Introduction: Long non-coding RNAs (lncRNAs) are key regulators in multiple cancers. lncRNA, SNHG1, was shown to be associated with tumorigenesis. However, little is known about the role SNHG1 plays in breast cancer. The aim of the study was to study the role and underlying mechanism of SNHG1 regulation in breast cancer. Methods: Quantitative real-time PCR was used to measure the levels of SNHG1, miR-382 and ZEB1 levels in breast cancer tissue or cells. The proliferation, colony formation, migration and invasion of breast cancer cells, under SNHG1 knockdown achieved by transfection of SNHG1-specific siRNAs, were assessed by Cell Counting Kit-8, colony forming, scratch wound and transwell assays. Bioinformatical analysis and luciferase assay were used to explore the interaction between SNHG1 and its potential miRNA target. Western blot was used to evaluate the expression of epithelial-to-mesenchymal transition (EMT) markers. MDA-MB-231 cells with or without SNHG1 knockdown were used to initiate tumor xenografts in vivo. Tumor growth and expression of SNHG1, miR-382-5p and EMT markers were evaluated. Results: SNHG1 upregulation was observed in breast cancer tissues and cells. Knockdown of SNHG1 attenuated breast cancer proliferation, colony formation, migration and invasion. A miRNA, miR-382-5p, was identified as the target of SNHG1. A reciprocal negative regulation was found between SNHG1 and miR-382-5p. SNHG1 knockdown attenuated EMT both in vitro and in vivo. miR-382-5p transfection reversed the tumor-promoting role by SNHG1. In vivo, SNHG1 knockdown decreased breast tumor growth. Conclusion: SNHG1 promotes breast cancer through the regulation of miR-382-5p and EMT markers. Our results report SNHG1 as a novel miRNA that govern the progression of breast cancer, providing a potential new therapeutic target in breast cancer.

One of the clinically major gynecological cancers is endometrial carcinoma that develops from the lining of the uterus. During the past years, different approaches have been developed to treat endometrial carcinoma, among which natural herbal medicine has recently faired as an effective method. The yellow Indian spice known as curcumin has been extolled for its healing powers and has recently been adopted for investigation by the scientific community as a potent anti-cancerous agent. This review focuses on the effect of curcumin on endometrial cancer (EC) and its role in specific pathways involved in carcinogenesis.

The adhesion G protein-coupled receptors latrophilins have been in the limelight for more than 20 years since their discovery as calcium-independent receptors for α-latrotoxin, a spider venom toxin with potent activity directed at neurotransmitter release from a variety of synapse types. Latrophilins are highly expressed in the nervous system. Although a substantial amount of studies has been conducted to describe the role of latrophilins in the toxin-mediated action, the recent identification of endogenous ligands for these receptors helped confirm their function as mediators of adhesion events. Here we hypothesize a role for latrophilins in inter-neuronal contacts and the formation of neuronal networks and we review the most recent information on their role in neurons. We explore molecular, cellular and behavioral aspects related to latrophilin adhesion function in mice, zebrafish, Drosophila melanogaster and Caenorhabditis elegans, in physiological and pathophysiological conditions, including autism spectrum, bipolar, attention deficit and hyperactivity and substance use disorders.

Xiaoshuan enteric-coated capsule (XSEC) is a Chinese medicinal compound widely used for treatment of ischemic cerebrovascular diseases. Enriched environment (EE) is an effective rehabilitative protocol designed to enhance sensorimotor, cognitive and social stimulation. This study aimed to apply magnetic resonance imaging (MRI) to non-invasively assess whether EE could augment the therapeutic benefits of XSEC on post-ischemic neurovascular remodeling. Male Sprague-Dawley rats were subjected to permanent middle cerebral artery occlusion (MCAO) and treated with XSEC and EE alone or combination for 30 consecutive days. Beam walking test and Morris water maze (MWM) test were performed to evaluate motor and cognitive function, respectively. Multimodal MRI was applied to examine alterations to brain structures, intracranial vessels, and cerebral perfusion on the 31st day after MCAO. Double-immunofluorescent staining was used to evaluate neurogenesis and angiogenesis. Western blot and RT-PCR were used to detect the expressions of vascular endothelial growth factor (VEGF), angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), and the axon guidance molecules. Combination therapy with XSEC and EE significantly reduced cystic volume compared with XSEC and EE monotherapies. In line with this, combination treated rats performed better in the beam walking test and exhibited improved spatial memory in the probe trial of the MWM. Moreover, XSEC and EE combination treatment improved cerebral blood flow (CBF), amplified angiogenesis and upregulated VEGF protein levels. This proangiogenic effect was consistent with the increased progenitor cell proliferation and neuronal differentiation in the peri-infarct cortex and striatum. Specifically, the combined therapy of XSEC and EE markedly increased the Netrin-1 and Robo-1 protein expression levels compared with vehicle group, while no difference was observed between XSEC or EE monotherapy and vehicle group. Together, these findings indicate that the combination of XSEC and EE benefits neurovascular reorganization. This correlates with restoration of CBF, promotion of neurogenesis and angiogenesis, and activation of the intrinsic axonal guidance molecules, thereby facilitating greater physical rehabilitation after ischemic stroke.

