T1 mapping from routine 3D T1-weighted inversion recovery sequences in clinical practice: comparison against reference inversion recovery fast field echo T1 scans and feasibility in multiple sclerosis.

BACKGROUND AND PURPOSE: Quantitative T1 mapping can be an essential tool for assessing tissue injury in multiple sclerosis (MS). We introduce T1-REQUIRE, a method that converts a single high-resolution anatomical 3D T1-weighted Turbo Field Echo (3DT1TFE) scan into a parametric T1 map that could be used for quantitative assessment of tissue damage. We present the accuracy and feasibility of this method in MS. METHODS: 14 subjects with relapsing-remitting MS and 10 healthy subjects were examined. T1 maps were generated from 3DT1TFE images using T1-REQUIRE, which estimates T1 values using MR signal equations and internal tissue reference T1 values. Estimated T1 of lesions, white, and gray matter regions were compared with reference Inversion-Recovery Fast Field Echo T1 values and analyzed via correlation and Bland-Altman (BA) statistics. RESULTS: 159 T1-weighted (T1W) hypointense MS lesions and 288 gray matter regions were examined. T1 values for MS lesions showed a Pearson's correlation of r = 0.81 (p < 0.000), R2 = 0.65, and Bias = 4.18%. BA statistics showed a mean difference of -53.95 ms and limits of agreement (LOA) of -344.20 and 236.30 ms. Non-lesional normal-appearing white matter had a correlation coefficient of r = 0.82 (p < 0.000), R2 = 0.67, Bias = 8.78%, mean difference of 73.87 ms, and LOA of -55.67 and 203.41 ms. CONCLUSIONS: We demonstrate the feasibility of retroactively derived high-resolution T1 maps from routinely acquired anatomical images, which could be used to quantify tissue pathology in MS. The results of this study will set the stage for testing this method in larger clinical studies for examining MS disease activity and progression.

Extract of Chenopodium album lowers blood pressure in rats through endothelium-dependent and -independent vasorelaxation.

OBJECTIVES: To investigate the antihypertensive effect of crude extract of Chenopodium album (Ca.Cr), based on its medicinal use in hypertension. METHODS: Ca.Cr and its fractions were tested in-vivo in normotensive anesthetized rats for blood pressure-lowering effect. In-vitro experiments were performed on isolated rat aortae to explore the vascular mechanism(s). RESULTS: In normotensive anesthetized rats, Ca.Cr produced a dose-dependent (1-300mg/kg) fall (30%mmHg) in mean arterial pressure (MAP). Among the fractions, nHexane was the most potent (46% fall). In rat aortic rings precontracted with phenylephrine (PE), Ca.Cr and its fractions (except Ca.Aq) produced endothelium-dependent vasorelaxation, which was partially reversed with endothelium removal and by pretreating intact aortic rings with L-NAME (10µM) and atropine (1µM). This relaxation to Ca.Cr and fractions (nHexane, ethylacetate and chloroform) was also eliminated with indomethacin pretreatment, however, it unmasked a vasoconstriction effect with Ca.Cr only. Surprisingly, the aqueous fraction produced a calcium sensitive strong vasoconstriction instead of vasorelaxation. The crude extract and its fractions (except Ca.Aq) also antagonized vasoconstriction induced with high K+ (80mM), suggesting calcium antagonistic effect. The aqueous fraction produced mild vasorelaxation against high K+. This effect was further confirmed when pretreatment of the aortic rings with different concentrations of crude extract and fractions suppressed CaCl2 concentration response curves, similar to verapamil. In acute toxicity test, Ca.Cr extract was found safe up to 5g/kg body weight in mice. CONCLUSION: These findings suggest that crude extract and fractions of C. album produced vasorelaxant effect through muscarinic receptors linked-NO pathway, prostaglandin (endothelium-dependent) and calcium antagonism (endothelium-independent), which explains the blood pressure lowering effect of C. album in rats.

P038 Ozanimod First-Dose Cardiac Effects in Patients with Moderately to Severely Active Ulcerative Colitis and Relapsing Multiple Sclerosis.

