Histamine releasing factor (HRF)--a human lymphokine--has been shown previously to release histamine from basophils in vitro. In this paper we show that HRF acted across the species barrier and released histamine from mouse peritoneal mast cells. This response was dose-dependent. Mast cells from both sensitized and non-sensitized mice were equally susceptible to the action of HRF. We observed synergistic action of HRF with specific allergen (ovalbumin) or HRF with anti-IgE antibody in releasing histamine from mast cells. Preincubation of mast cells with calcium ion chelating agent ethylenediaminetetraacetic acid (EDTA) or disodium cromoglycate induces only a small inhibition of histamine release caused by HRF. We conclude that histamine release from mouse peritoneal mast cells can serve as an in vitro test for the assay of human HRF.

Human neutrophil-derived histamine-releasing activity (HRA-N) was partially purified and found to contain a heat-stable 1400 to 2300-Da fraction which caused human basophils and rat basophil leukemia cells (RBL) to degranulate. The capacity of HRA-N to activate basophils was not related to the gender or atopic status of the basophil donor, but was related to anti-IgE responsiveness. Several lines of evidence suggest that HRA-N and anti-IgE induce histamine release through distinctly different mechanisms: 1) the time course of HRA-N- and anti-IgE-induced RBL histamine release are different; 2) HRA-N causes histamine release from RBL with and without surface-bound IgE; 3) lactic acid stripping of IgE from human basophils reduces anti-IgE-induced histamine release, but has no consistent effect on HRA-N-induced histamine release; and 4) passive sensitization of lactic acid-stripped basophils with IgE restores anti-IgE-induced histamine release but not HRA-N-induced histamine release. Several histamine-releasing factors (HRF) were compared with HRA-N. Human nasal HRF (HRF-NW, crude and partially purified fractions of 15 to 30, 3.5 to 9, and less than 3.5 kDa), like HRA-N, caused equal histamine release from both native and IgE-sensitized RBL. However, only the 15- to 30-kDa fraction caused histamine release from human basophils in the doses tested. Mononuclear cell HRF (HRF-M, crude and a partially purified 25 kDa Mr fraction) and platelet HRF (HRF-P, crude preparation) failed to cause histamine release from either native or IgE-sensitized RBL but caused 30 +/- 5.5% and 20 +/- 10% net histamine release from human basophils, respectively. HRA-N and HRF-NW were both stable to boiling. These data, taken together, suggest that the capacity of HRA-N to induce RBL and human basophil histamine release and of HRF-NW to stimulate RBL histamine release is independent of IgE. The data further suggest that HRA-N and HRF-NW can be distinguished by size, and that they both differ from mononuclear cell HRF and platelet HRF. Thus, it appears that inflammatory cells generate a family of distinct HRF.

A membrane-associated receptor for the C1q subcomponent of complement is widely distributed among different cell types. While a number of possible physiological functions of the C1q receptor (C1qR) on different cell types have been described, the way in which C1qR regulates complement activity remains unclear. This report describes the mechanism by which C1qR regulates activation of the first component of complement, C1. Using purified components of complement, we were able to show that membrane-associated C1qR as well as detergent-solubilized C1qR, purified from polymorphonuclear leukocytes, human umbilical vein endothelial cells or an endothelial cell line, EA.hy 926, are able to inhibit complement-mediated lysis of C1q-sensitized erythrocytes. Using hemolytic assays, we were able to demonstrate that C1qR prevents the association of C1q with C1r and C1s to form macromolecular C1. In addition, incubation of C1qR with the collagen-like stalks, but not with the globular heads of C1q, inhibits the effect of C1qR. This demonstrates that C1qR exerts its complement inhibitory effect by binding to the collagen-like stalk of C1q. No complement regulatory effect of C1qR was observed on preformed macromolecular C1. These data suggest that besides such-well-known complement regulatory molecules as CD55 (DAF), CD46 (MCP), CD35 (CR1) and CD59 (HRF), C1qR too is able to regulate complement activity.

