In Vivo Myelin Water Quantification Using Diffusion-Relaxation Correlation MRI: A Comparison of 1D and 2D Methods.

Multidimensional Magnetic Resonance Imaging (MRI) is a versatile tool for microstructure mapping. We use a diffusion weighted inversion recovery spin echo (DW-IR-SE) sequence with spiral readouts at ultra-strong gradients to acquire a rich diffusion-relaxation data set with sensitivity to myelin water. We reconstruct 1D and 2D spectra with a two-step convex optimization approach and investigate a variety of multidimensional MRI methods, including 1D multi-component relaxometry, 1D multi-component diffusometry, 2D relaxation correlation imaging, and 2D diffusion-relaxation correlation spectroscopic imaging (DR-CSI), in terms of their potential to quantify tissue microstructure, including the myelin water fraction (MWF). We observe a distinct spectral peak that we attribute to myelin water in multi-component T1 relaxometry, T1-T2 correlation, T1-D correlation, and T2-D correlation imaging. Due to lower achievable echo times compared to diffusometry, MWF maps from relaxometry have higher quality. Whilst 1D multi-component T1 data allows much faster myelin mapping, 2D approaches could offer unique insights into tissue microstructure and especially myelin diffusion.

Myelin water fraction estimation using small-tip fast recovery MRI.

PURPOSE: To demonstrate the feasibility of an optimized set of small-tip fast recovery (STFR) MRI scans for rapidly estimating myelin water fraction (MWF) in the brain. METHODS: We optimized a set of STFR scans to minimize the Cramér-Rao Lower Bound of MWF estimates. We evaluated the RMSE of MWF estimates from the optimized scans in simulation. We compared STFR-based MWF estimates (both modeling exchange and not modeling exchange) to multi-echo spin echo (MESE)-based estimates. We used the optimized scans to acquire in vivo data from which a MWF map was estimated. We computed the STFR-based MWF estimates using PERK, a recently developed kernel regression technique, and the MESE-based MWF estimates using both regularized non-negative least squares (NNLS) and PERK. RESULTS: In simulation, the optimized STFR scans led to estimates of MWF with low RMSE across a range of tissue parameters and across white matter and gray matter. The STFR-based MWF estimates that modeled exchange compared well to MESE-based MWF estimates in simulation. When the optimized scans were tested in vivo, the MWF map that was estimated using a 3-compartment model with exchange was closer to the MESE-based MWF map. CONCLUSIONS: The optimized STFR scans appear to be well suited for estimating MWF in simulation and in vivo when we model exchange in training. In this case, the STFR-based MWF estimates are close to the MESE-based estimates.

Associations between prenatal, childhood, and adolescent stress and variations in white-matter properties in young men.

OBJECTIVE: Previous studies have shown that both pre- and post-natal adversities, the latter including exposures to stress during childhood and adolescence, explain variation in structural properties of white matter (WM) in the brain. While previous studies have examined effects of independent stress exposures within one developmental period, such as childhood, we examine effects of stress across development using data from a prospective longitudinal study. More specifically, we ask how stressful events during prenatal development, childhood, and adolescence relate to variation in WM properties in early adulthood in young men recruited from a birth cohort. METHOD: Using data from 393 mother-son pairs from a community-based birth cohort from England (Avon Longitudinal Study of Parents and Children), we examined how stressful life events relate to variation in different structural properties of WM in the corpus callosum and across the whole brain in early adulthood in men aged 18-21 years. We distinguish between stress occurring during three developmental periods: a) prenatal maternal stress, b) postnatal stress within the first four years of life, c) stress during adolescence (age 12-16 years). To obtain a comprehensive quantification of variation in WM, we assess structural properties of WM using four different measures, namely fractional anisotropy (FA), mean diffusivity (MD), magnetization transfer ratio (MTR) and myelin water fraction (MWF). RESULTS: The developmental model shows that prenatal stress is associated with lower MTR and MWF in the genu and/or splenium of the corpus callosum, and with lower MTR in global (lobar) WM. Stress during early childhood is associated with higher MTR in the splenium, and stress during adolescence is associated with higher MTR in the genu and lower MD in the splenium. We see no associations between postnatal stress and variation in global (lobar) WM. CONCLUSIONS: The current study found evidence for independent effects of stress on WM properties during distinct neurodevelopmental periods. We speculate that these independent effects are due to differences in the developmental processes unfolding at different developmental time points. We suggest that associations between prenatal stress and WM properties may relate to abnormalities in neurogenesis, affecting the number and density of axons, while postnatal stress may interfere with processes related to myelination or radial growth of axons. Potential consequences of prenatal glucocorticoid exposure should be considered in obstetric care.

