Current antiretroviral therapy (ART) efficiently controls HIV-1 replication but fails to eradicate the virus. Even after years of successful ART, HIV-1 can conceal itself in a latent state in long-lived CD4(+) memory T cells. From this latent reservoir, HIV-1 rebounds during treatment interruptions. Attempts to therapeutically eradicate this viral reservoir have yielded disappointing results. A major problem with previously utilized activating agents is that at the concentrations required for efficient HIV-1 reactivation, these stimuli trigger high-level cytokine gene expression (hypercytokinemia). Therapeutically relevant HIV-1-reactivating agents will have to trigger HIV-1 reactivation without the induction of cytokine expression. We present here a proof-of-principle study showing that this is a possibility. In a high-throughput screening effort, we identified an HIV-1-reactivating protein factor (HRF) secreted by the nonpathogenic bacterium Massilia timonae. In primary T cells and T-cell lines, HRF triggered a high but nonsustained peak of nuclear factor kappa B (NF-kappaB) activity. While this short NF-kappaB peak potently reactivated latent HIV-1 infection, it failed to induce gene expression of several proinflammatory NF-kappaB-dependent cellular genes, such as those for tumor necrosis factor alpha (TNF-alpha), interleukin-8 (IL-8), and gamma interferon (IFN-gamma). Dissociation of cellular and viral gene induction was achievable, as minimum amounts of Tat protein, synthesized following application of a short NF-kappaB pulse, triggered HIV-1 transactivation and subsequent self-perpetuated HIV-1 expression. In the absence of such a positive feedback mechanism, cellular gene expression was not sustained, suggesting that strategies modulating the NF-kappaB activity profile could be used to selectively trigger HIV-1 reactivation.

BACKGROUND

Outbreaks of the casuarina moth, Lymantria xylina Swinehoe (Lepidoptera: Lymantriidae), which is a very important forest pest in Taiwan, have occurred every five to 10 years. This moth has expanded its range of host plants to include more than 65 species of broadleaf trees. LyxyMNPV (L. xylina multiple nucleopolyhedrovirus) is highly virulent to the casuarina moth and has been investigated as a possible biopesticide for controlling this moth. LdMNPV-like virus has also been isolated from Lymantria xylina larvae but LyxyMNPV was more virulent than LdMNPV-like virus both in NTU-LY and IPLB-LD-652Y cell lines. To better understand LyxyMNPV, the nucleotide sequence of the LyxyMNPV DNA genome was determined and analysed.

RESULTS

The genome of LyxyMNPV consists of 156,344 bases, has a G+C content of 53.4% and contains 157 putative open reading frames (ORFs). The gene content and gene order of LyxyMNPV were similar to those of LdMNPV, with 151 ORFs identified as homologous to those reported in the LdMNPV genome. Two genes (Lyxy49 and Lyxy123) were homologous to other baculoviruses, and four unique LyxyMNPV ORFs (Lyxy11, Lyxy19, Lyxy130 and Lyxy131) were identified in the LyxyMNPV genome, including a gag-like gene that was not reported in baculoviruses. LdMNPV contains 23 ORFs that are absent in LyxyMNPV. Readily identifiable homologues of the gene host range factor-1 (hrf-1), which appears to be involved in the susceptibility of L. dispar to NPV infection, were not present in LyxyMNPV. Additionally, two putative odv-e27 homologues were identified in LyxyMNPV. The LyxyMNPV genome encoded 14 bro genes compared with 16 in LdMNPV, which occupied more than 8% of the LyxyMNPV genome. Thirteen homologous regions (hrs) were identified containing 48 repeated sequences composed of 30-bp imperfect palindromes. However, they differed in the relative positions, number of repeats and orientation in the genome compared to LdMNPV.

CONCLUSIONS

The gene parity plot analysis, percent identity of the gene homologues and a phylogenetic analysis suggested that LyxyMNPV is a Group II NPV that is most closely related to LdMNPV but with a highly distinct genomic organisation.