Functional magnetic resonance imaging (fMRI) data analysis has been carried out recently in the framework of information theory, by means of the Shannon entropy. As a natural extension, a method based on the generalized Tsallis entropy was developed to the analysis event-related (ER-fMRI), where a brief stimulus is presented, followed by a long period of rest. The new technique aims for spatial localization neuronal activity due to a specific task. This method does not require a priori hypothesis of the hemodynamic response function (HRF) shape and the linear relation between BOLD responses with the presented task. Numerical simulations were performed so as to determine the optimal values of the Tsallis q parameter and the number of levels, L. In order to avoid undesirable divergences of the Tsallis entropy, only positive q values were studied. Results from simulated data (with L = 3) indicated that, for q = 0.8, the active brain areas are detected with the highest performance. Moreover, the method was tested for an in vivo experiment and demonstrated the ability to discriminate active brain regions that selectively responded to a bilateral motor task.

Mild heat treatment of HeLa cell nuclear extracts (NE) selectively inhibits pre-mRNA splicing. Heat-inactivated extracts can be complemented by a small amount of untreated NE. Utilizing this complementation assay and a combination of ion-exchange, affinity, and hydrophobic chromatography, a heat reversal factor (HRF) was purified from NE that is required to rescue pre-mRNA splicing from a heat-inactivated extract. This activity in its most purified form consistently copurified in a fraction containing two 70-kDa proteins and a minor polypeptide of approximately 100 kDa. It was free of the major small nuclear RNAs, sensitive to protease, and required to rescue spliceosome formation from a heat-inactivated nuclear extract. These results suggest that this factor is a protein that may be an important component in pre-mRNA splicing, or alternatively, it may be involved in renaturation of a heat-sensitive splicing factor.

A soluble form of homologous restriction factor (HRF-U) was isolated from normal human urine. With respect to m.w. (65,000) and immunoblotting characteristics, it resembled membrane HRF (HRF-M) that had been isolated from human E membranes. The protein exhibited limited cross-reactivity with the channel-forming proteins of C and cytotoxic lymphocytes. It inhibited reactive lysis of E by human C5b-9. Inhibition occurred at the attachment stage of C5b-7 to target cells, rather than at the C8 or C9 stage of membrane attack complex assembly which is inhibited by HRF-M. In this respect, HRF-U acts analogously to S protein of serum, but no immunochemical relationship between these two proteins was detected. HRF-U might be derived from the soluble HRF detected in cytoplasmic granules of killer lymphocytes.

BACKGROUND

Advanced glaucoma typically results in damage of the temporal neuroretinal rim. As vascular factors are of pathogenic importance in the development of glaucomatous damage, the present study investigated whether regional differences in perfusion might be the reason for the preferential damage of the temporal neuroretinal rim.

METHODS

Blood flow of the neuroretinal rim was measured with the laser Doppler flowmeter (LDF) Oculix 4000 (continuous measurement of an area of 160 microm diameter) and the Heidelberg retina flowmeter (HRF). Both instruments measure the capillary blood flow (flow), the relative velocity of erythrocytes (velocity) and the relative volume of moving erythrocytes (volume). We examined one randomly chosen eye of 55 healthy subjects without history of glaucoma aged 22-57 years (mean 30 years). Each subject was measured with the LDF and HRF, each time nasally and temporally, away from visible vessels. The intraocular pressure (IOP) was measured with the Goldmann tonometer. Heart rate and systolic and diastolic blood pressure were measured.

RESULTS

The LDF measurements of the optic nerve head showed nasal flow of 12.4+/-5.6 AU and temporal flow of 9.8+/-3.6 AU. The HRF showed a nasal flow of 477+/-161 AU and a temporal flow of 368+/-166 AU. The volume measurements done by LDF showed nasally a value of 0.68+/-0.40 AU and temporally a value of 0.46+/-0.21 AU. The HRF volume measurements showed nasal values of 16.1+/-4.3 AU and temporal values of 13.0+/-4.0 AU. The LDF velocity values were nasally 0.22+/-0.05 kHz and temporally 0.26+/-0.05 kHz. HRF measurements showed velocity values of 1.7+/-0.5 kHz nasally and 1.3+/-0.6 kHz temporally. The differences were highly statistically significant for flow (LDF P=0.00007, HRF P=0.0005), volume (LDF P=0.00002, HRF P=0.00004) and velocity (LDF P=0.0002, HRF P=0.00004). The IOP was 12.6 mmHg. Blood pressure was 118/75 mmHg and the heart rate was 73 beats per minute. There was no correlation between age, IOP, BP and HR and the HRF/LDF measurements.