Flow Cytometry Is a Powerful Tool for Assessment of the Viability of Fungal Conidia in Metalworking Fluids.

Fungal contamination of metalworking fluids (MWF) is a dual problem in automated processing plants because resulting fungal biofilms obstruct cutting, drilling, and polishing machines. Moreover, some fungal species of MWF comprise pathogens such as Fusarium solani Therefore, the development of an accurate analytical tool to evaluate conidial viability in MWF is important. We developed a flow cytometric method to measure fungal viability in MWF using F. solani as the model organism. To validate this method, viable and dead conidia were mixed in several proportions and flow was cytometrically analyzed. Subsequently, we assessed the fungicidal activity of two commercial MWF using flow cytometry (FCM) and compared it with microscopic analyses and plating experiments. We evaluated the fungal growth in both MWF after 7 days using quantitative PCR (qPCR) to assess the predictive value of FCM. Our results showed that FCM distinguishes live from dead conidia as early as 5 h after exposure to MWF, whereas the microscopic germination approach detected conidial viability much later and less accurately. At 24 h, microscopic analyses of germinating conidia and live/dead analyses by FCM correlated well, although the former consistently underestimated the proportion of viable conidia. In addition, the reproducibility and sensitivity of the flow cytometric method were high and allowed assessment of the fungicidal properties of two commercial MWF. Importantly, the obtained flow cytometric results on viability of F. solani conidia at both early time points (5 h and 24 h) correlated well with fungal biomass measurements assessed via a qPCR methodology 7 days after the start of the experiment.IMPORTANCE This result shows the predictive power of flow cytometry (FCM) in assessing the fungicidal capacity of MWF formulations. It also implies that FCM can be implemented as a rapid detection tool to estimate the viable fungal load in an industrial processing matrix (MWF).

Magnetic resonance imaging assessment of degenerative cervical myelopathy: a review of structural changes and measurement techniques.

Degenerative cervical myelopathy encompasses a spectrum of age-related structural changes of the cervical spine that result in static and dynamic injury to the spinal cord and collectively represent the most common cause of myelopathy in adults. Although cervical myelopathy is determined clinically, the diagnosis requires confirmation via imaging, and MRI is the preferred modality. Because of the heterogeneity of the condition and evolution of MRI technology, multiple techniques have been developed over the years in an attempt to quantify the degree of baseline severity and potential for neurological recovery. In this review, these techniques are categorized anatomically into those that focus on bone, ligaments, discs, and the spinal cord. In addition, measurements for the cervical spine canal size and sagittal alignment are also described briefly. These tools have resulted collectively in the identification of numerous useful parameters. However, the development of multiple techniques for assessing the same feature, such as cord compression, has also resulted in a number of challenges, including introducing ambiguity in terms of which methods to use and hindering effective comparisons of analysis in the literature. In addition, newer techniques that use advanced MRI are emerging and providing exciting new tools for assessing the spinal cord in patients with degenerative cervical myelopathy.

Adsorption of emulsified oil from metalworking fluid on activated bleaching earth-chitosan-SDS composites: Optimization, kinetics, isotherms.

The adsorption of emulsified oil from metalworking fluid (MWF) on activated bleaching earth (BE)-chitosan-sodium dodecyl sulfate (SDS) composites (BE/MCS) was investigated under a statistical design of experiments at a 95% confidence interval to identify the critical factors and to optimize the adsorption capacity. The BE/MCS adsorbents were characterized by means of X-ray diffraction, Fourier transform infrared spectroscopy, Brunauer-Emmett-Teller adsorption/desorption isotherms, contact angle analysis (sessile drop technique) and their zeta potential. From the results of a full 2(5) factorial design with three center points, the adsorbent weight and initial pH of the MWF had a significant antagonistic effect on the adsorption capacity while the initial MWF concentration and BE:chitosan:SDS weight ratio had a synergistic influence. Temperature factor has no discernible effect on the capacity. From the FCCC-RSM design, the optimal capacity range of 2840-2922.5 mg g(-1) was achieved at sorbent weight of 1.6-1.9 g, pH of 5.5-6.5, initial MWF concentration of 52-55 g l(-1) and BE:chitosan:SDS (w/w/w) ratio of 4.7:1:1-6.2:1:1. To test the validation and sensitivity of RSM model, the results showed that the estimated adsorption capacity was close to the experimental capacity within an error range of ±3%, suggesting that the RSM model was acceptable and satisfied. From three kinetics models (pseudo-first-order, pseudo-second-order model and Avrami's equation) and two adsorption isotherms (Langmuir model and Freundlich model), assessed using an error function (Err) and the coefficient of determination (R(2)), Avrami's equation and Freundlich isotherm model provided a good fitting for the data, suggesting the presence of more than one reaction pathway in the MWF adsorption process and the heterogeneous surface adsorption of the BC/ABE-5.5 composite.