BACKGROUND: Ozanimod, an oral sphingosine 1-phosphate (S1P) receptor modulator that selectively targets S1P1 and S1P5, is approved in the US for treating moderately to severely active ulcerative colitis (UC) and in multiple countries for treating relapsing forms of multiple sclerosis (MS). In a Phase 1 study of ozanimod in healthy participants, first-dose cardiac effects were mitigated with gradual dose escalation. Based on these results, an initial 7-day ozanimod dose escalation regimen was implemented in all Phase 2 and 3 UC and MS trials. The objective of this analysis was to evaluate the number of patients who were excluded from ozanimod treatment due to contraindications of pre-existing cardiac disorders and to evaluate the incidence of cardiac-related treatment-emergent adverse events (TEAEs) following first-dose ozanimod administration in all patients and patients with a history of non-exclusionary cardiac disorders in the UC and MS clinical trials. METHODS: For UC, the analysis included pooled data from the Phase 2 Touchstone (NCT01647516) and Phase 3 True North (NCT02435992) trials. For MS, the analysis included pooled data from the Phase 3 Radiance (NCT02047734) and Sunbeam (NCT02294058) trials. Patients with clinically relevant cardiac conditions or clinically significant electrocardiogram (ECG) disorders were excluded from the trials. On Day 1, all patients received ozanimod 0.23 mg (equivalent to ozanimod HCl 0.25 mg). Day 1 cardiac monitoring included collection of vital signs (including heart rate) prior to dosing and hourly for at least 6 hours after dosing, and ECG prior to dosing and at Hour 6 after dosing. RESULTS: Among patients screened, 26/2178 (1.2%) in the UC studies and 47/3351 (1.4%) in the MS studies were excluded due to protocol-defined pre-existing cardiac disorders. Of 496 patients who received ozanimod in the UC studies, 1 (0.2%) experienced a cardiac-related TEAE on Day 1 (asymptomatic bradycardia). Of 1774 patients who received ozanimod in the MS studies, 11 (0.6%) experienced a cardiac-related TEAE on Day 1. In both the UC and MS studies, no cases of second- or third-degree AV block were observed. A decrease in mean heart rate from baseline (UC, 0.7 bpm; MS, 1.2 bpm) was observed at first-dose that reached a nadir at Hour 5 and returned to baseline by Hour 6. Among 496 patients with UC who received ozanimod, 34 (6.9%) had a known history of cardiac disorders, of whom 1 experienced a cardiac-related TEAE on Day 1 (asymptomatic bradycardia). Among the 1774 patients with MS who received ozanimod, 96 (5.4%) had a known history of cardiac disorders, of whom 2 experienced symptomatic bradycardia on Day 1. CONCLUSION: In clinical trials of ozanimod, the number of patients with UC or MS who failed screening because of exclusionary cardiac disorders was low. Most patients with a history of cardiac disorders who were enrolled in ozanimod clinical trials did not have Day 1 cardiac events, and the events that occurred were manageable.

Repopulation of T, B, and NK cells following alemtuzumab treatment in relapsing-remitting multiple sclerosis.

