Purpose: To develop and test the performance of a deep learning-based algorithm for glaucomatous disc identification using monoscopic fundus photographs.

Design: Fundus photograph database study.

Participants: Four thousand three hundred ninety-four fundus photographs, including 3768 images from previous Sydney-based clinical studies and 626 images from publicly available online RIM-ONE and High-Resolution Fundus (HRF) databases with definitive diagnoses.

Methods: We merged all databases except the HRF database, and then partitioned the dataset into a training set (80% of all cases) and a testing set (20% of all cases). We used the HRF images as an additional testing set. We compared the performance of the artificial intelligence (AI) system against a panel of practicing ophthalmologists including glaucoma subspecialists from Australia, New Zealand, Canada, and the United Kingdom.

Main outcome measures: The sensitivity and specificity of the AI system in detecting glaucomatous optic discs.

Results: By using monoscopic fundus photographs, the AI system demonstrated a high accuracy rate in glaucomatous disc identification (92.7%; 95% confidence interval [CI], 91.2%-94.2%), achieving 89.3% sensitivity (95% CI, 86.8%-91.7%) and 97.1% specificity (95% CI, 96.1%-98.1%), with an area under the receiver operating characteristic curve of 0.97 (95% CI, 0.96-0.98). Using the independent online HRF database (30 images), the AI system again accomplished high accuracy, with 86.7% in both sensitivity and specificity (for ophthalmologists, 75.6% sensitivity and 77.8% specificity) and an area under the receiver operating characteristic curve of 0.89 (95% CI, 0.76-1.00).

Conclusions: This study demonstrated that a deep learning-based algorithm can identify glaucomatous discs at high accuracy level using monoscopic fundus images. Given that it is far easier to obtain monoscopic disc images than high-quality stereoscopic images, this study highlights the algorithm's potential application in large population-based disease screening or telemedicine programs.

The MXT tumor is an experimental mammary neoplasm which is maintained by serial transplantation using B6D2F1 mice, and which contains significant amounts of estrogen and progesterone receptors. The aim of the present study is to examine the effects of ovariectomy (OVX) or ovariectomy plus hypophysectomy (OVX-HX) on both the macroscopic growth and the cell proliferation of this tumor. This cell proliferation was evaluated by means of in vivo tritiated thymidine autoradiography. In addition, we investigated the effects of a GnRH analog (Gonadorelin: HRF, 5-oxo-Pro-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-hydrochloride) on MTX tumor cell proliferation on 7 day-OVX and 5 day-HX (OVX-HX) mice. The uterine luminal epithelium was chosen to monitor the methodology. Our data clearly demonstrate that there is a delay in the growth of MXT tumors grafted into hypophysectomized animals and, to a lesser degree, ovariectomized animals. With respect to proliferation, castration induced a dramatic decrease of the thymidine labelling index (TLI) in the tissue used to monitor the methodology (the uterine luminal epithemium); in contrast, no cell proliferation was induced by hypophysectomy or HRF administration. In 4-week-old MXT tumors, ovariectomy also markedly decreased the TLI within a few days of its taking place. However hypophysectomy, performed on castrated animals, induced a significant and transient increase of cell proliferation in this neoplasm, an increase which lasted from the 2nd to the 5th day following the operation. The high basal level of MXT cell proliferation recorded in OVX-HX animals decreased dramatically after the administration of HRF between 12 and 48 h prior to the sacrifice of the animals. It is concluded that the HRF exerts a direct effect on the MXT tumor cells, and this HRF might be essential for their growth.

A compact handpiece combining high resolution fluorescence (HRF) imaging with optical coherence tomography (OCT) was developed to provide real-time assessment of oral lesions. This multimodal imaging device simultaneously captures coregistered en face images with subcellular detail alongside cross-sectional images of tissue microstructure. The HRF imaging acquires a 712 × 594 μm² field-of-view at the sample with a spatial resolution of 3.5 μm. The OCT images were acquired to a depth of 1.5 mm with axial and lateral resolutions of 9.3 and 8.0 μm, respectively. HRF and OCT images are simultaneously displayed at 25 fps. The handheld device was used to image a healthy volunteer, demonstrating the potential for in vivo assessment of the epithelial surface for dysplastic and neoplastic changes at the cellular level, while simultaneously evaluating submucosal involvement. We anticipate potential applications in real-time assessment of oral lesions for improved surveillance and surgical guidance.