The incoming signals from injured sensory neurons upon peripheral inflammation are processed in the dorsal horn of spinal cord, where glial cells accumulate and play a critical role in initiating allodynia (increased pain in response to light-touch). However, how painful stimuli in the periphery engage glial reactivity in the spinal cord remains unclear. Here, we found that a hind paw inflammation induced by CFA produces robust morphological changes in spinal astrocytes and microglia compatible with the reactive phenotype. Strikingly, we discovered that a single intrathecal injection with venom peptides that inhibit calcium channels reversed all the glial pathological features of the peripheral inflammation. These effects were more apparent in rats treated with the Phα1β spider toxin (non-specific calcium channel antagonist) than ω-MVIIA cone snail toxin (selective N-type calcium channel antagonist). These data reveal for the first time a venom peptide acting on glial structural remodeling in vivo. We, therefore, suggest that calcium-dependent plasticity is an essential trigger for glial cells to initiate reactivity, which may represent a new target for the antinociceptive effects of Phα1β and ω-MVIIA toxins in inflammatory pain conditions.

The role of the Amyloid Precursor Protein (APP) in the pathology of Alzheimer's disease (AD) has been well studied. However, the normal function of APP in the nervous system is poorly understood. Here, we characterized the role of the Drosophila homolog (APPL) in the adult giant fiber (GF) neurons. We find that endogenous APPL is transported from the synapse to the soma in the adult. Live-imaging revealed that retrograde moving APPL vesicles co-traffic with L1-type cell adhesion molecule Neuroglian (Nrg). In APPL null mutants, stationary Nrg vesicles were increased along the axon, and the number of Nrg vesicles moving in retrograde but not anterograde direction was reduced. In contrast, trafficking of endo-lysosomal vesicles, which did not co-localize with APPL in GF axons, was not affected. This suggests that APPL loss of function does not generally disrupt axonal transport but that APPL has a selective role in the effectiveness of retrograde transport of proteins it co-traffics with. While the GF terminals of APPL loss of function animals exhibited pruning defects, APPL gain of function had no disruptive effect on GF morphology and function, or on retrograde axonal transport of Nrg. However, cell-autonomous developmental expression of a secretion-deficient form of APPL (APPL-SD), lacking the α-, β-, and, γ-secretase cleavage sites, resulted in progressive retraction of the GF terminals. Conditional expression of APPL-SD in mature GFs caused accumulation of Nrg in normal sized synaptic terminals, which was associated with severely reduced retrograde flux of Nrg labeled vesicles in the axons. Albeit β-secretase null mutants developed GF terminals they also exhibited Nrg accumulations. This suggests that cleavage defective APPL has a toxic effect on retrograde trafficking and that β-secretase cleavage has a function in Nrg sorting in endosomal compartments at the synapse. In summary, our results suggest a role for APPL and its proteolytic cleavage sites in retrograde trafficking, thus our findings are of relevance to the understanding of the endogenous role of APP as well as to the development of therapeutic treatments of Alzheimer's disease.