CONCLUSIONS

The measurements with two different methodologies showed a decreased blood flow of the temporal neuroretinal rim compared to the nasal side. These local differences might be one reason for the preferential damage of the temporal neuroretinal rim in advanced glaucoma.

Fibrotic changes after stereotactic body radiation therapy (SBRT) for stage I non-small cell lung cancer (NSCLC) are difficult to distinguish from local recurrences (LR), hampering proper patient selection for salvage therapy. This study validates previously reported high-risk computed tomography (CT) features (HRFs) for detection of LR in an independent patient cohort.

From a multicenter database, 13 patients with biopsy-proven LR were matched 1:2 to 26 non-LR control patients based on dose, planning target volume (PTV), follow-up time, and lung lobe. Tested HRFs were enlarging opacity, sequential enlarging opacity, enlarging opacity after 12 months, bulging margin, linear margin disappearance, loss of air bronchogram, and craniocaudal growth. Additionally, 2 new features were analyzed: the occurrence of new unilateral pleural effusion, and growth based on relative volume, assessed by manual delineation.

All HRFs were significantly associated with LR except for loss of air bronchogram. The best performing HRFs were bulging margin, linear margin disappearance, and craniocaudal growth. Receiver operating characteristic analysis of the number of HRFs to detect LR had an area under the curve (AUC) of 0.97 (95% confidence interval [CI] 0.9-1.0), which was identical to the performance described in the original report. The best compromise (closest to 100% sensitivity and specificity) was found at ≥4 HRFs, with a sensitivity of 92% and a specificity of 85%. A model consisting of only 2 HRFs, bulging margin and craniocaudal growth, resulted in a sensitivity of 85% and a specificity of 100%, with an AUC of 0.96 (95% CI 0.9-1.0) (HRFs ≥2). Pleural effusion and relative growth did not significantly improve the model.

We successfully validated CT-based HRFs for detection of LR after SBRT for early-stage NSCLC. As an alternative to number of HRFs, we propose a simplified model with the combination of the 2 best HRFs: bulging margin and craniocaudal growth, although validation is warranted.

We have previously isolated two matched transformed human T cell clones: one of which is resistant to HIV-1 replication and secretes an HIV-1 resistance factor(s) (HRF) and the second which retains the susceptibility of the parental cell line to HIV-1 infection. We employed cDNA arrays to investigate the spectrum of changes in cellular gene expression that correlate with the acquisition of HIV-1 resistance and the secretion of HRF. Using a tissue based immunology/hematology array, we identified 29 transcripts that were differentially expressed by HRF(+) and HRF(-) cells. HRF(+) cells showed a selective down-regulation of 11 genes involved in transcription, several of which are implicated in either susceptibility of cells to HIV-1 or the promotion of HIV-1 transcription itself. In the group of the up-regulated genes, three were linked directly to the cellular resistance to HIV-1. One of the cDNAs placed on the array, representing the hypothetical protein KIAA0117 hybridized only with poly A+ RNA probes derived from HRF(+) cells. The specific up-regulation of two genes, the transcription repressor (CTCF) and hypothetical protein KIAA0117 was confirmed by RT-PCR and Northern blot. The role of KIAA0117 transcript in the resistance to HIV-1 replication needs to be determined.