Methicillin-resistant Staphylococcus aureus (MRSA) burden is increasing worldwide in hospitals [healthcare-associated (HA)-MRSA] and in communities [community-associated (CA)-MRSA]. However, the impact of CA-MRSA within hospitals remains limited, particularly in Latin America. A countrywide representative survey of S. aureus infections was performed in Argentina by analyzing 591 clinical isolates from 66 hospitals in a prospective cross-sectional, multicenter study (Nov-2009). This work involved healthcare-onset infections-(HAHO, >48 hospitalization hours) and community-onset (CO) infections [including both, infections (HACO) in patients with healthcare-associated risk-factors (HRFs) and infections (CACO) in those without HRFs]. MRSA strains were genetically typed as CA-MRSA and HA-MRSA genotypes (CA-MRSAG and HA-MRSAG) by SCCmec- and spa-typing, PFGE, MLST and virulence genes profile by PCR. Considering all isolates, 63% were from CO-infections and 55% were MRSA [39% CA-MRSAG and 16% HA-MRSAG]. A significantly higher MRSA proportion among CO- than HAHO-S. aureus infections was detected (58% vs 49%); mainly in children (62% vs 43%). The CA-MRSAG/HA-MRSAG have accounted for 16%/33% of HAHO-, 39%/13% of HACO- and 60.5%/0% of CACO-infections. Regarding the epidemiological associations identified in multivariate models for patients with healthcare-onset CA-MRSAG infections, CA-MRSAG behave like HA-MRSAG within hospitals but children were the highest risk group for healthcare-onset CA-MRSAG infections. Most CA-MRSAG belonged to two major clones: PFGE-type N-ST30-SCCmecIVc-t019-PVL(+) and PFGE-type I-ST5-IV-SCCmecIVa-t311-PVL(+) (45% each). The ST5-IV-PVL(+)/ST30-IV-PVL(+) clones have caused 31%/33% of all infections, 20%/4% of HAHO-, 43%/23% of HACO- and 35%/60% of CACO- infections, with significant differences by age groups (children/adults) and geographical regions. Importantly, an isolate belonging to USA300-0114-(ST8-SCCmecIVa-spat008-PVL(+)-ACME(+)) was detected for the first time in Argentina. Most of HA-MRSAG (66%) were related to the Cordobes/Chilean clone-(PFGE-type A-ST5-SCCmecI-t149) causing 18% of all infections (47% of HAHO- and 13% of HACO-infections). Results strongly suggest that the CA-MRSA clone ST5-IV-PVL(+) has begun to spread within hospitals, replacing the traditional Cordobes/Chilean-HA-MRSA clone ST5-I-PVL(-), mainly in children. Importantly, a growing MRSA reservoir in the community was associated with spreading of two CA-MRSA clones: ST5-IV-PVL(+), mainly in children with HRFs, and ST30-IV-PVL(+) in adults without HRFs. This is the first nationwide study in Argentina providing information about the molecular and clinical epidemiology of CA-MRSA, particularly within hospitals, which is essential for designing effective control measures in this country and worldwide.

As near-infrared spectroscopy (NIRS) broadens its application area to different age and disease groups, motion artifacts in the NIRS signal due to subject movement is becoming an important challenge. Motion artifacts generally produce signal fluctuations that are larger than physiological NIRS signals, thus it is crucial to correct for them before obtaining an estimate of stimulus evoked hemodynamic responses. There are various methods for correction such as principle component analysis (PCA), wavelet-based filtering and spline interpolation. Here, we introduce a new approach to motion artifact correction, targeted principle component analysis (tPCA), which incorporates a PCA filter only on the segments of data identified as motion artifacts. It is expected that this will overcome the issues of filtering desired signals that plagues standard PCA filtering of entire data sets. We compared the new approach with the most effective motion artifact correction algorithms on a set of data acquired simultaneously with a collodion-fixed probe (low motion artifact content) and a standard Velcro probe (high motion artifact content). Our results show that tPCA gives statistically better results in recovering hemodynamic response function (HRF) as compared to wavelet-based filtering and spline interpolation for the Velcro probe. It results in a significant reduction in mean-squared error (MSE) and significant enhancement in Pearson's correlation coefficient to the true HRF. The collodion-fixed fiber probe with no motion correction performed better than the Velcro probe corrected for motion artifacts in terms of MSE and Pearson's correlation coefficient. Thus, if the experimental study permits, the use of a collodion-fixed fiber probe may be desirable. If the use of a collodion-fixed probe is not feasible, then we suggest the use of tPCA in the processing of motion artifact contaminated data.