Functional MRI (fMRI) is an indirect measure of neural activity as a result of the convolution of the hemodynamic response function (HRF) and latent (unmeasured) neural activity. Recent studies have shown variability of HRF across brain regions (intra-subject spatial variability) and between subjects (inter-subject variability). Ignoring this HRF variability during data analysis could impair the reliability of such fMRI results. Using whole-brain resting-state fMRI (rs-fMRI), we employed hemodynamic deconvolution to estimate voxel-wise HRF. Studying the impact of mental disorders on HRF variability, we identified HRF aberrations in soldiers (N = 87) with posttraumatic stress disorder (PTSD) and mild-traumatic brain injury (mTBI) compared to combat controls. Certain subcortical and default-mode regions were found to have significant HRF aberrations in the clinical groups. These brain regions have been previously associated with neurochemical alterations in PTSD, which are known to impact the shape of the HRF. We followed-up these findings with seed-based functional connectivity (FC) analysis using regions-of-interest (ROIs) whose HRFs differed between the groups. We found that part of the connectivity group differences reported from traditional FC analysis (no deconvolution) were attributable to HRF variability. These findings raise the question of the degree of reliability of findings from conventional rs-fMRI studies (especially in psychiatric populations like PTSD and mTBI), which are corrupted by HRF variability. We also report and discus, for the first time, voxel-level HRF alterations in PTSD and mTBI. To the best of our knowledge, this is the first study to report evidence for the impact of HRF variability on connectivity group differences. Our work has implications for rs-fMRI connectivity studies. We encourage researchers to incorporate hemodynamic deconvolution during pre-processing to minimize the impact of HRF variability.

OBJECTIVE

We aimed at studying the hemodynamic response (HR) to Interictal Epileptic Discharges (IEDs) using patient-specific and prolonged simultaneous ElectroEncephaloGraphy (EEG) and functional Near InfraRed Spectroscopy (fNIRS) recordings.

METHODS

The epileptic generator was localized using Magnetoencephalography source imaging. fNIRS montage was tailored for each patient, using an algorithm to optimize the sensitivity to the epileptic generator. Optodes were glued using collodion to achieve prolonged acquisition with high quality signal. fNIRS data analysis was handled with no a priori constraint on HR time course, averaging fNIRS signals to similar IEDs. Cluster-permutation analysis was performed on 3D reconstructed fNIRS data to identify significant spatio-temporal HR clusters. Standard (GLM with fixed HRF) and cluster-permutation EEG-fMRI analyses were performed for comparison purposes.

RESULTS

fNIRS detected HR to IEDs for 8/9 patients. It mainly consisted oxy-hemoglobin increases (seven patients), followed by oxy-hemoglobin decreases (six patients). HR was lateralized in six patients and lasted from 8.5 to 30 s. Standard EEG-fMRI analysis detected an HR in 4/9 patients (4/9 without enough IEDs, 1/9 unreliable result). The cluster-permutation EEG-fMRI analysis restricted to the region investigated by fNIRS showed additional strong and non-canonical BOLD responses starting earlier than the IEDs and lasting up to 30 s.

CONCLUSIONS

(i) EEG-fNIRS is suitable to detect the HR to IEDs and can outperform EEG-fMRI because of prolonged recordings and greater chance to detect IEDs; (ii) cluster-permutation analysis unveils additional HR features underestimated when imposing a canonical HR function (iii) the HR is often bilateral and lasts up to 30 s.