Two distinct cell signals have been isolated from the sponge host of the tropical sponge/macroalga symbiotic association Haliclona cymiformis/Ceratodictyon spongiosum. These water soluble cell signals (M(r) between 500 and 1000) modify separate steps in the carbon metabolism in both C. spongiosum and the microalga, Symbiodinium from the coral Plesiastrea versipora. The first signal, host release factor (HRF), stimulates the release of compounds derived from algal photosynthesis; the second signal, photosynthesis inhibiting factor (PIF), partially inhibits photosynthesis. Both HRF from the sponge H. cymiformis and HRF from the coral P. versipora stimulated the release of glycerol from Symbiodinium suggesting that they act at a similar step in the metabolism of this alga. This is the first time that such cell signals have been isolated from a sponge. We suggest that they belong to a family of similar cell signals from symbiotic invertebrates that modify algal carbon metabolism.

OBJECTIVE

Only the simultaneous analysis of periodic and nonlinear properties of heart rate fluctuations (HRF) can describe completely this complex physiological process. Up to now there is, apart from a study of our own, no systematic and correlative investigation using both parameter groups, also not in early development. Thus, we tried to describe in this manner these properties of HRF, the corresponding mean arterial pressure fluctuations (MAPF) and respiratory movements (RM) and their mutual relations in neonatal pig.

METHODS

In 6 term newborn piglets, periodic properties of HRF, RM, and MAPF were analyzed by spectral and coherence analysis, and deterministic-chaotic properties by calculation of correlation dimension (CD), Lyapunov exponent (LE), and construction of phase space plots. The assumption of deterministic chaotic components was supported by Theiler's test for nonlinearity, by always positive leading LEs, and by the results of a nonlinear deterministic model. These analyses were done in sleep states, general anaesthesia, hypoxic hypoxia, in ventilated state, and during cholinergic and additional beta-adrenergic blockade.

RESULTS

In all experimental states, HRF and MAPF have periodic and nonlinear, very probably deterministic-chaotic properties, but in different relations. In anaesthetized piglets, periodic properties of HRF and MAPF dominate. In hypoxia the decreasing LE and CD of HRF and CD of MAPF were connected with increasing MAPF power density. Cholinergic blockade caused a decreased overall HRF and MAPF power and a decreasing LE and CD, but beta-adrenergic blockade decreased a small part of power density of both in 0.02-0.08 Hz only. The results of CD, LE, Theiler's test and the low dimensional deterministic model data suggested mainly deterministic-chaotic properties in the nonlinear part of HRF and MAPF.

CONCLUSIONS

Already in neonatal piglets, both periodic and nonlinear, very probably deterministic chaotic properties of HRF and MAPF exist which change both during hypoxia and cholinergic blockade. They are partly cholinergically and--to a small extent--also beta-adrenergically mediated. The decrease of nonlinear complexity of HRF and MAPF during hypoxia suggests characteristic pathological change even in early development.

OBJECTIVE

Simultaneous electroencephalography and functional magnetic resonance imaging (EEG-fMRI) is considered as a powerful and non-invasive method that allows definition of the irritative zone. However, the complex interictal epileptic discharge (IED) may be present in some patients, and sometimes no active foci can be localized using General Linear Model (GLM) which is a widely adopted tool in EEG-fMRI study. The purpose of this study is to develop a new scheme to improve the detectability and localize the canonical HRF localizable foci.

METHODS

Various IEDs are classified using a combination of an independent component analysis (ICA) and a temporal correlation analysis between the independent components and the raw EEG channel; and the classified IEDs are then separately used for foci localization. This scheme is tested by ten patients with variable IEDs, including two patients whose activity could not be identified by common method.

RESULTS

Applying this scheme to the two patients, some foci consistent with electroclinical data were localized. When it was applied to the remaining eight patients with positive results using common method, 2-4 types of IEDs were classified, and the activity could be identified from at least one type of IED. The results were similar to that received from common method.

CONCLUSIONS

These results indicate that the proposed scheme could enhance the imaging of the localizable foci by isolating its IEDs. This scheme is potentially a useful tool for epilepsy clinic.