Within-subject analysis in fMRI essentially addresses two problems, i.e., the detection of activated brain regions in response to an experimental task and the estimation of the underlying dynamics, also known as the characterisation of Hemodynamic response function (HRF). So far, both issues have been treated sequentially while it is known that the HRF model has a dramatic impact on the localisation of activations and that the HRF shape may vary from one region to another. In this paper, we conciliate both issues in a region-based joint detection-estimation framework that we develop in the Bayesian formalism. Instead of considering function basis to account for spatial variability, spatially adaptive General Linear Models are built upon region-based non-parametric estimation of brain dynamics. Regions are first identified as functionally homogeneous parcels in the mask of the grey matter using a specific procedure [Thirion, B., Flandin, G., Pinel, P., Roche, A., Ciuciu, P., Poline, J.-B., August 2006. Dealing with the shortcomings of spatial normalization: Multi-subject parcellation of fMRI datasets. Hum. Brain Mapp. 27 (8), 678-693.]. Then, in each parcel, prior information is embedded to constrain this estimation. Detection is achieved by modelling activating, deactivating and non-activating voxels through mixture models within each parcel. From the posterior distribution, we infer upon the model parameters using Markov Chain Monte Carlo (MCMC) techniques. Bayesian model comparison allows us to emphasize on artificial datasets first that inhomogeneous gamma-Gaussian mixture models outperform Gaussian mixtures in terms of sensitivity/specificity trade-off and second that it is worthwhile modelling serial correlation through an AR(1) noise process at low signal-to-noise (SNR) ratio. Our approach is then validated on an fMRI experiment that studies habituation to auditory sentence repetition. This phenomenon is clearly recovered as well as the hierarchical temporal organisation of the superior temporal sulcus, which is directly derived from the parcel-based HRF estimates.

Recent advances in our understanding of neonatal pulmonary circulation and the underlying pathophysiology of hypoxemic respiratory failure (HRF)/persistent pulmonary hypertension of the newborn (PPHN) have resulted in more effective management strategies. Results from animal studies demonstrate that low alveolar oxygen tension (PAO2) causes hypoxic pulmonary vasoconstriction, whereas an increase in oxygen tension to normoxic levels (preductal arterial partial pressure of oxygen (PaO2) between 60 and 80 mm Hg and/or preductal peripheral capillary oxygen saturation between 90% and 97%) results in effective pulmonary vasodilation. Hyperoxia (preductal PaO2 >80 mm Hg) does not cause further pulmonary vasodilation, and oxygen toxicity may occur when high concentrations of inspired oxygen are used. It is therefore important to avoid both hypoxemia and hyperoxemia in the management of PPHN. In addition to oxygen supplementation, therapeutic strategies used to manage HRF/PPHN in term and late preterm neonates may include lung recruitment with optimal mean airway pressure and surfactant, inhaled and intravenous vasodilators and 'inodilators'. Clinical evidence suggests that administration of surfactant or inhaled nitric oxide (iNO) therapy at a lower acuity of illness can decrease the risk of extracorporeal membrane oxygenation/death, progression of HRF and duration of hospital stay. Milrinone may be beneficial as an inodilator and may have specific benefits following prolonged exposure to iNO plus oxygen owing to inhibition of phosphodiesterase (PDE)-3A. Additionally, sildenafil, and, in selected cases, hydrocortisone may be appropriate options after hyperoxia and oxidative stress owing to their effects on PDE-5 activity and expression. Continued investigation into these and other interventions is needed to optimize treatment and improve outcomes.

OBJECTIVE

The Heidelberg Retinal Flowmeter (HRF), a laser Doppler flowmetry device, has captured interest as a research and clinical tool for measurement of ocular blood flow. Concerns remain about the range and accuracy of the values that it reports.

METHODS

An in vitro blood-flow model was constructed to provide well-controlled laminar flow through a glass capillary for assessment by HRF. A change in material behind the glass capillary was used to simulate changing brightness conditions between eyes.

RESULTS

Velocities reported by the HRF correlated linearly to true velocities below 8.8 mm/sec. Beyond 8.8 mm/sec, HRF readings fluctuated randomly. True velocity and HRF reported velocities were highly correlated, with r = 0.967 (P < 0.001) from 0.0 mm/sec to 2.7 mm/sec mean velocity using a light background, and r = 0.900 (P < 0.001) from 2.7 mm/sec to 8.8 mm/sec using a darker background. However, a large change in the y-intercept occurred in the calibration curve with the background change.

CONCLUSIONS

The HRF may report velocities inaccurately because of varying brightness in the fundus. In the present experiment, a darker background produced an overreporting of velocities. An offset, possibly introduced by a noise correction routine, apparently contributed to the inaccuracies of the HRF measurements. Such offsets vary with local and global brightness. Therefore, HRF measurements may be error prone when comparing eyes. When used to track perfusion in a single eye over time, meaningful comparison may be possible if meticulous care is taken to align vessels and intensity controls to achieve a similar level of noise correction between measurements.