OBJECTIVE: To characterize long-term repopulation of peripheral immune cells following alemtuzumab-induced lymphopenia in relapsing-remitting MS (RRMS), with a focus on regulatory cell types, and to explore associations with clinical outcome measures. METHODS: The project was designed as a multicenter add-on longitudinal mechanistic study for RRMS patients enrolled in CARE-MS II, CARE-MS II extension at the University of Southern California and Stanford University, and an investigator-initiated study conducted at the Universities of British Columbia and Chicago. Methods involved collection of blood at baseline, prior to alemtuzumab administration, and at months 5, 11, 17, 23, 36, and 48 post-treatment. T cell, B cell, and natural killer (NK) cell subsets, chemokine receptor expression in T cells, in vitro cytokine secretion patterns, and regulatory T cell (Treg) function were assessed. Clinical outcomes, including expanded disability status score (EDSS), relapses, conventional magnetic resonance imaging (MRI) measures, and incidents of secondary autoimmunity were tracked. RESULTS: Variable shifts in lymphocyte populations occurred over time in favor of CD4+ T cells, B cells, and NK cells with surface phenotypes characteristic of regulatory subsets, accompanied by reduced ratios of effector to regulatory cell types. Evidence of increased Treg competence was observed after each treatment course. CD4+ and CD8+ T cells that express CXCR3 and CCR5 and CD8+ T cells that express CDR3 and CCR4 were also enriched after treatment, indicating heightened trafficking potential in activated T cells. Patterns of repopulation were not associated with measures of clinical efficacy or secondary autoimmunity, but exploratory analyses using a random generalized estimating equation (GEE) Poisson model provide preliminary evidence of associations between pro-inflammatory cell types and increased risk for gadolinium (Gd+) enhancing lesions, while regulatory subsets were associated with reduced risk. In addition, the risk for T2 lesions correlated with increases in CD3+CD8+CXCR3+ cells. CONCLUSIONS: Lymphocyte repopulation after alemtuzumab treatment favors regulatory subsets in the T cell, B cell, and NK cell compartments. Clinical efficacy may reflect the sum of interactions among them, leading to control of potentially pathogenic effector cell types. Several immune measures were identified as possible biomarkers of lesion activity. Future studies are necessary to more precisely define regulatory and effector subsets and their contributions to clinical efficacy and risk for secondary autoimmunity in alemtuzumab-treated patients, and to reveal new insights into mechanisms of immunopathogenesis in MS. TRIAL REGISTRATION: Parent trials for this study are registered with ClinicalTrials.gov: CARE-MS II: NCT00548405, CARE-MS II extension: NCT00930553 and ISS: NCT01307332.

Herpes Simplex Virus 2 Meningoencephalitis-Associated Bilateral Optic Neuritis and Radiculitis.

The most common ocular complication of herpes simplex virus (HSV) is acute retinal necrosis. We present a rare case of a patient with HSV-2 meningoencephalitis that developed severe vision-threatening optic neuritis. The patient was treated with steroids and IVIG, which allowed a rapid improvement in her vision.

A 24-month advanced magnetic resonance imaging study of multiple sclerosis patients treated with alemtuzumab.

BACKGROUND: Tissue damage in both multiple sclerosis (MS) lesions and normal-appearing white matter (NAWM) are important contributors to disability and progression. Specific aspects of MS pathology can be measured using advanced imaging. Alemtuzumab is a humanised monoclonal antibody targeting CD52 developed for MS treatment. OBJECTIVE: To investigate changes over 2 years of advanced magnetic resonance (MR) metrics in lesions and NAWM of MS patients treated with alemtuzumab. METHODS: A total of 42 relapsing-remitting alemtuzumab-treated MS subjects were scanned for 2 years at 3 T. T1 relaxation, T2 relaxation, diffusion tensor, MR spectroscopy and volumetric sequences were performed. Mean T1 and myelin water fraction (MWF) were determined for stable lesions, new lesions and NAWM. Fractional anisotropy was calculated for the corpus callosum (CC) and N-acetylaspartate (NAA) concentration was determined from a large NAWM voxel. Brain parenchymal fraction (BPF), cortical thickness and CC area were also calculated. RESULTS: No change in any MR measurement was found in lesions or NAWM over 24 months. BPF, cortical thickness and CC area all showed decreases in the first year followed by stability in the second year. CONCLUSION: Advanced MR biomarkers of myelin (MWF) and neuron/axons (NAA) show no change in NAWM over 24 months in alemtuzumab-treated MS participants.

Antiglutamic acid decarboxylase 65 (GAD65) antibody-associated epilepsy.