Physiological noise compensation in gradient-echo myelin water imaging.

In MRI, physiological noise which originates from cardiac and respiratory functions can induce substantial errors in detecting small signals in the brain. In this work, we explored the effects of the physiological noise and their compensation methods in gradient-echo myelin water imaging (GRE-MWI). To reduce the cardiac function induced inflow noise, flow saturation RF pulses were applied to the inferior portion of the head, saturating inflow blood signals. For the respiratory function induced B0 fluctuation compensation, a navigator echo was acquired, and respiration induced phase errors were corrected during reconstruction. After the compensations, the resulting myelin water images show substantially improved image quality and reproducibility. These improvements confirm the importance and usefulness of the physiological noise compensations in GRE-MWI.

Characterization of Cochlear Implant Artifact and Removal Based on Multi-Channel Wiener Filter in Unilateral Child Patients.

Cochlear implants (CI) allow deaf patients to improve language perception and improving their emotional valence assessment. Electroencephalographic (EEG) measures were employed so far to improve CI programming reliability and to evaluate listening effort in auditory tasks, which are particularly useful in conditions when subjective evaluations are scarcely appliable or reliable. Unfortunately, the presence of CI on the scalp introduces an electrical artifact coupled to EEG signals that masks physiological features recorded by electrodes close to the site of implant. Currently, methods for CI artifact removal have been developed for very specific EEG montages or protocols, while others require many scalp electrodes. In this study, we propose a method based on the Multi-channel Wiener filter (MWF) to overcome those shortcomings. Nine children with unilateral CI and nine age-matched normal hearing children (control) participated in the study. EEG data were acquired on a relatively low number of electrodes (n = 16) during resting condition and during an auditory task. The obtained results obtained allowed to characterize CI artifact on the affected electrode and to significantly reduce, if not remove it through MWF filtering. Moreover, the results indicate, by comparing the two sample populations, that the EEG data loss is minimal in CI users after filtering, and that data maintain EEG physiological characteristics.

Breastfeeding and early white matter development: A cross-sectional study.

Does breastfeeding alter early brain development? The prevailing consensus from large epidemiological studies posits that early exclusive breastfeeding is associated with improved measures of IQ and cognitive functioning in later childhood and adolescence. Prior morphometric brain imaging studies support these findings, revealing increased white matter and sub-cortical gray matter volume, and parietal lobe cortical thickness, associated with IQ, in adolescents who were breastfed as infants compared to those who were exclusively formula-fed. Yet it remains unknown when these structural differences first manifest and when developmental differences that predict later performance improvements can be detected. In this study, we used quiet magnetic resonance imaging (MRI) scans to compare measures of white matter microstructure (mcDESPOT measures of myelin water fraction) in 133 healthy children from 10 months through 4 years of age, who were either exclusively breastfed a minimum of 3 months; exclusively formula-fed; or received a mixture of breast milk and formula. We also examined the relationship between breastfeeding duration and white matter microstructure. Breastfed children exhibited increased white matter development in later maturing frontal and association brain regions. Positive relationships between white matter microstructure and breastfeeding duration are also exhibited in several brain regions, that are anatomically consistent with observed improvements in cognitive and behavioral performance measures. While the mechanisms underlying these structural differences remains unclear, our findings provide new insight into the earliest developmental advantages associated with breastfeeding, and support the hypothesis that breast milk constituents promote healthy neural growth and white matter development.

Investigation of respiratory and dermal symptoms associated with metal working fluids at an aircraft engine manufacturing facility.