This paper deals with the estimation of the blood oxygen level-dependent response to a stimulus, as measured in functional magnetic resonance imaging (fMRI) data. A precise estimation is essential for a better understanding of cerebral activations. The most recent works have used a nonparametric framework for this estimation, considering each brain region as a system characterized by its impulse response, the so-called hemodynamic response function (HRF). However, the use of these techniques has remained limited since they are not well-adapted to real fMRI data. Here, we develop a threefold extension to previous works. We consider asynchronous event-related paradigms, account for different trial types and integrate several fMRI sessions into the estimation. These generalizations are simultaneously addressed through a badly conditioned observation model. Bayesian formalism is used to model temporal prior information of the underlying physiological process of the brain hemodynamic response. By this way, the HRF estimate results from a tradeoff between information brought by the data and by our prior knowledge. This tradeoff is modeled with hyperparameters that are set to the maximum-likelihood estimate using an expectation conditional maximization algorithm. The proposed unsupervised approach is validated on both synthetic and real fMRI data, the latter originating from a speech perception experiment.

We previously identified a gene, host range factor 1 (hrf-1), in Lymantria dispar M nucleopolyhedrovirus (LdMNPV) which promoted Autographa californica M nucleopolyhedrovirus (AcMNPV) replication in a nonpermissive cell line IPLB-Ld652Y (Ld652Y). A recombinant AcMNPV, vAcLdPS, that bore hrf-1 controlled by two synthetic baculovirus late promoters and that replicated in Ld652Y cells was constructed. In this study, we constructed a new recombinant AcMNPV, vAcLdPD, bearing only hrf-1 controlled by its own promoter. vAcLdPD replicated in Ld652Y cells in the same manner as vAcLdPS, confirming that hrf-1 alone was sufficient to promote AcMNPV replication in Ld652Y cells. hrf-1 was transcribed as a delayed early gene in LdMNPV but as an immediate early gene in both recombinant AcMNPVs. Primer extension analysis showed that the initiator sequence TCAGT was used as the transcription start site in both LdMNPV and recombinant AcMNPVs. Additional sequencing revealed several regulatory motifs in the hrf-1 upstream region. hrf-1 transcripts in LdMNPV- and vAcLdPS-infected Ld652Y cells terminated near the polyadenylation signal at the end of hrf-1 ORF while in vAcLdPD, the hrf-1 transcripts terminated at a downstream polyadenylation signal at the end of ORF 603. Using Western blot analysis, we detected HRF-1 expression in both recombinant AcMNPV-infected Ld652Y cells but not in LdMNPV-infected Ld652Y cells.

OBJECTIVE

Accurate Heidelberg retina flowmeter (HRF) measurements require correct manual setting of the HRF photodetector sensitivity. The neuroretinal rim produces a weak signal relative to the peripapillary retina. A newly developed HRF alignment and sensitivity protocol, capable of accurate rim measurement, was investigated.

METHODS

18 eyes of nine healthy volunteers were examined by HRF. Three images of each eye were taken using three different imaging methods. Method 1: a conventional image (optic nerve head centred image with photodetector sensitivity optimised for the strong signal from the peripapillary retina); method 2: the setting of method 1 with photodetector sensitivity optimised for the weak signal from the rim; and method 3: the setting of method 2 with the temporal rim margin tangent to the lateral image border to remove the overpowering signal from the temporal peripapillary retina. The neuroretinal rim was defined by the Heidelberg retina tomograph (HRT). Blood flow and reflectivity values (DC component) in the rim area were compared for the three methods using pointwise analysis. Coefficients of variation of repeated measurements in 12 subjects have been calculated for method 3.

RESULTS

The neuroretinal rim area measured by method 1 had a significantly lower brightness compared with method 2 and 3 (p=0.0002 and p=0.0002, respectively). Method 2 provided proper sensitivity for the weak signals of the rim area based on rim tissue DC values; however, this sensitivity setting was too high for the strong signal from the peripapillary retina. Method 3 avoided the strong peripapillary signal with the proper signal from the rim and provided significantly higher flow values of the rim area at 75 and 90 percentile pixels (p=0.0065 and p=0.0038 respectively) compared with method 2. Interobserver repeatability ranged from 16.85% to 21.96% for the different parameters.

CONCLUSIONS

Method 3 provides an accurate and reproducible flow measurement of the neuroretinal rim area through proper sensitivity for the weak rim signal, alignment, and removal of the strong temporal signal from the image. This new method is recommended to improve accuracy of blood flow measurement in the neuroretinal rim.

Mononuclear cells from asthmatic patients produced a histamine releasing factor (HRF). Mononuclear cells produced this factor in culture spontaneously but significantly much more following specific allergen stimulation. This factor released histamine from both sensitized and unsensitized basophils in vitro. Mononuclear cells from healthy subjects produced HRF only after nonspecific mitogen/phytohemagglutinin stimulation. Asthmatic patients on immunotherapy with essential benefits failed to produce HRF.