Glutamic acid decarboxylase (GAD) antibody-associated encephalitis causes both acute seizures and chronic epilepsy with predominantly temporal lobe onset. This condition is challenging in diagnosis and management, and the incidence of GAD antibody (Ab)-related epilepsy could be much higher than commonly believed. Imaging and CSF evidence of inflammation along with typical clinical presentations, such as adult onset temporal lobe epilepsy (TLE) with unexplained etiology, should prompt testing for the diagnostic antibodies. High serum GAD Ab titer (≥2000U/mL or ≥20nmol/L) and evidence of intrathecal anti-GAD Ab synthesis support the diagnosis. Unlike other immune-mediated epilepsies, antiglutamic acid decarboxylase 65 (GAD65) antibody-mediated epilepsy is often poorly responsive to antiepileptic drugs (AEDs) and only moderately responsive to immune therapy with steroids, intravenous immunoglobulin (IVIG), or plasma exchange (PLEX). Long-term treatment with more aggressive immunosuppressants such as rituximab (RTX) and/or cyclophosphamide is often necessary and may be more effective than current immunosuppressive approaches. The aim of this review is to review the physiology, pathology, clinical presentation, related ancillary tests, and management of GAD Ab-associated autoimmune epilepsy by searching the keywords and to promote the recognition and the initiation of proper therapy for this condition.

Cross-immunoreactivity between bacterial aquaporin-Z and human aquaporin-4: potential relevance to neuromyelitis optica.

Neuromyelitis optica (NMO) is a chronic inflammatory disease of the CNS that is mediated, in part, by a self-reactive Ab against the astrocyte aquaporin-4 protein. In the current study, we examined the possibility and the biological significance of cross-immunoreactivity between bacterial aquaporin-Z and human aquaporin-4 proteins. Sequence-alignment analysis of these proteins revealed several regions of significant structural homology. Some of the homologous regions were also found to overlap with important immune and disease-relevant epitopes. Cross-immunoreactivity between aquaporin-Z and aquaporin-4 was investigated and ascertained in multiple immune-based assays using sera from patients with neuromyelitis optica, immune mouse serum, and Abs raised against aquaporin-Z. The biological significance of this phenomenon was established in series of experiments demonstrating that induction of an immune response against aquaporin-Z or its homologous regions can also trigger an autoimmune reaction against aquaporin-4 and inflammation of the CNS. Our study indicates that the autoimmune response against aquaporin-4 in neuromyelitis optica may be triggered by infection-induced cross-immunoreactivity and presents a new perspective on the pathogenesis of this disease.

Onosma hispidum L. extract reverses hyperlipidemia, hypertension, and associated vascular dysfunction in rats.

Onosma hispidum.L (O. hispidum) belongs to the family Boregineacea. A preliminary study and its medicinal use suggested its role in the management of hyperlipidemia. The present study aimed to assess the effect of methanolic root extract of O. hispidum in hyperlipidemia and associated vascular dysfunction. Oral administration of O. hispidum crude extract (Oh. Cr) to tyloxopol and high fat diet-induced hyperlipidemic Sprague-Dawley rats for 10 and 28 days significantly reduced total triglycerides and cholesterol (p < 0.001), compared to hyperlipidemic rats. Oh. Cr 250 mg/kg orally treated rats significantly (p < 0.001) reduced both the total body weight and atherogenic index in tylaxopol and HFD rats. In HMG-CoA assay, the inhibition of the enzyme was significant in Oh.Cr (250 mg/kg) treated group. Histopathological studies indicated that the group treated with Oh.Cr 250 mg/kg/day showed regular morphology of aortic intima, media and adventitia, and improved the endothelial damage. To investigate the vascular dysfunction, isolated rat aorta rings from all groups were pre-contracted with 1 µM phenylephrine (PE), and the effect of acetylcholine (Ach) was monitored. In the aorta isolated from Oh.Cr (50 mg/kg) treated group, Ach completely relaxed the PE-induced contraction with EC50 value of 0.05 µg/mL 0.015 (0.01-0.2) compared to the hyperlipidemic control group (<30% relaxation). In atorvastatin (10 mg/kg) treated rat aorta, Ach showed 50% relaxation. The Oh.Cr extract also reduced (105.92 ± 1.14 to 66.63 ± 0.85 mmHg) mean arterial pressure in hyperlipidemic hypertensive rats. These findings suggest that extract of O. hispidum is an effective remedy for hypercholesterolemia, and hypertriglyceridemia, which acts through inhibition of HMG-CoA and improving vascular dysfunction.

