatigue in people living with HIV.

Simultaneous electroencephalography and functional magnetic resonance imaging (EEG/fMRI) have been proposed to contribute to the definition of the epileptic seizure onset zone. Following interictal epileptiform discharges, one usually assumes a canonical hemodynamic response function (HRF), which has been derived from fMRI studies in healthy subjects. However, recent findings suggest that the hemodynamic properties of the epileptic brain are likely to differ significantly from physiological responses. Here, we propose a simple and robust approach that provides HRFs, defined as a limited set of gamma functions, optimized so as to elicit strong activations after standard model-driven statistical analysis at the single subject level. The method is first validated on healthy subjects using experimental data acquired during motor, visual and memory encoding tasks. Second, interictal EEG/fMRI data measured in 10 patients suffering from epilepsy are analyzed. Results show dramatic changes of activation patterns, depending on whether physiological or pathological assumptions are made on the hemodynamics of the epileptic brain. Our study suggests that one cannot assume a priori that HRFs in epilepsy are similar to the canonical model. This may explain why a significant fraction of EEG/fMRI exams in epileptic patients are inconclusive after standard data processing. The heterogeneous perfusion in epileptic regions indicates that the properties of brain vasculature in epilepsy deserve careful attention.

EEG-fMRI in epileptic patients is commonly analyzed using the general linear model (GLM), which assumes a known hemodynamic response function (HRF) to epileptic spikes in the EEG. In contrast, independent component analysis (ICA) can extract Blood-Oxygenation Level Dependent (BOLD) responses without imposing constraints on the HRF. This technique was evaluated on data generated by superimposing artificial responses on real background fMRI signals. Simulations were run using a wide range of EEG spiking rates, HRF amplitudes, and activation regions. The data were decomposed by spatial ICA into independent components. A deconvolution method then identified component time courses significantly related to the simulated spikes, without constraining the shape of the HRF. Components matching the simulated activation regions ("concordant components") were found in 84.4% of simulations, while components at discordant locations were found in 12.2% of simulations. These false activations were often related to large artifacts that coincidentally occurred simultaneously with some of the random simulated spikes. The performance of the method depended closely on the simulation parameters; when the number of spikes was low, concordant components could only be identified when HRF amplitudes were large. Although ICA did not depend on the shape of the HRF, data processed with the GLM did not reveal the appropriate activation region when the HRF varied slightly from the canonical shape used in the model. ICA may thus be able to extract BOLD responses from EEG-fMRI data in epileptic patients, in a way that is robust to uncertainty and variability in the shape of the HRF.

In earlier studies, we showed that abiotic stresses, such as ionizing radiation, heavy metals, temperature and water, trigger an increase in homologous recombination frequency (HRF). We also demonstrated that many of these stresses led to inheritance of high-frequency homologous recombination, HRF. Although an increase in recombination frequency is an important indicator of genome rearrangements, it only represents a minor portion of possible stress-induced mutations. Here, we analyzed the influence of heat, cold, drought, flood and UVC abiotic stresses on two major types of mutations in the genome, point mutations and small deletions/insertions. We used two transgenic lines of Arabidopsis thaliana, one allowing an analysis of reversions in a stop codon-containing inactivated β-glucuronidase transgene and another one allowing an analysis of repeat stability in a microsatellite-interrupted β-glucuronidase transgene. The transgenic Arabidopsis line carrying the β-glucuronidase-based homologous recombination substrate was used as a positive control. We showed that the majority of stresses increased the frequency of point mutations, homologous recombination and microsatellite instability in somatic cells, with the frequency of homologous recombination being affected the most. The analysis of transgenerational changes showed an increase in HRF to be the most prominent effect observed in progeny. Significant changes in recombination frequency were observed upon exposure to all types of stress except drought, whereas changes in microsatellite instability were observed upon exposure to UVC, heat and cold. The frequency of point mutations in the progeny of stress-exposed plants was the least affected; an increase in mutation frequency was observed only in the progeny of plants exposed to UVC. We thus conclude that transgenerational changes in genome stability in response to stress primarily involve an increase in recombination frequency.