The relationship between blood flow velocities in retrobulbar vessels and blood flow at the optic nerve in glaucoma patients was assessed in a prospective study. The Heidelberg retina flowmeter (HRF) was used to assess optic nerve head blood flow in 13 open-angle glaucoma patients. In the same patients, color Doppler imaging (CDI) measurements were obtained from the ophthalmic artery, the central retinal artery and the posterior ciliary arteries. Using data for one randomly selected eye per subject, correlations between HRF recordings and CDI measurements were evaluated by means of Spearman's rank correlation factor. All three HRF parameters correlated with CDI measurements obtained from retrobulbar vessels. The most marked correlations were those of the HRF parameter 'volume' with the end-diastolic velocity in the ophthalmic artery and the medial posterior ciliary artery (R = 0.79, p = 0.0012 and R = 0.81, p = 0.0007, respectively), and the peak systolic velocity in the lateral posterior ciliary artery (R = 0.82, p = 0.0006). The present study suggests that glaucoma patients with altered blood flow in retrobulbar vessels are likely to show an alteration in optic nerve blood flow as measured with the HRF.

BACKGROUND

Analysis of drugs in wastewater is gaining more interest, as new approaches to estimate drug consumption from the amount of drug residues in wastewater have been proposed. The aim of this study was to compare the quantitative performance of high-resolution mass spectrometry with that of triple quadrupole mass spectrometry.

METHODS

A Q-Exactive mass spectrometer was operated in full scan (HRFS) (70 000 FWHM) and product scan (HRPS) (17 500 FWHM) modes. The first and third quadrupoles of the QqQ MS/MS instrument were operated at 0.7 FWHM. A mass-extracted window of 5 ppm around the theoretical m/z of each analyte was used to construct chromatograms. An HESI-II ion source was used for the ionization of target compounds. In-line-SPE-LC configuration was used for the extraction and separation of target analytes.

RESULTS

All three methods showed good linearity and repeatability. High-resolution detection of product ions exhibited better sensitivity and selectivity for some compounds. For most of the tested compounds, LOQs ranged from 0.46 to 20 ng L(-1) . Good agreement between measured and nominal concentrations was observed for most of the compounds at different levels of fortification. Both MS/MS methods showed good selectivity, while HRFS gave some false positive results.

CONCLUSIONS

The Q-Exactive mass spectrometer proved to be suitable for trace detection and quantification of most of the tested drugs in wastewater, with performance comparable to that of the commonly used MS/MS triple quadrupole, but with better selectivity.

Model-based analysis methods for fMRI data assume a priori knowledge of the time course of the hemodynamic response (HR) in reaction to experimental stimuli or events. This knowledge is incorporated into the hemodynamic response function (HRF), which is a common model of the HR. Although it is already known that the HR varies across individuals and brain regions, few studies have investigated how variations within one session affect the results of statistical analysis using the general linear model (GLM). In this study, we formally tested for a possible variation of the BOLD response during prolonged functional measurement (120 min). To provoke performance of simple visual, motor, and cognitive tasks, we opted for a combination of a variant of the Stroop task and rotating L's. In selected regions of interest, time courses were extracted and compared with regard to mean and maximum amplitudes throughout the time of functional measurement. Additionally, parameter estimates derived from the GLM were tested for differences over time. Although differences between conditions were found to be significant, results did not show significant variance due to a within-factor time. Similarly, a temporal change in the relation between conditions, in terms of an interaction between the within-factor time and the within-factor condition, was not detectable by a repeated measures ANOVA. Similar results were obtained for analysis of mean and maximum amplitudes as well as for the analyses of parameter estimates.

In Penny et al. [Penny, W., Ghahramani, Z., Friston, K.J. 2005. Bilinear dynamical systems. Philos. Trans. R. Soc. Lond. B Biol. Sci. 360(1457) 983-993], a particular case of the Linear Dynamical Systems (LDSs) was used to model the dynamic behavior of the BOLD response in functional MRI. This state-space model, called bilinear dynamical system (BDS), is used to deconvolve the fMRI time series in order to estimate the neuronal response induced by the different stimuli of the experimental paradigm. The BDS model parameters are estimated using an expectation-maximization (EM) algorithm proposed by Ghahramani and Hinton [Ghahramani, Z., Hinton, G.E. 1996. Parameter Estimation for Linear Dynamical Systems. Technical Report, Department of Computer Science, University of Toronto]. In this paper we introduce modifications to the BDS model in order to explicitly model the spatial variations of the haemodynamic response function (HRF) in the brain using a non-parametric approach. While in Penny et al. [Penny, W., Ghahramani, Z., Friston, K.J. 2005. Bilinear dynamical systems. Philos. Trans. R. Soc. Lond. B Biol. Sci. 360(1457) 983-993] the relationship between neuronal activation and fMRI signals is formulated as a first-order convolution with a kernel expansion using basis functions (typically two or three), in this paper, we argue in favor of a spatially adaptive GLM in which a local non-parametric estimation of the HRF is performed. Furthermore, in order to overcome the overfitting problem typically associated with simple EM estimates, we propose a full Variational Bayes (VB) solution to infer the BDS model parameters. We demonstrate the usefulness of our model which is able to estimate both the neuronal activity and the haemodynamic response function in every voxel of the brain. We first examine the behavior of this approach when applied to simulated data with different temporal and noise features. As an example we will show how this method can be used to improve interpretability of estimates from an independent component analysis (ICA) analysis of fMRI data. We finally demonstrate its use on real fMRI data in one slice of the brain.