Background. The purpose of this study was to examine the effect of a 12-week summer break on school day physical activity and health-related fitness (HRF) in children from schools receiving a Comprehensive School Physical Activity Program (CSPAP). Methods. Participants were school-aged children (N = 1,232; 624 girls and 608 boys; mean age = 9.5 ± 1.8 years) recruited from three low-income schools receiving a CSPAP. Physical activity and HRF levels were collected during the end of spring semester 2015 and again during the beginning of fall semester 2015. Physical activity was assessed using the Yamax DigiWalker CW600 pedometer. HRF measures consisted of body mass index (BMI) and the Progressive Aerobic Cardiovascular Endurance Run (PACER). Results. Results from a doubly MANCOVA analysis indicated that pedometer step counts decreased from 4,929 steps in the spring to 4,445 steps in the fall (mean difference = 484 steps; P < 0.001; Cohen's d = 0.30) and PACER laps decreased from 31.2 laps in the spring to 25.8 laps in the fall (mean difference = 5.4 laps; P < 0.001; Cohen's d = 0.33). Conclusions. Children from schools receiving a CSPAP intervention had lower levels of school day physical activity and cardiorespiratory endurance following a 12-week summer break.

OBJECTIVE

To assess the macular microcirculation blood flow with Doppler laser scanning (HRF-Heidelberg Retinal Flowmeter), in patients with complicated rhegmatogenous retinal detachment (RRD), after pars plana vitrectomy (PPV), with silicone oil tamponade.

METHODS

Eleven patients (6 males and 5 females), aged 38-64 years, mean age: 52.4 years, with unilateral macula-on complicated RRD were included in a study. In all cases conventional (20-gauge) pars plana vitectomy with silicone oil tamponade was performed. Control group consists of the fellow eyes.

RESULTS

In the early postoperative period (1-3 days after surgery), in all operated eyes the mean values of macular microcirculation blood flow were significantly reduced in the comparison with those of the control eyes (p = 0.01). The reduction of mean values of macular microcirculation blood flow was still observed in all silicone-oil-filled eyes one month after surgery as compared to the contralateral eyes (p = 0.01). There was no correlation between the values of macular microcirculation blood flow and the duration of RRD, baseline BCVA, refractive error, number of retinal tears, and the patient age.

CONCLUSIONS

The preliminary results of this study suggest that PPV with silicone oil tamponade influences over the retinal blood flow. We have observed that silicone oil may have a negative long-term effect on the retinal microcirculation as it was noted one month after surgery.

For the robust estimation of evoked brain activity from functional Near Infrared Spectroscopy (fNIRS) signals, it is crucial to reduce nuisance signals from systemic physiology and motion. The current best practice incorporates short separation (SS) fNIRS measurements as regressors in a General Linear Model (GLM). However, several challenging signal characteristics such as non-instantaneous and non-constant coupling are not yet addressed by this approach and additional auxiliary signals are not optimally exploited. We have recently introduced a new methodological framework for the unsupervised multivariate analysis of fNIRS signals using Blind Source Separation (BSS) methods. Building onto the framework, in this manuscript we show how to incorporate the advantages of regularized temporally embedded Canonical Correlation Analysis (tCCA) into the supervised GLM. This approach allows flexible integration of any number of auxiliary modalities and signals. We provide guidance for the selection of optimal parameters and auxiliary signals for the proposed GLM extension. Its performance in the recovery of evoked HRFs is then evaluated using both simulated ground truth data and real experimental data and compared with the GLM with short separation regression. Our results show that the GLM with tCCA significantly improves upon the current best practice, yielding significantly better results across all applied metrics: Correlation (HbO max. +45%), Root Mean Squared Error (HbO max. -55%), F-Score (HbO up to 3.25-fold) and p-value as well as power spectral density of the noise floor. The proposed method can be incorporated into the GLM in an easily applicable way that flexibly combines any available auxiliary signals into optimal nuisance regressors. This work has potential significance both for conventional neuroscientific fNIRS experiments as well as for emerging applications of fNIRS in everyday environments, medicine and BCI, where high Contrast to Noise Ratio is of importance for single trial analysis.

Although lobectomy is a viable alternative to total thyroidectomy (TT) in low-risk 1 to 4 cm papillary thyroid carcinoma (PTC), lobectomy is associated with higher locoregional recurrence risk and need for completion TT upon discovery of a previously unrecognized histologic high-risk feature (HRF). The present study evaluated long-term cost-effectiveness between lobectomy and TT.