Effectiveness of rituximab versus oral immunosuppressive therapies in neuromyelitis optica spectrum disorder in a racially diverse cohort of subjects: A single-center retrospective study.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune, inflammatory disorder characterized by severe relapses and high level of disability. In clinical trials of NMOSD, Black patients are under-represented, < 12%, compared to a relatively high prevalence of NMSOD in this population, 10/100,000. Despite the higher prevalence of NMOSD in Black and Asian patients, there is limited knowledge of the effectiveness of disease modifying treatments across racially diverse groups. OBJECTIVE: To assess the effectiveness of rituximab and oral immunosuppressive agents in a cohort of NMOSD patients, the majority of whom are Black, in a real-world, clinical setting. METHODS: A single-center retrospective study was conducted at the University of Chicago Medical Center. INCLUSION CRITERIA: (1) diagnosis according to the 2015 International Panel for NMO Diagnosis (IPND) Criteria, (2) positive anti-aquaporin-4 antibodies on ELISA or cell-based tests, (3) initiation of immunosuppressant therapy within 5 years of disease onset, (4) first-line treatment with rituximab, mycophenolate (MMF), or azathioprine (AZA). Patients with negative anti-AQP4 titers were excluded. Kaplan-Meier survival analysis was used to estimate proportion of relapse-free patients following initiation of first line immunosuppressive therapy. A Cox proportional hazards regression model assessed the association of risk of relapsing with first-line immunosuppressive treatments with and without adjustments of pre-specified factors (age at disease onset, duration of disease, sex, race, CNS location of relapse). RESULTS: 7 of 29 patients (24%) receiving rituximab experienced a relapse within the first 3 years of treatment vs. 13 of 23 patients (57%) receiving either AZA or MMF. Within the first 6 months of treatment, 2 (6.9%) patients treated with rituximab experienced a relapse vs. 7 (30.4%) patients treated with either MMF or AZA. In the 29 patients treated with rituximab, the 1-year and 3-year proportion of relapse-free patients was 88.8% and 70.9%. For the 23 patients treated with either AZA or MMF, the 1-year and 3-year proportion of relapse-free patients was 69.5% and 38.7%. In the univariate analysis, the risk of relapse was significantly higher in patients treated with AZA or MMF compared to those treated with rituximab (hazard ratio [HR] of 2.48 [0.99 - 6.21]; p = 0.046). CONCLUSION: In this real-world study involving a majority of Black NMOSD patients, rituximab was relatively more effective in preventing relapses within 3 years of therapy initiation than AZA and MMF. Rituximab remains an effective option for treating NMOSD, especially when there are delays in treatment due to access and economic issues associated with newer treatments.

Effectiveness of ocrelizumab on clinical and MRI outcome measures in multiple sclerosis across black and white cohorts: A single-center retrospective study.

OBJECTIVE: To examine differences in the therapeutic response to ocrelizumab in multiple sclerosis (MS) patients who self-identified as either White or Black, assessed longitudinally by expanded disability status scale (EDSS) progression and MRI brain volume loss. METHODS: MS subjects treated with ocrelizumab were retrospectively identified. Clinical data were available for 229 subjects (White 146; Black 83) and MRI data from for 48 subjects (White 31; Black 17). Outcome measures were changes in the EDSS and brain volume over time. EDSS were analyzed as raw scores, ambulatory (EDSS <5.0) vs. ambulatory with assistance (5.5 ≤ EDSS ≤ 6.5) status, and EDSS severity (< 3.0, 3.0-5.0, and > 5.5 ≤ 6.5). General linear mixed model was used for statistical analysis. FreeSurfer was used for volumetric analysis. RESULTS: The Black cohort had overrepresentation of females (78% vs. 62%, p = 0.013), lower age (median, 45 (IQR 39-51) vs. 49 (38-58), p = 0.08), lower Vitamin D levels (33 (21-45) vs. 40 (29-52), p = 0.002), and higher EDSS (4 (2-6) vs. 2.5 (1-6), p = 0.019). There was no progression of EDSS scores over the 2-year observation period. The covariates with significant influence on the baseline EDSS scores were older age, race, longer disease duration, prior MS treatment, and lower vitamin D levels. No differences were observed between the racial groups over time in the cortical, thalamic, caudate, putamen, and brainstem gray matter volumes nor in the cortical thickness or total lesion volume. CONCLUSION: In this real-world clinical and radiological study, ocrelizumab treatment was highly effective in stabilizing clinical and MRI measures of disease progression in Blacks and Whites, despite higher baseline disability in the Black cohort.