OBJECTIVE

The mapping of haemodynamic changes related to interictal epileptic discharges (IED) in simultaneous electroencephalography (EEG) and functional MRI (fMRI) studies is usually carried out by means of EEG-correlated fMRI analyses where the EEG information specifies the model to test on the fMRI signal. The sensitivity and specificity critically depend on the accuracy of EEG detection and the validity of the haemodynamic model. In this study we investigated whether an information theoretic analysis based on the mutual information (MI) between the presence of epileptic activity on EEG and the fMRI data can provide further insights into the haemodynamic changes related to interictal epileptic activity. The important features of MI are that: 1) both recording modalities are treated symmetrically; 2) no requirement for a-priori models for the haemodynamic response function, or assumption of a linear relationship between the spiking activity and BOLD responses, and 3) no parametric model for the type of noise or its probability distribution is necessary for the computation of MI.

METHODS

Fourteen patients with pharmaco-resistant focal epilepsy underwent EEG-fMRI and intracranial EEG and/or surgical resection with positive postoperative outcome (seizure freedom or considerable reduction in seizure frequency) was available in 7/14 patients. We used nonparametric statistical assessment of the MI maps based on a four-dimensional wavelet packet resampling method. The results of MI were compared to the statistical parametric maps obtained with two conventional General Linear Model (GLM) analyses based on the informed basis set (canonical HRF and its temporal and dispersion derivatives) and the Finite Impulse Response (FIR) models.

RESULTS

The MI results were concordant with the electro-clinically or surgically defined epileptogenic area in 8/14 patients and showed the same degree of concordance as the results obtained with the GLM-based methods in 12 patients (7 concordant and 5 discordant). In one patient, the information theoretic analysis improved the delineation of the irritative zone compared with the GLM-based methods.

CONCLUSIONS

Our findings suggest that an information theoretic analysis can provide clinically relevant information about the BOLD signal changes associated with the generation and propagation of interictal epileptic discharges. The concordance between the MI, GLM and FIR maps support the validity of the assumptions adopted in GLM-based analyses of interictal epileptic activity with EEG-fMRI in such a manner that they do not significantly constrain the localization of the epileptogenic zone.

BACKGROUND

Adjuvant chemotherapy is recommended in patients with stage II colon cancer with high-risk features (HRF). However, there is no quantification of the amount of risk conferred by each HRF or the overall survival (OS) benefit gained by chemotherapy based on the risk factor.

OBJECTIVE

To assess survival benefits associated with adjuvant chemotherapy among stage II colon cancer patients having one or more HRF [T4 tumors, less than 12 lymph nodes examined (< 12LN), positive margins, high-grade tumor, perineural invasion (PNI), and lymphovascular invasion (LVI)].

METHODS

Patients diagnosed with stage II colon cancer between 2010 and 2013 were identified from California Cancer Registry. Propensity score weighted all-cause mortality hazard ratios (HR) were calculated for combinations of HRF.

RESULTS

A total of 5160 stage II colon cancer patients were identified, of which 2398 had at least one HRF and 510 of 2398 (21%) received adjuvant chemotherapy. Compared with patients with a single HRF, presence of any 2 or ≥ 3 HRF showed increasingly poorer survival [HR 1.42, 95% confidence interval (CI) 1.16-1.73 and HR 2.50, 95% CI 1.96-3.20, respectively]. Chemotherapy was associated with improved overall survival only among patients with T4 as the single HRF (HR 0.51, 95% CI 0.34-0.78) or combinations involving T4 as T4/< 12 LN (HR 0.31, 95% CI 0.11-0.90), T4/high grade (HR 0.26, 95% CI 0.11-0.61), and T4/LVI (HR 0.16, 95% CI 0.04-0.61).

CONCLUSIONS

Not all high-risk features have similar adverse effects on OS. T4 tumors and their combination with other HRF achieve the most survival benefit with adjuvant therapy. Type and number of high-risk features should be taken into consideration when recommending adjuvant chemotherapy in stage II colon cancer.