Orientation selectivity is a fundamental property of visual cortical neurons and plays a crucial role in pattern perception. Although many studies have dedicated to explain how the orientation selectivity emerged, the mechanism underlying orientation selectivity is still not clear. In this work, we investigated the synchronization between spikes and local field potentials (LFP) in gamma band, with the aim of providing a new avenue to analyze the orientation selectivity. The experimental data were recorded by utilizing two chronically implanted multi-electrode arrays, where each array consisted of 48 electrodes and was placed over V1 and V4, respectively, in two macaques performing a selective visual attention task. An unbiased and robust measure for quantifying the synchronization between spikes and LFP was employed in the analysis process, which is termed as spike-triggered correlation matrix synchronization (SCMS) and performs reliably for limited samples of data. We observed the spike-LFP synchronization in three cases, i.e., spikes and LFP in V1, spikes and LFP in V4, spikes in V4 and LFP in V1. From the orientation tuning curves based on the spike-LFP synchronization, it is found that there is a strong correlation between the synchronization and grating orientation. The neurons in both V1 and V4 exhibit orientation selectivity, but V1 is stronger. In addition, the spike-LFP synchronization strength between V1 and V4 also shows orientation selectivity to drifting gratings. It means that the synchronization not only reflects the basic features of visual stimulation, but also describes the orientation tuning characteristics of neurons in different regions. Our results suggest that the spike-LFP synchronization can be used as an alternative and effective method to study the mechanism for generating orientation selectivity of visual neurons.

Conjunctival inflammation disturbs the blood-tear barrier and thus affects the tear film stability and composition. We aimed to develop a non-invasive and reliable method to induce conjunctivitis in dogs, a large animal model for translational work on ocular surface disease in humans. Six beagle dogs underwent a randomized, vehicle-controlled, balanced crossover trial-on six separate days, one eye received topical artificial tears (vehicle), while the other eye received one of six concentrations of histamine solution (0.005-500 mg/ml). At sequential times after eyedrop administration, a conjunctivitis score was given to each eye based on the degree of palpebral and bulbar conjunctival hyperemia and chemosis, ocular pruritus, and discharge. Total protein content (TPC) and serum albumin were quantified in tear fluid at baseline and 20 min. Additionally, 13 dogs presenting for various ophthalmic diseases with associated conjunctivitis were examined. Experimentally induced conjunctivitis developed rapidly (<1 min) following topical histamine administration and lasted for 1-3 h (four lowest doses) to 6-8 h (two highest doses). The severity of conjunctivitis was dose-dependent. Histamine was overall well tolerated, although transient blepharitis, aqueous flare, and ocular hypertension occurred in a few dogs receiving histamine ≥375 mg/ml. TPC and serum albumin levels increased in tears of eyes receiving histamine ≥1.0 mg/ml, being significantly higher than vehicle and baseline in eyes receiving histamine ≥375 mg/ml. Lacrimal albumin levels were also increased in 13 dogs with naturally acquired conjunctivitis, up 2.7-14.9 fold compared to contralateral healthy eyes. Histamine-induced conjunctivitis represents a robust model for translational work on the ocular surface given the low cost, non-invasiveness, self-resolving nature, ability to adjust the duration and severity of the disease, and shared features with naturally occurring ocular diseases. Histamine solutions of 1, 10, and 375 mg/ml induce mild, moderate, and severe conjunctivitis in dogs, respectively. Leakage of serum albumin in tear fluid of eyes with conjunctivitis suggests a breakdown of the blood-tear barrier.

The level of maladaptive myocardial remodeling consistently contributes to the poor prognosis of patients following a myocardial infarction (MI). In this study, we investigated whether and how sodium tanshinone IIA sulfonate (STS) would attenuate the post-infarct cardiac remodeling in mice model of MI developing after surgical ligation of the left coronary artery. All mice subjected to experimental MI or to the sham procedure were then treated for the following 4 weeks, either with STS or with a vehicle alone. Results of our studies indicated that STS treatment of MI mice prevented the left ventricular dilatation and improved their cardiac function. Results of further tests, aimed at mechanistic explanation of the beneficial effects of STS, indicated that treatment with this compound enhanced the autophagy and, at the same time, inhibited apoptosis of the cardiomyocytes. Meaningfully, we have also established that myocardium of STS-treated mice displayed significantly higher levels of adenosine monophosphate kinase than their untreated counterparts and that this effect additionally associated with the significantly diminished activities of apoptotic promoters: mammalian target of rapamycin and P70S6 kinase. Moreover, we also found that additional administration of the adenosine monophosphate kinase inhibitor (compound C) or autophagy inhibitor (chloroquine) practically eliminated the observed beneficial effects of STS. In conclusion, we suggest that the described multistage mechanism triggered by STS treatment enhanced autophagy, thereby attenuating pathologic remodeling of the post-infarct hearts.