BACKGROUND: Each year, 1.2 million metalworkers are exposed to metalworking fluids (MWFs), which can cause dermal and respiratory disease. The National Institute for Occupational Safety and Health (NIOSH) conducted a health hazard evaluation of MWF exposures at an aircraft engine manufacturing facility. The objectives were to determine employee exposures to endotoxin and MWFs in the air, characterize symptoms experienced by employees working with MWFs, compare them to symptoms of employees unexposed to MWFs, and make recommendations for reducing exposures based on results. METHODS: Four hundred seven workers were categorized as MWF exposed or MWF unexposed and completed questionnaires. Estimated prevalence ratios (PR) of dermatitis, asthma, and work-related asthma (WRA) symptoms were calculated. Airborne concentrations of MWF and endotoxin were measured, and work practices observed. RESULTS: MWF exposed workers had a significantly higher prevalence of dermatitis on wrists/forearms (PR 2.59; 95% CI 1.22, 5.46), asthma symptoms (PR 1.49; 95% CI 1.05, 2.13), and WRA symptoms (PR 2.10; 95% CI 1.22, 3.30) than unexposed workers. Airborne concentrations of MWF were below the NIOSH recommended exposure limit (REL) for MWF aerosols (thoracic particulate mass). CONCLUSIONS: Despite MWF exposures below the NIOSH REL, exposed workers had a higher prevalence of asthma, WRA, and dermatitis symptoms than unexposed workers. Recommendations to reduce exposure included configuring mist collectors to automatically turn on when the machine is in use, and enforcing enclosure use.

Sex moderates the association between age and myelin water fraction in the cingulum and fornix among older adults without dementia.

Background: Decreasing white matter integrity in limbic pathways including the fornix and cingulum have been reported in Alzheimer's disease (AD), although underlying mechanisms and potential sex differences remain understudied. We therefore sought to explore sex as a moderator of the effect of age on myelin water fraction (MWF), a measure of myelin content, in older adults without dementia (N = 52). Methods: Participants underwent neuropsychological evaluation and 3 T MRI at two research sites. Multicomponent driven equilibrium single pulse observation of T1 and T2 (mcDESPOT) quantified MWF in 3 a priori regions including the fornix, hippocampal cingulum (CgH), and cingulate cingulum (CgC). The California Verbal Learning Test-Second Edition assessed learning and delayed recall. Multiple linear regressions assessed for (1) interactions between age and sex on regional MWF and (2) associations of regional MWF and memory. Results: (1) There was a significant age by sex interaction on MWF of the fornix (p = 0.002) and CgC (p = 0.005), but not the CgH (p = 0.192); as age increased, MWF decreased in women but not men. (2) Fornix MWF was associated with both learning and recall (ps < 0.01), but MWF of the two cingulum regions were not (p > 0.05). Results were unchanged when adjusting for hippocampal volume. Conclusion: The current work adds to the literature by illuminating sex differences in age-related myelin decline using a measure sensitive to myelin and may help facilitate detection of AD risk for women.

Association of brain tissue cerebrospinal fluid fraction with age in healthy cognitively normal adults.

Background and purpose: Our objective was to apply multi-compartment T2 relaxometry in cognitively normal individuals aged 20-80 years to study the effect of aging on the parenchymal CSF fraction (CSFF), a potential measure of the subvoxel CSF space. Materials and methods: A total of 60 volunteers (age range, 22-80 years) were enrolled. Voxel-wise maps of short-T2 myelin water fraction (MWF), intermediate-T2 intra/extra-cellular water fraction (IEWF), and long-T2 CSFF were obtained using fast acquisition with spiral trajectory and adiabatic T2prep (FAST-T2) sequence and three-pool non-linear least squares fitting. Multiple linear regression analyses were performed to study the association between age and regional MWF, IEWF, and CSFF measurements, adjusting for sex and region of interest (ROI) volume. ROIs include the cerebral white matter (WM), cerebral cortex, and subcortical deep gray matter (GM). In each model, a quadratic term for age was tested using an ANOVA test. A Spearman's correlation between the normalized lateral ventricle volume, a measure of organ-level CSF space, and the regional CSFF, a measure of tissue-level CSF space, was computed. Results: Regression analyses showed that there was a statistically significant quadratic relationship with age for CSFF in the cortex (p = 0.018), MWF in the cerebral WM (p = 0.033), deep GM (p = 0.017) and cortex (p = 0.029); and IEWF in the deep GM (p = 0.033). There was a statistically highly significant positive linear relationship between age and regional CSFF in the cerebral WM (p < 0.001) and deep GM (p < 0.001). In addition, there was a statistically significant negative linear association between IEWF and age in the cerebral WM (p = 0.017) and cortex (p < 0.001). In the univariate correlation analysis, the normalized lateral ventricle volume correlated with the regional CSFF measurement in the cerebral WM (ρ = 0.64, p < 0.001), cortex (ρ = 0.62, p < 0.001), and deep GM (ρ = 0.66, p < 0.001). Conclusion: Our cross-sectional data demonstrate that brain tissue water in different compartments shows complex age-dependent patterns. Parenchymal CSFF, a measure of subvoxel CSF-like water in the brain tissue, is quadratically associated with age in the cerebral cortex and linearly associated with age in the cerebral deep GM and WM.