Long-term Efficacy of Satralizumab in AQP4-IgG-Seropositive Neuromyelitis Optica Spectrum Disorder From SAkuraSky and SAkuraStar.

BACKGROUND AND OBJECTIVES: Satralizumab, an interleukin 6 receptor inhibitor, reduced the risk of protocol-defined relapse (PDR) vs placebo in 2 independent, double-blind studies in patients with neuromyelitis optica spectrum disorder (NMOSD). We assessed the long-term efficacy of satralizumab in patients with aquaporin-4-immunoglobulin G (IgG)-seropositive (AQP4-IgG+) NMOSD. METHODS: Following the double-blind periods of SAkuraSky (satralizumab + baseline immunosuppressive treatment [IST]) and SAkuraStar (satralizumab monotherapy), patients could enter the open-label extension (OLE, satralizumab 120 mg Q4W ± IST). This analysis included all AQP4-IgG+ patients who received ≥1 dose of satralizumab in the double-blind and/or OLE periods, from patients' first dose to the data cutoff (February 22, 2021). PDR in the OLE period was determined by the investigator without external adjudication. We evaluated time to first investigator-reported PDR (iPDR), severe iPDR (≥2 point increase in the Expanded Disability Status Scale [EDSS] score), and sustained EDSS worsening (EDSS score increase of ≥2, ≥1, or ≥0.5 points for patients with baseline scores of 0, 1-5, or ≥5.5, respectively, confirmed ≥24 weeks post-initial worsening), plus the annualized iPDR rate (ARR). RESULTS: Forty-six of 55 AQP4-IgG+ patients (84%) in SAkuraSky and 57/64 patients in SAkuraStar (89%) continued from the double-blind periods into the OLEs. In total, 111 AQP4-IgG+ patients received ≥1 dose of satralizumab in the double-blind and/or OLE periods and were included in these analyses (SAkuraSky: 49; SAkuraStar: 62). The median (range) duration of satralizumab exposure was 4.4 (0.1-7.0) years in SAkuraSky and 4.0 (0.1-6.0) years in SAkuraStar, with a combined 440.1 patient-years of treatment. Seventy-one of 111 patients (64%) received satralizumab for ≥192 weeks (3.7 years). At this time point, 71% (SAkuraSky) and 73% (SAkuraStar) of satralizumab-treated patients were free from iPDR, 91% (SAkuraSky) and 90% (SAkuraStar) were free from severe iPDR, and 90% (SAkuraSky) and 86% (SAkuraStar) had no sustained EDSS worsening. The overall adjusted ARR (95% CI) was 0.12 (0.08-0.18) in SAkuraSky and 0.08 (0.05-0.13) in SAkuraStar and remained stable over time. DISCUSSION: These long-term results from the OLE periods of the SAkura studies demonstrate the continued efficacy of satralizumab over more than 3.5 years of treatment. High proportions of patients remained free from relapse, severe relapse, or worsening disease, with a consistently low ARR. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov registration numbers: NCT02028884 (SAkuraSky) and NCT02073279 (SAkuraStar). CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that satralizumab reduces the risk of relapse in patients with AQP4-IgG+ NMOSD beyond the first 96 weeks of treatment.