Alzheimer's disease (AD) is a neurodegenerative disorder in which the death of brain cells takes place leading to loss of memory and decreased cognitive ability. AD is a leading cause of death worldwide and is progressive in nature with symptoms worsening over time. Machine learning-based computational predictive models based on 2D and 3D descriptors have been effective in identifying potential active compounds. However, the use of data from molecular dynamics (MD) trajectories for training machine learning models still needs to be explored. In the present study, descriptors have been extracted from the MD trajectories of caspase-8 ligand complexes to train models using artificial neural networks and random forest algorithms. Caspase-8 plays a key role in causing AD by cleaving amyloid precursor proteins during apoptosis leading to increased formation of the amyloid-beta peptide. A total of 43 ligands were docked using the glide module of Schrodinger software, and short MD simulations of 10 ns were performed for the calculation of MD descriptors. The MD descriptors were also combined with the 2D and 3D descriptors of chemical compounds, and individual descriptor based as well as combination models were generated. This study demonstrated that MD descriptors could be effectively used for the characterization of bioactive compounds along with lead prioritization and optimization.

Background: Research has indicated that calcitonin gene-related peptide (CGRP) receptor antagonists can be effective in the acute treatment of migraine. Six major drugs are included within this category: telcagepant, olcegepant, BI 44370, rimegepant (BMS-927711), MK3207, and ubrogepant. However, no previous studies have performed network meta-analyses to directly compare the effects of these drugs. In the present study, we assessed the therapeutic qualities of these six different drugs to inform further clinical research. Methods: We searched PubMed, Embase, Ovid MEDLINE, Web of Science, and the Cochrane Central Register for Controlled Trials for relevant randomized controlled trials (RCTs) published through to October 2018. Two reviewers performed a network meta-analysis of efficacy and toxicity on the basis of odds ratios (ORs). Results: Ten randomized controlled trials involving 8,174 patients were included in our analysis. Olcegepant (OR: 4.09; CI: 1.81, 9.25), ubrogepant (OR: 2.11; CI: 1.10, 4.05), and BI 44370 (OR: 3.36; CI: 2.24, 5.04) were more effective in ensuring pain relief 2 h after treatment than was placebo treatment. BI 44370 was associated with an increased risk of adverse events when compared with placebo treatment (OR: 1.57; CI: 1.32, 1.88). Surface under the cumulative ranking curve analysis revealed that olcegepant was most effective and ubrogepant was associated with the lowest risk of adverse events among the six treatment options. Conclusion: Olcegepant was more effective, and ubrogepant had lower toxicity than the remaining treatments. CGRP antagonists are promising for the acute treatment of migraine, especially among patients who are unable to take triptans.

Background/Aims: Gut microbiota has been reported to correlate with a higher mortality and worse prognosis of cardiovascular diseases. Trimethylamine N-oxide (TMAO) is a gut microbiota-dependent metabolite of specific dietary nutrients, which is linked to cardiac fibrosis. Recent reports have suggested that the activation of Nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome contributed to cardiac fibrosis. However, whether TMAO mediates cardiac fibrosis via activating NLRP3 inflammasome remains unclear. Methods and Results: To determine the role of TMAO-mediated cardiac fibrosis, we established mouse models of doxorubicin (DOX)-induced cardiac fibrosis with or without TMAO in drinking water. TMAO exacerbated DOX-induced cardiac dysfunction, heart weight and cardiac fibrosis manifested by enhanced collagen accumulation, higher profibrotic levels and elevated inflammatory factors as well as NLRP3 inflammasome activation. Using primary cultured mouse cardiac fibroblast, our results indicated that TMAO promoted proliferation, migration and collagen secretion in a dose-dependent manner by TGF-β/Smad3 signaling. Furthermore, TMAO treatment induced NLRP3 inflammasome activation including oxidative stress in cultured cardiac fibroblast. Importantly, the silencing of NLRP3 presented a protection effect against cardiac fibrosis including cellular proliferation, migration and collagen deposition in vitro. Conclusion: Our data suggested that TMAO aggravated DOX-induced mouse cardiac fibrosis, at least in part, through activation of the NLRP3 inflammasome, providing a new potential target for preventing the progression of cardiac fibrosis.