Functional magnetic resonance imaging (fMRI) studies typically employ rapid, event-related designs for behavioral reasons and for reasons associated with statistical efficiency. Efficiency is calculated from the precision of the parameters (Betas) estimated from a General Linear Model (GLM) in which trial onsets are convolved with a Hemodynamic Response Function (HRF). However, previous calculations of efficiency have ignored likely variability in the neural response from trial to trial, for example due to attentional fluctuations, or different stimuli across trials. Here we compare three GLMs in their efficiency for estimating average and individual Betas across trials as a function of trial variability, scan noise and Stimulus Onset Asynchrony (SOA): "Least Squares All" (LSA), "Least Squares Separate" (LSS) and "Least Squares Unitary" (LSU). Estimation of responses to individual trials in particular is important for both functional connectivity using "Beta-series correlation" and "multi-voxel pattern analysis" (MVPA). Our simulations show that the ratio of trial-to-trial variability to scan noise impacts both the optimal SOA and optimal GLM, especially for short SOAs<5s: LSA is better when this ratio is high, whereas LSS and LSU are better when the ratio is low. For MVPA, the consistency across voxels of trial variability and of scan noise is also critical. These findings not only have important implications for design of experiments using Beta-series regression and MVPA, but also statistical parametric mapping studies that seek only efficient estimation of the mean response across trials.

OBJECTIVE

School-age children with developmental coordination disorder (DCD) have poor health-related fitness (HRF), but little is known about when these deficits emerge. The purpose of this study was to determine if 4- and 5-yr-old children who meet the criteria for DCD exhibit poorer HRF compared with typically developing (TD) children, and if this relationship is mediated by vigorous physical activity (VPA) engagement.

METHODS

Five hundred and ninety-two children participated (age, 5.0 ± 0.6 yr) from the Coordination and Activity Tracking in CHildren study. Motor skills were assessed using the Movement Assessment Battery for Children-2, with groups defined as having DCD (≤5th percentile), at risk for DCD (6th-16th percentile), and TD (>16th percentile). Measures of body composition included body mass index, waist circumference, and body fat percentage. Musculoskeletal fitness assessments included standing long jump distance, as well as peak and mean power assessed using a 30-s Wingate protocol on a pediatric cycle ergometer. Time to exhaustion on a progressive, treadmill test was used to determine aerobic fitness. Flexibility and VPA were assessed using a sit-and-reach test and 7-d accelerometry, respectively.

RESULTS

Children in the DCD group had the poorest musculoskeletal and aerobic fitness, whereas TD children had the highest. No differences in body composition among groups were found. Daily VPA was similar among groups and did not explain HRF differences.

CONCLUSIONS

Preschool children with DCD have decreased anaerobic and aerobic fitness compared with TD children; however, VPA and body composition seem to be less affected by DCD in the early years. Early motor interventions may be able to improve fitness and reduce the risk of hypoactivity and obesity as children with DCD get older.

Besides the well-known roles of oxytocin on birth, maternal bonding, and lactation, recent evidence shows that this hypothalamic hormone possesses cardioprotective, anti-inflammatory and parasympathetic neuromodulation properties. In this study, we explore the heart rate fluctuations (HRF) in an endotoxemic rodent model that was accompanied by the administration of exogenous oxytocin. The assessment of HRF has been widely used as an indirect measure of the cardiac autonomic function. In this context, adult male Dark Agouti rats were equipped with a telemetric transmitter to continuously and remotely measure the electrocardiogram, temperature, and locomotion. In a between-subjects experimental design, rats received the following peripheral treatment: saline solution as a vehicle (V); lipopolysaccharide (LPS); oxytocin (Ox); lipopolysaccharide + oxytocin (LPS+Ox). Linear and non-linear parameters of HRF were estimated starting 3h before to 24h after treatments. Our results showed that exogenous oxytocin does not modify by itself the HRF of oxytocin-treated rats in comparison to vehicle-treated rats. However, in animals undergoing endotoxemia it: a) provokes a less anticorrelated pattern in HRF, b) decreased mean heart rate, c) moderated the magnitude and duration of the LPS-induced hyperthermia, and d) increased locomotion, up to 6h after the LPS injection. The less anticorrelated pattern in the HRF and decreased mean heart rate may reflect a cardiac pacemaker coupling with cholinergic influences mediated by oxytocin during LPS-induced endotoxemia. Finally, the anti-lethargic and long-term temperature moderating effects of the administration of oxytocin during endotoxemia could be a consequence of the systemic anti-inflammatory properties of oxytocin.