Our base case was a hypothetical female cohort aged 40 years with a low-risk 2.5 cm PTC. A Markov decision tree model was constructed to compare cost-effectiveness between lobectomy and TT after 25 years. Patients with an unrecognized HRF (including aggressive histology, microscopic extrathyroidal extension, lymphovascular invasion, positive resection margin, nodal metastasis >5 mm, and multifocality) underwent completion TT after lobectomy. Outcome probabilities, utilities, and costs were estimated from the literature. The threshold for cost-effectiveness was set at US$50,000/quality-adjusted life-year (QALY). Sensitivity and threshold analyses were used to examine model uncertainty.

After 25 years, each patient who underwent lobectomy instead of TT cost an extra US$772.08 but gained an additional 0.300 QALY. The incremental cost-effectiveness ratio was US$2577.65/QALY. In the sensitivity analysis, the lobectomy arm began to become cost-effective only after 3 years. Despite varying the reported prevalence of clinically unrecognized HRFs, complication from surgical procedures, annualized recurrence rates, unit cost of surgical procedure or complication, and utility score, lobectomy remained more cost-effective than TT.

Despite the higher locoregional recurrence risk and having almost half of the patients undergoing completion TT after lobectomy upon discovery of a previously unrecognized HRF, initial lobectomy was a more cost-effective long-term option than initial TT for 1 to 4 cm PTCs without clinically recognized HRFs.

Translationally controlled tumor protein (TCTP), also called histamine releasing factor (HRF) or fortilin, is a multifunctional protein present in almost all eukaryotic organisms. TCTP is involved in a range of basic cell biological processes, such as promotion of growth and development, or cellular defense in response to biological stresses. Cellular TCTP levels are highly regulated in response to a variety of physiological signals, and regulatory mechanism at various levels have been elucidated. Given the importance of TCTP in maintaining cellular homeostasis, it is not surprising that dysregulation of this protein is associated with a range of disease processes. Here, we review recent progress that has been made in the characterisation of the basic biological functions of TCTP, in the description of mechanisms involved in regulating its cellular levels and in the understanding of dysregulation of TCTP, as it occurs in disease processes such as cancer.

Keywords: TCTP (HRF, fortilin); autophagy; biological stress reactions; cancer; cardiovascular diseases; growth and development; regulated protein degradation; regulation of protein synthesis.

Protozoan pathogens secrete nanosized particles called extracellular vesicles (EVs) to facilitate their survival and chronic infection. Here, we show the inhibition by Plasmodium berghei NK65 blood stage-derived EVs of the proliferative response of CD4⁺ T cells in response to antigen presentation. Importantly, these results were confirmed in vivo by the capacity of EVs to diminish the ovalbumin-specific delayed type hypersensitivity response. We identified two proteins associated with EVs, the histamine releasing factor (HRF) and the elongation factor 1α (EF-1α) that were found to have immunosuppressive activities. Interestingly, in contrast to WT parasites, EVs from genetically HRF- and EF-1α-deficient parasites failed to inhibit T cell responses in vitro and in vivo. At the level of T cells, we demonstrated that EVs from WT parasites dephosphorylate key molecules (PLCγ1, Akt, and ERK) of the T cell receptor signalling cascade. Remarkably, immunisation with EF-1α alone or in combination with HRF conferred a long-lasting antiparasite protection and immune memory. In conclusion, we identified a new mechanism by which P. berghei-derived EVs exert their immunosuppressive functions by altering T cell responses. The identification of two highly conserved immune suppressive factors offers new conceptual strategies to overcome EV-mediated immune suppression in malaria-infected individuals.