The marine bristle worm Platynereis dumerilii is a useful functional model system for the study of the circadian clock and its interplay with others, e.g., circalunar clocks. The focus has so far been on the worm's head. However, behavioral and physiological cycles in other animals typically arise from the coordination of circadian clocks located in the brain and in peripheral tissues. Here, we focus on peripheral circadian rhythms and clocks, revisit and expand classical circadian work on the worm's chromatophores, investigate locomotion as read-out and include molecular analyses. We establish that different pieces of the trunk exhibit synchronized, robust oscillations of core circadian clock genes. These circadian core clock transcripts are under strong control of the light-dark cycle, quickly losing synchronized oscillation under constant darkness, irrespective of the absence or presence of heads. Different wavelengths are differently effective in controlling the peripheral molecular synchronization. We have previously shown that locomotor activity is under circadian clock control. Here, we show that upon decapitation worms exhibit strongly reduced activity levels. While still following the light-dark cycle, locomotor rhythmicity under constant darkness is less clear. We also observe the rhythmicity of pigments in the worm's individual chromatophores, confirming their circadian pattern. These size changes continue under constant darkness, but cannot be re-entrained by light upon decapitation. Our works thus provides the first basic characterization of the peripheral circadian clock of P. dumerilii. In the absence of the head, light is essential as a major synchronization cue for peripheral molecular and locomotor circadian rhythms, while circadian changes in chromatophore size can continue for several days in the absence of light/dark changes and the head. Thus, in Platynereis the dependence on the head depends on the type of peripheral rhythm studied. These data show that peripheral circadian rhythms and clocks should also be considered in "non-conventional" molecular model systems, i.e., outside Drosophila melanogaster, Danio rerio, and Mus musculus, and build a basic foundation for future investigations of interactions of clocks with different period lengths in marine organisms.

Introduction: The time of day when cardiovascular events are most likely to occur is thought to be aligned with the circadian rhythm of physiological variables. Chronotype has been shown to influence the time of day when cardiovascular events happen, with early chronotypes reported to be more susceptible in the morning and late chronotypes in the evening. However, no studies have investigated the influence of chronotype on physiological variables responsible for cardiovascular regulation in healthy individuals. Methods: 312 individuals completed the Munich ChronoType Questionnaire to assess chronotype. Twenty participants were randomly selected to continue into the main study. In a repeated-measures experiment, participants were tested between 08:00 and 10:00 h and again between 18:00 and 20:00 h. Measurements of mean arterial pressure, heart rate and vascular endothelial vasodilation via flow-mediated dilatation (FMD) were obtained at each session. Results: Individual diurnal differences in mean arterial pressure and heart rate show no significant relationship with chronotype. Diurnal differences in FMD showed a significant correlation (p = 0.010), driven by a clear significant relationship in the evening and not the morning (p < 0.001). Conclusion: These preliminary data indicate that chronotype influences the diurnal variation of endothelial vasodilation measured using flow-mediated dilatation. Furthermore, we show that the influence of chronotype is much stronger in the evening, highlighting an increased susceptibility for later types. These findings are consistent with the diurnal rhythm in cardiovascular events and uncover potential mechanisms of local mediators that may underpin the influence of chronotype in the onset of these events.

The preliminary efficacy of interview training using an android robot whose appearance and movements resemble those of an actual human for treating social and communication difficulties in individuals with autism spectrum disorders (ASD) has been demonstrated. Patient preferences regarding the appearance of robots are crucial for incentivizing them to undergo robot-assisted therapy. However, very little is known about how the realistic nature of an android robot is related to incentivizing individuals with ASD in an interview setting. In this study, individuals with ASD underwent an interview with a human interviewer and an android robot. Twenty-three individuals with ASD (age, 17-25 years) participated in this study. After the interview, the participants were evaluated in terms of their motivation to practice an interview with an android robot and their impression of the nature of the android robot in terms of humanness. As expected, subjects exhibited higher motivation to undergo interview training with an android robot than with a human interviewer. Higher motivation to undergo an interview with the android robot was negatively correlated with the participants' impressions of the extent to which the android robot exhibited humanness. This study brings us one step closer to understanding how such an android robot should be designed and implemented to provide sufficiently realistic interview training that can be of therapeutic value.