Endotoxin in Aerosol Particles from Metalworking Fluids Measured with a Sioutas Cascade Impactor.

OBJECTIVES: The aim of this study was to characterize personal occupational exposure to endotoxin in size-separated airborne particles of MWF aerosol, using a Sioutas cascade impactor (SCI). METHODS: Exposure to inhalable fractions of MWF aerosol and endotoxin was measured by personal sampling of 52 individuals over an 8-h work shift using a PAS-6 sampler in parallel with a SCI (<0.25, 0.25-0.5, 0.5-1.0, 1.0-2.5, and 2.5-10 µm). Aerosol mass concentration was measured for each worker with a real-time instrument (DataRAM) during a full shift. Samples of MWF were collected from the machines and central tanks during the work shift. RESULTS: A total of 117 measurements of inhalable MWF aerosols were made among 52 workers. The geometric mean of inhalable MWF aerosol was 0.16 mg m-3 air. The geometric mean of endotoxin concentration on the inhalable sampler was 0.15 EU m-3. Airborne endotoxin was found on all size fractions from the impactor, with the major part seen in the fraction (2.5-10 µm). There was a correlation between the inhalable fraction of endotoxin measured by the PAS-6 sampler and on the SCI sampler (2.5-10 µm), estimated to be 0.51 for all samples (P < 0.0001). The concentration of endotoxin varied between the MWFs, as did the proportion of Gram-negative bacteria among the culturable bacteria (>80% in one MWF and <1.5% in the other three). CONCLUSIONS: The personal exposure to inhalable fractions of endotoxin contained in the MWF aerosol were low, where most of the endotoxin were found in fraction (2.5-10 µm), measured by SCI. There are differences between factories and MWF systems regarding the distribution of endotoxin and so results from one context should not be generalized to other plants and systems. Compressed air was used for less than 10 min shift-1. The mixed-effect model showed that working with open machines and grinding as cutting task were important determinants of exposure to inhalable aerosol. It is important to keep occupational exposure to aerosols low with the help of good ventilation systems, enclosed machines, and organization of work.

A proposal: How to study pro-myelinating proteins in MS.

Multiple sclerosis (MS) is an inflammatory and degenerative disease of the CNS. An unmet need in MS is repair i.e.,promoting endogenous regeneration and remyelination after demyelinating inflammatory injury. Remyelination is critical in neuronal preservation and the prevention of clinical progression. There is a good deal of evidence for histological repair and remyelination in MS patients. Repair is driven by several prominent endogenous pro-myelinating proteinsincluding neural cellular adhesion molecule (N-CAM) and brain derived neurotrophic factor (BDNF) among others. To follow changes during acute re-myelination in vivo in MS subjects, non conventional MRI techniques are necessary such as quantitative susceptibility mapping (QSM) that detects the release of Fe from dying oligodendroglial cells and myelin water imaging (MWI) that detects water captured within newly formed myelin. The best time to monitor changes in pro-myelinating proteins and link those changes to imaging evolution is immediately after the acute inflammatory response in MS lesions (gadolinium enhancement [Gd+]) during an intense period of remyelination. We can monitor MS subjects with new Gd + lesions with periodic imaging along with sampling of blood and CSF and determine if myelin formation is linked with increases in pro-myelinating proteins. This would lead to potential therapeutic manipulation with directly administered proteins to promote CNS re-myelination in animal models and in early clinical trials.

Improved magnetic resonance myelin water imaging using multi-channel denoising convolutional neural networks (MCDnCNN).