UNASSIGNED

In the CHAMPION PHOENIX trial, the potent, rapidly acting, intravenous platelet adenosine diphosphate receptor antagonist cangrelor reduced the 48-h incidence of major adverse cardiac events (MACE; death, myocardial infarction, stent thrombosis, or ischaemia-driven revascularization) compared with a loading dose of clopidogrel in patients undergoing percutaneous coronary intervention (PCI). We sought to determine whether the efficacy of cangrelor during PCI varies in patients with simple vs. complex target lesion coronary anatomy.

UNASSIGNED

Blinded angiographic core laboratory analysis was completed in 10 854 of 10 942 (99.2%) randomized patients in CHAMPION PHOENIX (13 418 target lesions). Outcomes were analysed according to the number of angiographic PCI target lesion high-risk features (HRF) present (bifurcation, left main, thrombus, angulated, tortuous, eccentric, calcified, long, or multi-lesion treatment). The number of patients with 0, 1, 2, and ≥3 HRFs was 1817 (16.7%), 3442 (31.7%), 2901 (26.7%), and 2694 (24.8%), respectively. The 48-h MACE rate in clopidogrel-treated patients increased progressively with lesion complexity (from 3.3% to 4.4% to 6.9% to 8.7%, respectively, P < 0.0001). Cangrelor reduced the 48-h rate of MACE by 21% {4.7% vs. 5.9%, odds ratio (OR) [95% confidence interval (95% CI)] 0.79 (0.67, 0.93), P = 0.006} compared with clopidogrel, an effect which was consistent regardless of PCI lesion complexity (Pinteraction = 0.66) and presentation with stable ischaemic heart disease (SIHD) or an acute coronary syndrome (ACS). By multivariable analysis, the number of high-risk PCI characteristics [OR (95% CI) 1.68 (1.20, 2.36), 2.78 (2.00, 3.87), and 3.23 (2.33, 4.48) for 1, 2, and 3 HRFs compared with 0 HRFs, all P < 0.0001] and treatment with cangrelor vs. clopidogrel [OR (95% CI) 0.78 (0.66, 0.92), P = 0.004] were independent predictors of the primary 48-h MACE endpoint. Major bleeding rates were unrelated to lesion complexity and were not increased by cangrelor.

UNASSIGNED

Peri-procedural MACE after PCI is strongly dependent on the number of treated high-risk target lesion features. Compared with a loading dose of clopidogrel, cangrelor reduced MACE occurring within 48 h after PCI in patients with SIHD and ACS regardless of baseline lesion complexity. The absolute benefit:risk profile for cangrelor will therefore be greatest during PCI in patients with complex coronary anatomy.

UNASSIGNED

NCT01156571.

Slow and rapid event-related designs are used in fMRI and functional near-infrared spectroscopy (fNIRS) experiments to temporally characterize the brain hemodynamic response to discrete events. Conventional averaging (CA) and the deconvolution method (DM) are the two techniques commonly used to estimate the Hemodynamic Response Function (HRF) profile in event-related designs. In this study, we conducted a series of simulations using synthetic and real NIRS data to examine the effect of the main confounding factors, including event sequence timing parameters, different types of noise, signal-to-noise ratio (SNR), temporal autocorrelation and temporal filtering on the performance of these techniques in slow and rapid event-related designs. We also compared systematic errors in the estimates of the fitted HRF amplitude, latency and duration for both techniques. We further compared the performance of deconvolution methods based on Finite Impulse Response (FIR) basis functions and gamma basis sets. Our results demonstrate that DM was much less sensitive to confounding factors than CA. Event timing was the main parameter largely affecting the accuracy of CA. In slow event-related designs, deconvolution methods provided similar results to those obtained by CA. In rapid event-related designs, our results showed that DM outperformed CA for all SNR, especially above -5 dB regardless of the event sequence timing and the dynamics of background NIRS activity. Our results also show that periodic low-frequency systemic hemodynamic fluctuations as well as phase-locked noise can markedly obscure hemodynamic evoked responses. Temporal autocorrelation also affected the performance of both techniques by inducing distortions in the time profile of the estimated hemodynamic response with inflated t-statistics, especially at low SNRs. We also found that high-pass temporal filtering could substantially affect the performance of both techniques by removing the low-frequency components of HRF profiles. Our results emphasize the importance of characterization of event timing, background noise and SNR when estimating HRF profiles using CA and DM in event-related designs.