When modelling FMRI and other MRI time-series data, a Bayesian approach based on adaptive spatial smoothness priors is a compelling alternative to using a standard generalized linear model (GLM) on presmoothed data. Another benefit of the Bayesian approach is that biophysical prior information can be incorporated in a principled manner; however, this requirement for a fixed non-spatial prior on a parameter would normally preclude using spatial regularization on that same parameter. We have developed a Gaussian-process-based prior to apply adaptive spatial regularization while still ensuring that the fixed biophysical prior is correctly applied on each voxel. A parameterized covariance matrix provides separate control over the variance (the diagonal elements) and the between-voxel correlation (due to off-diagonal elements). Analysis proceeds using evidence optimization (EO), with variational Bayes (VB) updates used for some parameters. The method can also be applied to non-linear forward models by using a linear Taylor expansion centred on the latest parameter estimates. Applying the method to FMRI with a constrained haemodynamic response function (HRF) shape model shows improved fits in simulations, compared to using either the non-spatial or spatial-smoothness prior alone. We also analyse multi-inversion arterial spin labelling data using a non-linear perfusion model to estimate cerebral blood flow and bolus arrival time. By combining both types of prior information, this new prior performs consistently well across a wider range of situations than either prior alone, and provides better estimates when both types of prior information are relevant.

OBJECTIVE

Prone positioning is used to improve oxygenation in patients with hypoxemic respiratory failure (HRF). However, its role in clinical practice is not yet clearly defined. The aim of this meta-analysis was to assess the effect of prone positioning on relevant clinical outcomes, such as intensive care unit (ICU) and hospital mortality, days of mechanical ventilation, length of stay, incidence of ventilator-associated pneumonia (VAP) and pneumothorax, and associated complications.

METHODS

We used literature search of MEDLINE, Current Contents, and Cochrane Central Register of Controlled Trials. We focused only on randomized controlled trials reporting clinical outcomes in adult patients with HRF. Four trials met our inclusion criteria, including 662 patients randomized to prone ventilation and 609 patients to supine ventilation.

RESULTS

The pooled odds ratio (OR) for the ICU mortality in the intention-to-treat analysis was 0.97 (95% confidence interval [CI], 0.77-1.22), for the comparison between prone and supine ventilated patients. Interestingly, the pooled OR for the ICU mortality in the selected group of the more severely ill patients favored prone positioning (OR, 0.34; 95% CI, 0.18-0.66). The duration of mechanical ventilation and the incidence of pneumothorax were not different between the 2 groups. The incidence of VAP was lower but not statistically significant in patients treated with prone positioning (OR, 0.81; 95% CI, 0.61-1.10). However, prone positioning was associated with a higher risk of pressure sores (OR, 1.49; 95% CI, 1.17-1.89) and a trend for more complications related to the endotracheal tube (OR, 1.30; 95% CI, 0.94-1.80).

CONCLUSIONS

Despite the inherent limitations of the meta-analytic approach, it seems that prone positioning has no discernible effect on mortality in patients with HRF. It may decrease the incidence of VAP at the expense of more pressure sores and complications related to the endotracheal tube. However, a subgroup of the most severely ill patients may benefit most from this intervention.

OBJECTIVE

To combine parallel imaging with 3D single-shot acquisition (echo volumar imaging, EVI) in order to acquire high temporal resolution volumar functional MRI (fMRI) data.

METHODS

An improved EVI sequence was associated with parallel acquisition and field of view reduction in order to acquire a large brain volume in 200 msec. Temporal stability and functional sensitivity were increased through optimization of all imaging parameters and Tikhonov regularization of parallel reconstruction. Two human volunteers were scanned with parallel EVI in a 1.5T whole-body MR system, while submitted to a slow event-related auditory paradigm.