Detection of functional magnetic resonance imaging (fMRI) activation in white matter has been increasingly reported despite historically being controversial. Much of the development work to-date has used high-field 4 T MRI and specialized pulse sequences. In the current study, we utilized conventional 3 T MRI and a commonly applied gradient-echo-planar imaging sequence to evaluate white matter (WM) fMRI sensitivity within a common framework. Functional WM activity was replicated in target regions of interest within the corpus callosum, at the group and individual levels. As expected there was a reduction in overall WM activation sensitivity. Individual analyses revealed that 8 of the 13 individuals showed white matter activation, showing a lower percentage of individuals with WM activation detected. Importantly, WM activation results were sensitive to analyses that applied alternate hemodynamic response functions, with an increase in the group level cluster when hemodynamic response function (HRF) onset slope was reduced. The findings supported the growing evidence that WM activation is detectable, with activation levels are closer to thresholds used for routine 3T MRI studies. Optimization factors, such as the HRF model, appear to be important to further enhance the characterization of WM activity in fMRI.

The blood oxygen level dependent (BOLD) signal evoked by brief neural stimulation, the hemodynamic response function (HRF), is a critical feature of neurovascular coupling. The HRF is directly related to local transient changes in oxygen supplied by cerebral blood flow (CBF) and oxygen demand, the cerebral metabolic rate of oxygen (CMRO2). Previous efforts to explain the HRF have relied upon the hypothesis that CBF produces a non-linear venous dilation within the cortical parenchyma. Instead, the observed dynamics correspond to prompt arterial dilation without venous volume change. This work develops an alternative biomechanical model for the BOLD response based on the hypothesis that prompt upstream dilation creates an arterial flow impulse amenable to linear description. This flow model is coupled to a continuum description of oxygen transport. Measurements using high-resolution fMRI demonstrate the efficacy of the model. The model predicts substantial spatial variations of the oxygen saturation along the length of capillaries and veins, and fits the varied gamut of measured HRFs by the combined effects of corresponding CBF and CMRO2 responses. Three interesting relationships among the hemodynamic parameters are predicted. First, there is an offset linear correlation with approximately unity slope between CBF and CMRO2 responses. Second, the HRF undershoot is strongly correlated to the corresponding CBF undershoot. Third, late-time-CMRO2 response can contribute to a slow recovery to baseline, lengthening the HRF undershoot. The model provides a powerful mathematical framework to understand the dynamics of neurovascular and neurometabolic responses that form the BOLD HRF.

Sulfoxaflor (CAS# 946578-00-3) is a novel active substance with insecticidal properties mediated via its agonism on the highly abundant insect nicotinic acetylcholine receptor (nAChR). In developmental and reproductive toxicity studies, gestational exposure caused fetal abnormalities (primarily limb contractures) and reduced neonatal survival in rats, but not rabbits, following high-dose dietary exposure. Sulfoxaflor induced these effects via a novel mode of action (MoA) mediated by the fetal-type muscle nAChR with the following key events: (1) binding to the receptor, (2) agonism on the receptor, causing (3) sustained muscle contracture in the near-term fetus and neonatal offspring. This sustained muscle contracture results in misshapen limbs, bent clavicles, and reduced diaphragm function, which compromises respiration in neonatal rats at birth, reducing their survival. This review evaluates the weight of evidence for this MoA based upon the Bradford Hill criteria, includes a cross-comparison of applied and internal doses in a variety of in vitro, ex vivo, and in vivo study designs, examines alternative MoAs, and applies a Human relevance framework (HRF) to ascertain human risk for this rat MoA. The review indicated, with a high level of confidence, that the sulfoxaflor-induced fetal abnormalities and neonatal death in rats occur via a single MoA comprising sustained activation of the rat fetal-type muscle nAChR resulting in a sustained muscle contracture. This MoA is considered not relevant to humans, given fundamental qualitative differences in sulfoxaflor agonism on the rat versus the human muscle nAChR. Specifically, sulfoxaflor does not cause agonism on either the human fetal- or adult-type muscle nAChR.