Objective: The number of students using prescription drugs to improve cognitive performance has increased within the last years. There is first evidence that the expectation to receive a performance-enhancing drug alone can result in improved perceived and actual cognitive performance, suggesting a substantial placebo effect. In addition, expecting a placebo can result in lower perceived and actual cognitive performance, suggesting a nocebo effect. Yet, the underlying mechanisms of these effects remain to be elucidated. The aim of our study was to investigate whether the expectation of receiving a performance-increasing drug or a performance-impairing drug leads to changes in actual and perceived cognitive performance, compared to a control group without expectation manipulation. Methods: A total of N = 75 healthy adults were recruited for an experiment to "try cognitive performance-modulating drugs." A participant's actual cognitive performance (alertness, working memory, sustained attention, and divided attention) using the standardized test of attentional performance (TAP) as well as their performance expectation were assessed. Participants were randomly assigned in equal numbers to either receiving a placebo performance increasing nasal spray ("Modafinil") or a nocebo performance impairing nasal spray ("Vividrin®") or no nasal spray (natural history). After placebo/nocebo nasal spray administration, cognitive performance was reassessed. Subsequent to the second assessment, participants rated their perceived change in cognitive performance, as well as adverse symptoms. Results: Unlike hypothesized, a positive or negative performance expectation did not result in changes in actual performance, corresponding to the induced expectation. Participants in the placebo-Modafinil group rated their perceived change in cognitive performance subsequent to the application of the nasal spray significantly better (d = 1.16) compared to the nocebo-Vividrin® group. Additionally, participants who expected to receive Modafinil felt less tired than participants in the Vividrin® group (d = 0.96). Conclusion: Manipulation of performance expectation affects the perceived change in performance and tiredness, but not the actual cognitive performance in healthy adults. This may explain why college students use such drugs despite their little impact on actual cognitive functioning.

The intuition of clarity-valence association seems to be pervasive in daily life, however, whether there exists a potential association between clarity (i.e., operationalized as visual resolution) and affect in human cognition remains unknown. The present study conducted five experiments, and demonstrated the clarity-valence congruency effect, that is, the evaluations showed performance advantage in the congruent conditions (clear-positive, blurry-negative). Experiments 1 through 3 demonstrated the influence of the perception of clarity on the conceptualization of affective valence, while Experiments 4 and 5 verified the absence of the influence of conceptualization on perception, thus the unidirectionality of clarity-valence association in cognition is confirmed. The findings extend the affective perceptual-conceptual associations into the dimension of clarity, thus providing support for the ideas of embodied cognition as well as implications for our preference for clarity and aversion to blur.

The purpose of this study was to research the relationship between executive functions and academic performance in primary education (6-12 years). Based on 21 samples (n = 7,947), a meta-analysis of random effects demonstrated a moderately significant weighted effect size (r = 0.365) and was found to be a good predictor of academic performance. For the subjects of language and mathematics, the results of the random effects model were similar and slightly higher for mathematics (r = 0.350; r = 0.365). Thus, the theory that executive functions have greater influence on mathematical performance is supported, especially in aspects such as coding, organization, and the immediate retrieval of information. Regarding the different executive function components (working memory, inhibition, cognitive flexibility, and planning), working memory had the highest presence (k = 14, n = 3,740) and predictive weight for performance, with an effect size of r = 0.370 for random effects, with a moderate level of significance. The moderating effect of variables such as gender and age were also analyzed. After performing a meta-regression, gender resulted in a value of R 2 = 0.49; the age variable was not significant. This result is especially important since age has traditionally been considered to be the moderating variable of executive functions. The review reveals a good predictive power of executive functions in the primary education stage, and it is even higher at the early ages, indicating its great significance in describing future performance. The study also revealed the competencies and specific aspects of the executive functions that affect the way in which its components intervene in the academic area, demonstrating the mediating effect of variables such as physical fitness, motor skills, and memory processes.