Receptive fields (RFs) in visual cortex are organized in antagonistic, center-surround, configurations. RF properties change systematically across eccentricity and between visual field maps. However, it is unknown how center-surround configurations are organized in human visual cortex across lamina. We use sub-millimeter resolution functional MRI at 7Tesla and population receptive field (pRF) modeling to investigate the pRF properties in primary visual cortex (V1) across cortical depth. pRF size varies according to a U-shaped function, indicating smaller pRF center size in the middle compared to superficial and deeper intra-cortical portions of V1, consistent with non-human primate neurophysiological measurements. Moreover, a similar U-shaped function is also observed for pRF surround size. However, pRF center-surround ratio remains constant across cortical depth. Simulations suggest that this pattern of results can be directly linked to the flow of signals across cortical depth, with the visual input reaching the middle of cortical depth and then spreading towards superficial and deeper layers of V1. Conversely, blood-oxygenation-level-dependent (BOLD) signal amplitude increases monotonically towards the pial surface, in line with the known vascular organization across cortical depth. Independent estimates of the haemodynamic response function (HRF) across cortical depth show that the center-surround pRF size estimates across cortical depth cannot be explained by variations in the full-width half maximum (FWHM) of the HRF.

Background: A major objective of precision medicine is the elucidation of non-invasive biomarkers of cardiovascular (CV) risk. Recently, we introduced a new dynamical marker of sino-atrial instability, termed heart rate fragmentation (HRF), which outperformed traditional and nonlinear heart rate variability metrics in separating ostensibly healthy subjects from patients with coronary artery disease. Accordingly, we hypothesized that HRF may be a dynamical biomarker of adverse cardiovascular events (CVEs). Methods: This study employed data from a cohort of participants in the Multi-Ethnic Study of Atherosclerosis (MESA), a prospective study of sub-clinical heart disease. Interbeat interval time series (n = 1963), derived from the electrocardiographic channel of the polysomnogram study, were analyzed using the newly introduced metrics of fragmentation, as well as traditional heart rate variability (HRV) indices and the short-term detrended fluctuation analysis exponent. Cox regression analysis was used to assess the association between HR dynamic indices and CV outcomes in unadjusted and adjusted models. Results: The mean (± SD) follow-up time was 2.97 ± 0.63 years. In adjusted models, higher fragmentation was significantly associated with incident CVEs (number of events; hazard ratio [95% confidence interval]: n = 72, 1.43 [1.16-1.76]) and CV death (n = 21; 1.65 [1.15-2.36]). The traditional HRV and the fractal indices were not associated with CVEs or CV death. The most discriminatory fragmentation indices added significant value to Framingham and MESA CV risk indices in all analyses. Conclusion: Our findings show that HRF has promise as a non-invasive, automatable biomarker of CV risk. The basic mechanisms underlying fragmentation remain to be delineated. Its association with incident outcomes raises the possibility of connections to degenerative changes in the multisystem network controlling SAN function.

BACKGROUND

We have previously defined IgE+ as the IgE on basophils from a subset of highly allergic asthmatic subjects that release histamine after stimulation with histamine-releasing factor (HRF). The mechanism of IgE+ remains an enigma. Recently, there have been reports of monomeric highly cytokinergic IgEs causing mediator release, cytokine release, and phosphorylation events in cultured rodent and human mast cells in the absence of antigen.

OBJECTIVE

We investigated whether human IgE+ might exist as highly cytokinergic IgE in the human system.

METHODS

IgE+ was defined as causing greater than 10% histamine release by using HRF as a stimulus of human basophils. By definition, IgE- did not support histamine release to HRF. Once defined, serum and various purified human IgEs were used to stimulate purified human basophils or cultured human mast cells. The cells were examined for histamine release, extracellular signal-regulated kinase (ERK) phosphorylation, and IL-13 secretion.