Background: Myelin water imaging (MWI) is powerful and important for studying and diagnosing neurological and psychiatric diseases. In particular, myelin water fraction (MWF) is derived from MWI data for quantifying myelination. However, MWF estimation is typically sensitive to noise. Improving the accuracy of MWF estimation based on WMI data acquired using a magnetic resonance (MR) multiple gradient recalled echo (mGRE) imaging sequence is desired. Methods: The proposed method employs a recently introduced the multi-channel denoising convolutional neural networks (MCDnCNN). Five different MCDnCNN models, denoted as Delevel1, Delevel2, Delevel3, Delevel4 and DelevelMix corresponding to five noise levels (Level1, Level2, Level3, Level4 and LevelMix), were trained using the data of the first echo of the mGRE brain images acquired from 15 healthy human subjects. Using simulated noisy data that employed a hollow cylinder model, we first evaluated the improvement in estimating MWF based on data denoised by the five different MCDnCNNs, by comparing the MWF maps calculated from the denoised data with ground truth. Next, we again evaluated the improvement using real-world in vivo datasets of 11 human participants acquired using the mGRE sequence. The datasets were first denoised by five different MCDnCNNs (Delevel1, 2, 3, 4 and DelevelMix), and subsequently their MWF maps were calculated and compared with the MWF maps directly calculated from the raw mGRE images without being denoised. Results: Experiments using the simulation data denoised by the appropriate MCDnCNN models showed that the standard deviation (SD) of the absolute error (AE) of the derived MWF results was significantly reduced (maximal reduction =15.5%, Level3 simulated noisy data, orientation angle =0, all the five MCDnCNN models). In the test using in vivo data, estimating MWF based on data particularly denoised by the appropriate MCDnCNN models was found to be the best, compared to otherwise not using the appropriate models. The results demonstrated that the appropriate MCDnCNN models may permit high-quality MWF mapping, i.e., substantial reduction of random variation in estimating MWF-maps while preserving accuracy and structural details. Conclusions: Appropriate MCDnCNN models as proposed may improve both the accuracy and precision in estimating MWF maps, thereby making it a more clinically feasible alternative.

Quantitative susceptibility mapping versus phase imaging to identify multiple sclerosis iron rim lesions with demyelination.

BACKGROUND AND PURPOSE: To compare quantitative susceptibility mapping (QSM) and high-pass-filtered (HPF) phase imaging for (1) identifying chronic active rim lesions with more myelin damage and (2) distinguishing patients with increased clinical disability in multiple sclerosis. METHODS: Eighty patients were scanned with QSM for paramagnetic rim detection and Fast Acquisition with Spiral Trajectory and T2prep for myelin water fraction (MWF). Chronic lesions were classified based on the presence/absence of rim on HPF and QSM images. A lesion-level linear mixed-effects model with MWF as the outcome was used to compare myelin damage among the lesion groups. A multiple patient-level linear regression model was fit to establish the association between Expanded Disease Status Scale (EDSS) and the log of the number of rim lesions. RESULTS: Of 2062 lesions, 188 (9.1%) were HPF rim+/QSM rim+, 203 (9.8%) were HPF rim+/QSM rim-, and the remainder had no rim. In the linear mixed-effects model, HPF rim+/QSM rim+ lesions had significantly lower MWF than both HPF rim+/QSM rim- (p < .001) and HPF rim-/QSM rim- (p < .001) lesions, while the MWF difference between HPF rim+/QSM rim- and HPF rim-/QSM rim- lesions was not statistically significant (p = .130). Holding all other factors constant, the log number of QSM rim+ lesion was associated with EDSS increase (p = .044). The association between the log number of HPF rim+ lesions and EDSS was not statistically significant (p = .206). CONCLUSIONS: QSM identifies paramagnetic rim lesions that on average have more myelin damage and stronger association with clinical disability than those detected by phase imaging.

Concerted EP2 and EP4 Receptor Signaling Stimulates Autocrine Prostaglandin E2 Activation in Human Podocytes.