Introduction: Abuse of nitrous oxide (N2O) has an unusually high lifetime prevalence in developed countries and represents a serious concern worldwide. Myeloneuropathy following the inhalant abuse is commonly attributed to the disturbance of vitamin B12 metabolism, with severe motor deficits are often noted. The present study aims to elucidate its underlying pathophysiology. Methods: Eighteen patients with N2O abuse or vitamin B12 deficiency were recruited. Comprehensive central and peripheral neuro-diagnostic tests were performed, including whole spine MRI, and thermal quantitative sensory testing (QST). Specifically, paired motor and sensory nerve excitability tests were performed in order to obtain a complete picture of the sensorimotor axonal damage. Results: The mean duration of N2O exposure for the N2O abuse patients was 17.13 ± 7.23 months. MRI revealed T2 hyperintensity in 87.5% of the N2O abuse patients and 50% of the vitamin B12 deficiency patients. In N2O abuse patients, the motor nerve excitability test showed decreased in peak response (7.08 ± 0.87 mV, P = 0.05), increased latency (7.09 ± 0.28 ms, P < 0.01), increased superexcitability (-32.95 ± 1.74%, P < 0.05), and decreased accommodation to depolarizing current [TEd (40-60 ms) 56.53 ± 0.70%, P < 0.05]; the sensory test showed only decreased peak response (30.54 ± 5.98 μV, P < 0.05). Meanwhile, motor test in vitamin B12 deficiency patients showed only decreased accommodation to depolarizing current [TEd (40-60 ms) 55.72 ± 1.60%, P < 0.01]; the sensory test showed decreased peak response (25.86 ± 3.44 μV, P < 0.05) increased superexcitability (-28.58 ± 3.71%, P < 0.001), increased subexcitability (8.31 ± 1.64%, P < 0.05), and decreased accommodation to depolarizing current [TEd (peak) 67.31 ± 3.35%, P < 0.001]. Conclusion: Compared to vitamin B12 deficiency, N2O abuse patients showed prominent motor superexcitability changes and less prominent sensory superexcitability changes, hinting a unique pathological process different from that of vitamin B12 deficiency. N2O abuse might cause axonal dysfunction not only by blocking methionine metabolism but also by toxicity affecting the paranodal region.

Background and Purpose: Susceptibility-weighted imaging (SWI) has emerged as a useful clinical tool in many neurological diseases including multiple sclerosis (MS). This study aims to investigate the relationship between SWI signal changes due to iron deposition in MS lesions and tissue blood perfusion and microstructural abnormalities to better understand their underlying histopathologies. Methods: Forty-six patients with relapsing remitting MS were recruited for this study. Conventional FLAIR, pre- and post-contrast T1-weighted imaging, SWI, diffusion tensor imaging (DTI), and dynamic susceptibility contrast (DSC) perfusion MRI were performed in these patients at 3T. The SWI was processed using both magnitude and phase information with one slice minimal intensity projection (mIP) and phase multiplication factor of 4. MS lesions were classified into 3 types based on their lesional signal appearance on SWI mIP relative to perilesional normal appearing white matter (peri-NAWM): Type-1: hypointense, Type-2: isointense, and Type-3: hyperintense lesions. The DTI and DSC MRI data were processed offline to generate DTI-derived mean diffusivity (MD) and fractional anisotropy (FA) maps, as well as DSC-derived cerebral blood flow (CBF) and cerebral blood volume (CBV) maps. Comparisons of diffusion and perfusion measurements between lesions and peri-NAWM, as well between different types of lesions, were performed. Results: A total of 137 lesions were identified on FLAIR in these patients that include 40 Type-1, 46 Type-2, and 51 Type-3 lesions according to their SWI intensity relative to peri-NAWM. All lesion types showed significant higher MD and lower FA compared to their peri-NAWM (P < 0.0001). Compared to Type-1 lesions (likely represent iron deposition), Type-2 lesions had significantly higher MD and lower FA (P < 0.001) as well as lower perfusion measurements (P < 0.05), while Type 3 lesions had significantly higher perfusion (P < 0.001) and lower FA (P < 0.05). Compared to Type-2, Type-3 lesions had higher perfusion (P < 0.0001) and marginally higher MD and lower FA (P < 0.05). Conclusion: The significant differences in diffusion and perfusion MRI metrics associated with MS lesions, that appear with different signal appearance on SWI, may help to identify the underlying destructive pathways of myelin and axons and their evolution related to inflammatory activities.