RESULTS

We found that neither IgE+ nor IgE- induced ERK phosphorylation, histamine release, and IL-13 release from freshly isolated basophils in the absence of a specific antigen. However, human IgE alone did stimulate ERK phosphorylation in cultured human mast cells and IL-3-primed human basophils.

CONCLUSIONS

Human IgE+ is not an equivalent of the mouse highly cytokinergic IgE. However, human IgE did have effects on cultured mast cells and basophils. The effect of highly cytokinergic IgE on ERK phosphorylation and cytokine secretion might be due to the priming effect of human basophils and mast cells.

Functional magnetic resonance imaging (fMRI) based on BOLD signal has been used to indirectly measure the local neural activity induced by cognitive tasks or stimulation. Most fMRI data analysis is carried out using the general linear model (GLM), a statistical approach which predicts the changes in the observed BOLD response based on an expected hemodynamic response function (HRF). In cases when the task is cognitively complex or in cases of diseases, variations in shape and/or delay may reduce the reliability of results. A novel exploratory method using fMRI data, which attempts to discriminate between neurophysiological signals induced by the stimulation protocol from artifacts or other confounding factors, is introduced in this paper. This new method is based on the fusion between correlation analysis and the discrete wavelet transform, to identify similarities in the time course of the BOLD signal in a group of volunteers. We illustrate the usefulness of this approach by analyzing fMRI data from normal subjects presented with standardized human face pictures expressing different degrees of sadness. The results show that the proposed wavelet correlation analysis has greater statistical power than conventional GLM or time domain intersubject correlation analysis.

In language production, naming a picture with a gender-marked determiner phrase is faster in the presence of a distractor noun with the same grammatical gender (congruent condition) as compared with a different grammatical gender (incongruent condition). We investigated the neural correlates of this determiner congruency effect in German with functional magnetic resonance imaging (fMRI). Participants named pictures of real objects with determiner phrases (e.g. "der Tisch"-the table) in the presence of a gender-congruent or gender-incongruent distractor noun. Different comparisons allow the following functional segregation within the prefrontal cortex. First, the comparison between picture naming versus rest revealed a steeper slope of the haemodynamic response function (HRF) in the gender-congruent than the gender-incongruent condition in the left BA 44, suggesting the involvement of BA 44 in determiner selection. HRF amplitude differences between the congruent and the incongruent condition were observed outside the language network in the right fronto-median wall (congruent>> incongruent), and in the left premotor cortex, middle frontal gyrus, cerebellum, and inferior parietal lobe (incongruent>> congruent). The latter regions are known to be involved in the processing of incongruence and conflict in general. The data thus reveal the involvement of the left BA 44 in the selection of determiners for language production.

The recent emergence of anti-immunoglobulin E (IgE) drugs and their candidates for humans has endorsed the significance of IgE-dependent pathways in allergic disorders. IgE is distributed locally in the tissues or systemically to confer a sensory mechanism in a domain of adaptive immunity to the otherwise innate type of effector cells, namely, mast cells and basophils. Bound on the high-affinity IgE receptor FcεRI, IgE enables fast memory responses against revisiting threats of venoms, parasites, and bacteria. However, the dysregulation of IgE-dependent reactions leads to potentially life-threatening allergic diseases, such as asthma and anaphylaxis. Therefore, reactivity of the IgE sensor is fine-tuned by various IgE-associating molecules. In this review, we discuss the mechanistic basis for how IgE-dependent mast cell activation is regulated by the IgE-associating molecules, including the newly developed therapeutic candidates.

Keywords: CD23; FcεRI; IgE; basophils; glycosylation; histamine-releasing factor (HRF); mast cells; omalizumab; structure.