RESULTS

Thanks to parallel acquisition, the EVI volumes display a low level of geometric distortions and signal losses. After removal of low-frequency drifts and physiological artifacts, activations were detected in the temporal lobes of both volunteers and voxelwise hemodynamic response functions (HRF) could be computed. On these HRF different habituation behaviors in response to sentence repetition could be identified.

CONCLUSIONS

This work demonstrates the feasibility of high temporal resolution 3D fMRI with parallel EVI. Combined with advanced estimation tools, this acquisition method should prove useful to measure neural activity timing differences or study the nonlinearities and nonstationarities of the BOLD response.

BACKGROUND

Endogenous histamine-releasing factors (HRFs) are involved in 30-60% of patients with chronic urticaria (CU). Evidence for their existence comes from in vivo studies of autoreactivity with the autologous serum skin test (ASST), in vitro immunoassays demonstrating autoantibodies against the immunoglobulin E (IgE) or the high affinity IgE receptor (FcepsilonRI) and serum-induced histamine release (HR) from basophils and mast cells. We have examined the correlation between the ASST and a new basophil histamine-releasing assay (the HR-Urtikaria test) in a group of well-characterized CU patients and subsequently determined the frequency of HR-Urticaria-positive sera from a larger population of CU patients.

METHODS

Group 1 consisted of 28 patients with CU (16 were ASST-positive) 20 patients with atopic dermatitis, 24 patients with allergy to birch and nine healthy controls. Group 2 consisted of 873 unselected CU patients.

METHODS

White blood cells containing 1-2% basophils from a healthy nonatopic donor were incubated with patients sera in the presence of interleukin (IL)-3. Histamine was measured by the glass fibre method.

RESULTS

Using the ASST as the true outcome, the HR-Urticaria test showed a sensitivity and specificity of 75% in group 1 using a cut-off value for HR of >16.5%. None of the controls was positive in the HR-Urticaria test. In group 2, we found no difference in the frequency of positives between male (34.6%, n = 254) and female adults (35.1%, n = 576) but twice as many females as males were tested.

CONCLUSIONS

Our studies have shown that the HR-Urticaria test has a good sensitivity and specificity for endogenous HRFs demonstrated by the ASST in patients with CU and that about one-third of unselected patients with CU have a positive result.

OBJECTIVE

Monomeric IgE molecules, when bound to the high-affinity receptor, exhibit a vast heterogeneity in their ability to induce survival promotion and cytokine production in mast cells. At one end of this spectrum, highly cytokinergic (HC) IgEs can induce potent survival promotion, degranulation, cytokine production, migration, etc., whereas at the other end, poorly cytokinergic (PC) IgEs can do so inefficiently. In this study, we investigated whether IgEs recognize autoantigens and whether IgEs' binding of autoantigens correlates with difference s in HC versus PC properties.

METHODS

Enzyme-linked immunosorbent assays were performed to test whether IgEs bind antigens. Histamine-releasing factor in human sera was quantified by western blotting. Cultured mast cells derived from human cord blood were used to test the effects of human sera on cytokine production.

RESULTS

Most (7/8) of mouse monoclonal HC IgEs exhibited polyreactivity to double-stranded DNA (dsDNA), single-stranded DNA (ssDNA), β-galactosidase, thyroglobulin and/or histamine-releasing factor. By contrast, mouse PC IgEs failed to react with these antigens. A human monoclonal HC IgE also showed polyreactivity to histamine-releasing factor, dsDNA and ssDNA. Interestingly, sera from atopic dermatitis patients showed increased reactivity to ssDNA and β-galactosidase and increased levels of histamine-releasing factor. Some atopic dermatitis patients, but not healthy individuals, had substantial serum levels of HRF-reactive IgE. Sera from atopic dermatitis patients with high titers of DNA-reactive IgE could induce several fold more IL-8 secretion in human mast cells than sera from healthy individuals.

CONCLUSIONS

The results show that most HC, but not PC, IgEs exhibit polyreactivity to autoantigens, supporting the autoimmune mechanism in the pathogenesis of atopic dermatitis.