The majority of plasma cells in rheumatoid arthritis (RA) synovium produce rheumatoid factors (RF). IgG RF predominate in the immune complexes found in RA synovial fluid and have been implicated in the pathogenesis of RA. IgG4 RF are a major component of IgG RF produced in serum and synovium of RA patients, even though this subclass comprises only 4% of the serum IgG. We produced an IgG4 mAb, hRF-1, with RF reactivity from the synovial tissue of a patient with RA. mAb hRF-1 had binding specificity for mammalian IgG similar to Staphylococcus aureus protein A, which is characteristic of RF from patients with RA. To determine the molecular basis of this particular RF reactivity, the heavy and light chain genes of mAb hRF-1 were amplified by PCR, cloned, and ligated into the pSG5 plasmid for expression in COS-7 cells. Chain recombination experiments localized the Fc-binding reactivity to the hRF-1 heavy chain. Using a series of chimeric Ab sequences, the Fc-binding reactivity was mapped to the constant region of IgG4 rather than the variable region involved in classic RF reactivity. Multiple domains, including Hinge, CH2, and CH3 of the IgG4 constant region were required for Fc binding. Our studies demonstrate an example of RF-like Fc-binding reactivity that is conferred by the gamma-4 constant region rather than the classic Ag binding site and suggest that increased production of IgG4 may contribute to the pathogenesis of RA.

The specificity of the hemodynamic response function (HRF) is determined spatially by the vascular architecture and temporally by the evolution of hemodynamic changes. Here, we used functional photoacoustic microscopy (fPAM) to investigate single cerebral blood vessels of rats after left forepaw stimulation. In this system, we analyzed the spatiotemporal evolution of the HRFs of the total hemoglobin concentration (HbT), cerebral blood volume (CBV), and hemoglobin oxygen saturation (SO(2)). Changes in specific cerebral vessels corresponding to various electrical stimulation intensities and durations were bilaterally imaged with 36 × 65-μm(2) spatial resolution. Stimulation intensities of 1, 2, 6, and 10 mA were applied for periods of 5 or 15 s. Our results show that the relative functional changes in HbT, CBV, and SO(2) are highly dependent not only on the intensity of the stimulation, but also on its duration. Additionally, the duration of the stimulation has a strong influence on the spatiotemporal characteristics of the HRF as shorter stimuli elicit responses only in the local vasculature (smaller arterioles), whereas longer stimuli lead to greater vascular supply and drainage. This study suggests that the current fPAM system is reliable for studying relative cerebral hemodynamic changes, as well as for offering new insights into the dynamics of functional cerebral hemodynamic changes in small animals.

BACKGROUND

In this paper, a novel functional near-infrared spectroscopy (fNIRS)-based brain-computer interface (BCI) framework for control of prosthetic legs and rehabilitation of patients suffering from locomotive disorders is presented.

METHODS

fNIRS signals are used to initiate and stop the gait cycle, while a nonlinear proportional derivative computed torque controller (PD-CTC) with gravity compensation is used to control the torques of hip and knee joints for minimization of position error. In the present study, the brain signals of walking intention and rest tasks were acquired from the left hemisphere's primary motor cortex for nine subjects. Thereafter, for removal of motion artifacts and physiological noises, the performances of six different filters (i.e. Kalman, Wiener, Gaussian, hemodynamic response filter (hrf), Band-pass, finite impulse response) were evaluated. Then, six different features were extracted from oxygenated hemoglobin signals, and their different combinations were used for classification. Also, the classification performances of five different classifiers (i.e. k-Nearest Neighbour, quadratic discriminant analysis, linear discriminant analysis (LDA), Naïve Bayes, support vector machine (SVM)) were tested.

RESULTS

The classification accuracies obtained from SVM using the hrf were significantly higher (p < 0.01) than those of the other classifier/ filter combinations. Those accuracies were 77.5, 72.5, 68.3, 74.2, 73.3, 80.8, 65, 76.7, and 86.7% for the nine subjects, respectively.

CONCLUSIONS

The control commands generated using the classifiers initiated and stopped the gait cycle of the prosthetic leg, the knee and hip torques of which were controlled using the PD-CTC to minimize the position error. The proposed scheme can be effectively used for neurofeedback training and rehabilitation of lower-limb amputees and paralyzed patients.