Functional MRI analyses commonly rely on the assumption that the temporal dynamics of hemodynamic response functions (HRFs) are independent of the amplitude of the neural signals that give rise to them. The validity of this assumption is particularly important for techniques that use fMRI to resolve sub-second timing distinctions between responses, in order to make inferences about the ordering of neural processes. Whether or not the detailed shape of the HRF is independent of neural response amplitude remains an open question, however. We performed experiments in which we measured responses in primary visual cortex (V1) to large, contrast-reversing checkerboards at a range of contrast levels, which should produce varying amounts of neural activity. Ten subjects (ages 22-52) were studied in each of two experiments using 3 Tesla scanners. We used rapid, 250 ms, temporal sampling (repetition time, or TR) and both short and long inter-stimulus interval (ISI) stimulus presentations. We tested for a systematic relationship between the onset of the HRF and its amplitude across conditions, and found a strong negative correlation between the two measures when stimuli were separated in time (long- and medium-ISI experiments, but not the short-ISI experiment). Thus, stimuli that produce larger neural responses, as indexed by HRF amplitude, also produced HRFs with shorter onsets. The relationship between amplitude and latency was strongest in voxels with lowest mean-normalized variance (i.e., parenchymal voxels). The onset differences observed in the longer-ISI experiments are likely attributable to mechanisms of neurovascular coupling, since they are substantially larger than reported differences in the onset of action potentials in V1 as a function of response amplitude.

We report studies of the nonlinear nature of blood oxygen level-dependent (BOLD) responses to short transient deactivations in human visual cortex. Both functional magnetic resonance imaging (fMRI) and near-infrared spectroscopy (NIRS) have been used to compare and contrast the hemodynamic response functions (HRFs) associated with transient activation and deactivation in primary visual cortex. We show that signal decreases for short duration deactivations are smaller than corresponding signal increases in activation studies. Moreover, the standard balloon model of BOLD effects may be modified to account for the observed nonlinear nature of deactivations by appropriate changes to simple hemodynamic parameters without recourse to new assumptions about the nature of the coupling between activity and oxygen use.

This prospective study was planned to determine the intercourse between translationally controlled tumor protein (TCTP)/histamine releasing factor (HRF)/histamine pathway and angiogenesis in chronic lymphocytic leukemia (CLL). A total of 153 CLL patients were included. Serum histamine levels were higher in CLL patients. A positive correlation was found between microvessel density (MVD)-mast cell (MC) count; MVD-TCTP/HRF and MC count-TCTP/HRF. Microvessel density, MC and ZAP 70 were significantly higher in TCTP/HRF-positive group. Time to first treatment was shorter in patients with increased MVD and TCTP/HRF. Further data is essential to ascertain the role of TCTP/HRF pathway in tumor angiogenesis and CLL prognosis.

Hypochoeris radicata, an invasive plant species, is a large and growing threat to ecosystem integrity on Jeju Island, a UNESCO World Heritage site. Therefore, research into the utilization of H. radicata is important and urgently required in order to solve this invasive plant problem in Jeju Island. The broader aim of our research is to elucidate the biological activities of H. radicata, which would facilitate the conversion of this invasive species into high value-added products. The present study was undertaken to identify the pharmacological effects of H. radicata flower on the production of inflammatory mediators in macrophages. The results indicate that the ethyl acetate fraction of H. radicata extract (HRF-EA) inhibited the production of pro-inflammatory molecules such as NO, iNOS, PGE2, and COX-2, and cytokines such as TNF-α, IL-1ß, and IL-6 in LPS-stimulated RAW 264.7 cells. Furthermore, the phosphorylation of MAPKs such as p38, ERK, and JNK was suppressed by HRF-EA in a concentration-dependent manner. In addition, through HPLC and UPLC fingerprinting, luteolins were also identified and quantified as extract constituents. On the basis of these results, we suggest that H. radicata may be considered possible anti-inflammatory candidates for pharmaceutical and/or cosmetic applications.

OBJECTIVE

fMRI is the convolution of the hemodynamic response function (HRF) and unmeasured neural activity. HRF variability (HRFv) across the brain could, in principle, alter functional connectivity (FC) estimates from resting-state fMRI (rs-fMRI). Given that HRFv is driven by both neural and non-neural factors, it is problematic when it confounds FC. However, this aspect has remained largely unexplored even though FC studies have grown exponentially. We hypothesized that HRFv confounds FC estimates in the brain's default-mode-network.