The mu rhythm is a field oscillation in the ∼10Hz range over the sensorimotor cortex. For decades, the suppression of mu (event-related desynchronization) has been used to index movement planning, execution, and imagery. Recent work reports that non-motor processes, such as spatial attention and movement observation, also desynchronize mu, raising the possibility that the mu rhythm is associated with the activity of multiple brain regions and systems. In this study, we tested this hypothesis by recording simultaneous resting-state EEG-fMRI from healthy subjects. Independent component analysis (ICA) was applied to extract the mu components. The amplitude (power) fluctuations of mu were estimated as a time series using a moving-window approach, which, after convolving with a canonical hemodynamic response function (HRF), was correlated with blood-oxygen-level-dependent (BOLD) signals from the entire brain. Two main results were found. First, mu power was negatively correlated with BOLD from areas of the sensorimotor network, the attention control network, the putative mirror neuron system, and the network thought to support theory of mind. Second, mu power was positively correlated with BOLD from areas of the salience network, including anterior cingulate cortex and anterior insula. These results are consistent with the hypothesis that sensorimotor mu rhythm is associated with multiple brain regions and systems. They also suggest that caution should be exercised when attempting to interpret mu modulation in terms of a single brain network.

Urea cycle disorders (UCDs) are a group of rare inherited metabolic disorders. Affected individuals often present with hyperammonemic encephalopathy (HE) and have an increased risk of severe neurologic disease and early death. The study aims to provide epidemiologic data and to describe the disease manifestation and short-term outcome.

Cross-border surveillance of newly diagnosed patients with UCDs - below 16 years of age - was performed from July 2012 to June 2015 in Germany and Austria and from January 2012 to December 2015 in Switzerland. Inquiries were sent monthly to all Pediatric Departments in Germany and Switzerland, and quarterly to the Austrian Metabolic Group. In addition, data were collected via a second source (metabolic laboratories) in all three countries.

Between July 2012 and June 2015, fifty patients (Germany: 39, Austria: 7, Switzerland: 4) with newly diagnosed UCDs were reported and later confirmed resulting in an estimated cumulative incidence of 1 in 51,946 live births. At diagnosis, thirty-nine patients were symptomatic and 11 asymptomatic [10 identified by newborn screening (NBS), 1 by high-risk-family screening (HRF)]. The majority of symptomatic patients (30 of 39 patients) developed HE with (n = 25) or without coma (n = 5), 28 of them with neonatal onset. Despite emergency treatment 15 of 30 patients with HE already died during the newborn period. Noteworthy, 10 of 11 patients diagnosed by NBS or HRF remained asymptomatic. Comparison with the European registry and network for intoxication type metabolic diseases (E-IMD) demonstrated that cross-national surveillance identified a higher number of clinically severe UCD patients characterized by earlier onset of symptoms, higher peak ammonium concentrations in plasma and higher mortality.

Cross-border surveillance is a powerful tool to identify patients with UCDs demonstrating that (1) the cumulative incidence of UCDs is lower than originally suggested, (2) the mortality rate is still high in patients with neonatal onset of symptoms, and (3) onset type and peak plasma ammonium concentration predict mortality.

Phoenix dacylifera is an ancient palm species rich in (poly)phenols. These phenolic compounds were tentatively identified by using liquid chromatography coupled with ion spray mass spectrometry in tandem mode (LC/MS/MS) with negative ion detection. Negative identification of the compounds was based on their retention times and mass spectra in full scan mode (MS), and in different MS/MS modes. For the first time, complete hypothesis, and routs for both p-coumaroylshikimic acids (CoSA) and caffeoylshikimic acids (CSA) were suggested and confirmed by Density Fonctional Theory (DFT) study. Notably, of the 53 compounds characterized, 19 hydroxycinnamates derivatives were tentativelycharacterized in male flowers of date palm and 15 of them were recorded for the first time. In addition, five organic acids, six B-type proanthocyanidins, two anthocyanidin and 21 flavonoid derivatives have been tentatively characterized. Identification of B-type proanthocyanidins were based on the diagnostic ions resulting from heterocyclic ring fission (HRF) and retro-Diels-Alder (RDA) reaction of flavan-3-ol provided information on the hydroxylation pattern and the type of inter-flavan bond proanthocyanidins. The sequence of proanthocyanidins was detected through ions extracted from quinone methide (QM) cleavage of the inter-flavan bond.