Glomerular hyperfiltration is an important mechanism in the development of albuminuria. During hyperfiltration, podocytes are exposed to increased fluid flow shear stress (FFSS) in Bowman's space. Elevated Prostaglandin E2 (PGE2) synthesis and upregulated cyclooxygenase 2 (Cox2) are associated with podocyte injury by FFSS. We aimed to elucidate a PGE2 autocrine/paracrine pathway in human podocytes (hPC). We developed a modified liquid chromatography tandem mass spectrometry (LC/ESI-MS/MS) protocol to quantify cellular PGE2, 15-keto-PGE2, and 13,14-dihydro-15-keto-PGE2 levels. hPC were treated with PGE2 with or without separate or combined blockade of prostaglandin E receptors (EP), EP2, and EP4. Furthermore, the effect of FFSS on COX2, PTGER2, and PTGER4 expression in hPC was quantified. In hPC, stimulation with PGE2 led to an EP2- and EP4-dependent increase in cyclic adenosine monophosphate (cAMP) and COX2, and induced cellular PGE2. PTGER4 was downregulated after PGE2 stimulation in hPC. In the corresponding LC/ESI-MS/MS in vivo analysis at the tissue level, increased PGE2 and 15-keto-PGE2 levels were observed in isolated glomeruli obtained from a well-established rat model with glomerular hyperfiltration, the Munich Wistar Frömter rat. COX2 and PTGER2 were upregulated by FFSS. Our data thus support an autocrine/paracrine COX2/PGE2 pathway in hPC linked to concerted EP2 and EP4 signaling.

Multi-component relaxation in clinically isolated syndrome: Lesion myelination may predict multiple sclerosis conversion.

We performed a longitudinal case-control study on patients with clinically isolated syndrome (CIS) with the aid of quantitative whole-brain myelin imaging. The aim was (1) to parse early myelin decay and to break down its distribution pattern, and (2) to identify an imaging biomarker of the conversion into clinically definite Multiple Sclerosis (MS) based on in vivo measurable changes of myelination. Imaging and clinical data were collected immediately after the onset of first neurological symptoms and follow-up explorations were performed after 3, 6, and, 12 months. The multi-component Driven Equilibrium Single Pulse Observation of T1/T2 (mcDESPOT) was applied to obtain the volume fraction of myelin water (MWF) in different white matter (WM) regions at every time-point. This measure was subjected to further voxel-based analysis with the aid of a comparison of the normal distribution of myelination measures with an age and sex matched healthy control group. Both global and focal relative myelination content measures were retrieved. We found that (1) CIS patients at the first clinical episode suggestive of MS can be discriminated from healthy control WM conditions (p < 0.001) and therewith reproduced our earlier findings in late CIS, (2) that deficient myelination in the CIS group increased in T2 lesion depending on the presence of gadolinium enhancement (p < 0.05), and (3) that independently the CIS T2 lesion relative myelin content provided a risk estimate of the conversion to clinically definite MS (Odds Ratio 2.52). We initially hypothesized that normal appearing WM myelin loss may determine the severity of early disease and the subsequent risk of clinically definite MS development. However, in contrast we found that WM lesion myelin loss was pivotal for MS conversion. Regional myelination measures may thus play an important role in future clinical risk stratification.

New rapid, accurate T2 quantification detects pathology in normal-appearing brain regions of relapsing-remitting MS patients.

INTRODUCTION: Quantitative T2 mapping may provide an objective biomarker for occult nervous tissue pathology in relapsing-remitting multiple sclerosis (RRMS). We applied a novel echo modulation curve (EMC) algorithm to identify T2 changes in normal-appearing brain regions of subjects with RRMS (N = 27) compared to age-matched controls (N = 38). METHODS: The EMC algorithm uses Bloch simulations to model T2 decay curves in multi-spin-echo MRI sequences, independent of scanner, and scan-settings. T2 values were extracted from normal-appearing white and gray matter brain regions using both expert manual regions-of-interest and user-independent FreeSurfer segmentation. RESULTS: Compared to conventional exponential T2 modeling, EMC fitting provided more accurate estimations of T2 with less variance across scans, MRI systems, and healthy individuals. Thalamic T2 was increased 8.5% in RRMS subjects (p < 0.001) and could be used to discriminate RRMS from healthy controls well (AUC = 0.913). Manual segmentation detected both statistically significant increases (corpus callosum & temporal stem) and decreases (posterior limb internal capsule) in T2 associated with RRMS diagnosis (all p < 0.05). In healthy controls, we also observed statistically significant T2 differences for different white and gray matter structures. CONCLUSIONS: The EMC algorithm precisely characterizes T2 values, and is able to detect subtle T2 changes in normal-appearing brain regions of RRMS patients. These presumably capture both axon and myelin changes from inflammation and neurodegeneration. Further, T2 variations between different brain regions of healthy controls may correlate with distinct nervous tissue environments that differ from one another at a mesoscopic length-scale.