METHODS

We tested this hypothesis using both simulations (where the ground truth is known and modulated) as well as rs-fMRI data obtained in a 7T MRI scanner (N = 47, healthy). FC was obtained using 2 pipelines: data with hemodynamic deconvolution (DC) to estimate the HRF and minimize HRFv, and data with no deconvolution (NDC, HRFv-ignored). DC and NDC FC networks were compared, along with regional HRF differences, revealing potential false connectivities that resulted from HRFv.

RESULTS

We found evidence supporting our hypothesis using both simulations and experimental data. With simulations, we found that HRFv could cause a change of up to 50% in FC. With rs-fMRI, several potential false connectivities attributable to HRFv, with majority connections being between different lobes, were identified. We found a double exponential relationship between the magnitude of HRFv and its impact on FC, with a mean/median error of 30.5/11.5% caused in FC by HRF confounds.

CONCLUSIONS

HRFv, if ignored, could cause identification of false FC. FC findings from HRFv-ignored data should be interpreted cautiously. We suggest deconvolution to minimize HRFv.

Functional magnetic resonance imaging (fMRI) of the blood oxygen level dependent (BOLD) response has commonly been used to investigate the neuropathology underlying cognitive and sensory deficits in patients with schizophrenia (SP) by examining the positive phase of the BOLD response, assuming a fixed shape for the hemodynamic response function (HRF). However, the individual phases (positive and post-stimulus undershoot (PSU)) of the HRF may be differentially affected by a variety of underlying pathologies. The current experiment used a multisensory detection task with a rapid event-related fMRI paradigm to investigate both the positive and PSU phases of the HRF in SP and healthy controls (HC). Behavioral results indicated no significant group differences during task performance. Analyses that examined the shape of the HRF indicated two distinct group differences. First, SP exhibited a reduced and/or prolonged PSU following normal task-related positive BOLD activation in secondary auditory and visual sensory areas relative to HC. Second, SP did not show task-induced deactivation in the anterior node of the default-mode network (aDMN) relative to HC. In contrast, when performing traditional analyses that focus on the positive phase, there were no group differences. Interestingly, the magnitude of the PSU in secondary auditory and visual areas was positively associated with the magnitude of task-induced deactivation within the aDMN, suggesting a possible common neural mechanism underlying both of these abnormalities (failure in neural inhibition). Results are consistent with recent views that separate neural processes underlie the two phases of the HRF and that they are differentially affected in SP. Hum Brain Mapp 37:745-755, 2016. © 2015 Wiley Periodicals, Inc.

Visceral leishmaniasis (VL) is a potentially fatal disease, in which the treatment based on chemotherapy is considered toxic. The cure of disease is associated with the life-long Th1-type immunity against the infection. The Th1-related cytokines production by peripheral blood mononuclear cells (PBMCs) seems to be crucial for host control of parasite load and clinical cure. In the current study, we used five proteins (IgE-dependent histamine-releasing factor [HRF], LiHyD, LiHyV, LiHyT and LiHyp6) recently shown to be antigenic and/or immunogenic in the canine VL, aiming to evaluate the antigen-specific antibody levels and cytokine production in PBMCs culture supernatants collected from VL patients before and after anti-VL treatment. In the results, when PBMCs were exposed to rHRF, rLiHyD and rLiHyT, higher IFN-γ and lower IL-10 levels were observed in all patients that were treated and clinically cured. Analysis of specific antibody subclasses was in line with in vitro cellular response, since a higher IgG2 production was found in the treated and cured patients, when compared to the IgG1 subclass levels. In addition, evaluating the diagnostic efficacy of the recombinant molecules, the rHRF, rLiHyD and rLiHyT proteins showed the best results in the serology assays to identify all VL patients, as well as these antigens were not recognized by antibodies in sera from non-infected subjects or those with leishmaniasis-related diseases. Our results corroborate the view that clinical cure of VL is associated with a sustained Th1-related response, and indicate the potential use of rHRF, rLiHyD and rLiHyT as immune biomarkers of VL treatment.