Factors that can induce the release of histamine from basophils have been studied for more than 30 years. A protein termed histamine-releasing factor (HRF) was purified and molecularly cloned in 1995. HRF can stimulate histamine release and IL-4 and IL-13 production from IgE-sensitized basophils and mast cells. HRF-like activities were found in bodily fluids during the late phase of allergic reactions, implicating HRF in allergic diseases. However, definitive evidence for the role of HRF in allergic diseases has remained elusive. On the other hand, we found effects of monomeric IgE on the survival and activation of mast cells without the involvement of a specific antigen, as well as heterogeneity of IgEs in their ability to cause such effects. The latter property of IgE molecules seemed to be similar to the heterogeneity of IgEs in their ability to prime basophils in response to HRF. This similarity led to our recent finding that ~30% of IgE molecules can bind to HRF via their Fab interactions with two binding sites within the HRF molecule. The use of peptide inhibitors that block HRF-IgE interactions revealed an essential role of HRF to promote skin hypersensitivity and airway inflammation. This review summarizes this and more recent findings and provides a perspective on how they impact our understanding of allergy pathogenesis and potentially change the treatment of allergic diseases.

OBJECTIVE

To measure microvascular blood flow in patients with unilateral exfoliation syndrome (XFS) without glaucoma or ocular hypertension and to compare the values in the eyes with clinically detected exfoliation, their nonexfoliative fellow eyes of the same patients and control eyes.

METHODS

Twenty-two patients with clinically detected unilateral XFS and 30 age-matched healthy subjects were included in this study. Group 1 consisted of 22 eyes with clinical XFS, and the nonexfoliative fellow eyes of the same patients formed Group 2. The control group (Group 3) comprised te randomly selected eyes of 30 age-matched healthy subjects. Ocular blood flow values (volume, flow and velocity) were recorded from the opti nerve head (ONH) and peripapillary retina (PPR) using the Heidelberg retinal flowmeter (HRF). The difference between the three groups were compared statistically.

RESULTS

The mean values of blood flow obtained from the ONH and PPR in eyes with clinically detected exfoliation (Group 1) and their nonexfoliative fellow eyes (Group 2) were both significantly lower than the values for the control eyes (Group 3). The differences in ocular blood flow between the eyes with exfoliation and the nonexfoliative fellow eyes were not statistically significant [one-way analysis of variance (ANOVA), Dunnett's T3 test, p>>/= 0.05].

CONCLUSIONS

These findings suggest that the eyes with clinically detected unilateral XFS were associated with reduced blood flow values in both the ONH and the PPR. The nonexfoliative fellow eyes also have lower blood flow values than the control eyes.

Event-related analyses of functional MRI (fMRI) typically assume that the onset and offset of neuronal activity match stimuli onset and offset, and that evoked fMRI signal changes follow the canonical haemodynamic response function (HRF). Some event types, however, may be unsuited to this approach: brief stimuli might elicit an extended neuronal response; anticipatory effects might result in activity preceding the event; or altered neurovascular coupling may result in a non-canonical HRF. An example is interictal epileptiform discharges (IEDs), which may show a non-canonical HRF and fMRI signal changes preceding their onset as detected on EEG. In such cases, less constrained analyses - capable of detecting early, non-canonical responses - may be necessary. A consequence of less constrained analyses, however, is that artefactual sources of signal change - motion or physiological noise for example - may also be detected and mixed with the neuronally-generated signals. In this paper, to address this issue, we describe an event-related independent components analysis (eICA) that identifies different sources of event-related signal change that can then be separately assessed to identify likely artefacts and separate primary from propagated activity. We also describe a group analysis that identifies eICA components that are spatially and temporally consistent across subjects and provides an objective approach for selecting group-specific components likely to be of neural origin. We apply eICA to patients with rolandic epilepsy - with stereotypical IEDs arising from a focus in the rolandic fissure - and demonstrate that a single event-related component, concordant with this source location, is detected.

Functional magnetic resonance imaging (fMRI) has revealed much about altered CNS function in HIV/AIDS. In this study, we compared the blood oxygen level dependent hemodynamic response function (BOLD HRF) signal in HIV/AIDS and control subjects as a necessary pre-condition for fMRI studies of higher level cognitive function. Using event-related fMRI, subjects performed a simple sensory-motor activity allowing the measurement of the BOLD HRF in the precentral gyrus. There were no significant differences in the HRF when viewed as a function of age, hemisphere, or HIV serostatus. However, significant results were found after dividing the subjects by NIMH impairment classifications. There were 16 control subjects, 19 Normal/Asymptomatic Neuropsychological Impairment (ANI), and 11 Minor Neurocognitive Disorder (MNCD)/HIV-Associated Dementia (HAD) subjects. The HRF of MNCD/HAD subjects did not return to baseline after 16s, suggesting subtle alterations in neuronal function, which may affect event-related fMRI studies.