Homonymous hemimacular thinning: a unique presentation of optic tract injury in neuromyelitis optica.

A 42-year-old African American woman with a 5-year history of neuromyelitis optica was found to have an incongruous homonymous hemianopia. Optical coherence tomography (OCT) showed corresponding left homonymous hemimacular thinning. Magnetic resonance imaging of the brain demonstrated a demyelinating lesion in the left optic tract (OT) just anterior to the lateral geniculate nucleus and diffusion tensor magnetic resonance tractography confirmed axonal fiber loss in the left OT. This case illustrates the complementary and confirmatory roles of visual field testing, macular OCT, and neuroimaging in an OT lesion, which caused selective hemimacular thinning through retrograde degeneration.

Application of a novel T1 retrospective quantification using internal references (T1-REQUIRE) algorithm to derive quantitative T1 relaxation maps of the brain.

Most MRI sequences used clinically are qualitative or weighted. While such images provide useful information for clinicians to diagnose and monitor disease progression, they lack the ability to quantify tissue damage for more objective assessment. In this study, an algorithm referred to as the T1-REQUIRE is presented as a proof-of-concept which uses nonlinear transformations to retrospectively estimate T1 relaxation times in the brain using T1-weighted MRIs, the appropriate signal equation, and internal, healthy tissues as references. T1-REQUIRE was applied to two T1-weighted MR sequences, a spin-echo and a MPRAGE, and validated with a reference standard T1 mapping algorithm in vivo. In addition, a multiscanner study was run using MPRAGE images to determine the effectiveness of T1-REQUIRE in conforming the data from different scanners into a more uniform way of analyzing T1-relaxation maps. The T1-REQUIRE algorithm shows good agreement with the reference standard (Lin's concordance correlation coefficients of 0.884 for the spin-echo and 0.838 for the MPRAGE) and with each other (Lin's concordance correlation coefficient of 0.887). The interscanner studies showed improved alignment of cumulative distribution functions after T1-REQUIRE was performed. T1-REQUIRE was validated with a reference standard and shown to be an effective estimate of T1 over a clinically relevant range of T1 values. In addition, T1-REQUIRE showed excellent data conformity across different scanners, providing evidence that T1-REQUIRE could be a useful addition to big data pipelines.

Investigation into the Antihypertensive Effects of Diosmetin and Its Underlying Vascular Mechanisms Using Rat Model.

OBJECTIVE: Diosmetin is a flavonoid that is found in many important medicinal plants that have antihypertensive therapeutic potential. Diosmetin has been shown to have antiplatelet, anti-inflammatory and antioxidant properties, which suggests that it could be a potential candidate for use in antihypertensive therapy. METHODS: In vivo and in vitro methods were used for our investigation into the antihypertensive effects of diosmetin. RESULTS: Diosmetin significantly decreased the mean arterial pressure (MAP). The effects of diosmetin on the MAP and heart rate were more pronounced in hypertensive rats. To explore the involvement of the muscarinic receptors-linked NO pathway, Nω-nitro-L-arginine methyl ester (L-NAME) and atropine were pre-administered in vivo. The pretreatment with L-NAME did not significantly change the effects of diosmetin on the MAP by excluding the involvement of NO. Unlike L-NAME, the atropine pretreatment reduced the effects of diosmetin on the MAP, which demonstrated the role of the muscarinic receptors. In the in vitro study, diosmetin at lower concentrations produced endothelium-dependent and -independent (at higher concentrations) vasorelaxation, which was attenuated significantly by the presence of atropine and indomethacin but not L-NAME. Diosmetin was also tested for high K+-induced contractions. Diosmetin induced significant relaxation (similar to verapamil), which indicated its Ca2+ antagonistic effects. This was further confirmed by diosmetin shifting the CaCl2 CRCs toward the right due to its suppression of the maximum response. Diosmetin also suppressed phenylephrine peak formation, which indicated its antagonist effects on the release of Ca2+. Moreover, BaCl2 significantly inhibited the effects of diosmetin, followed by 4-AP and TEA, which suggested that the K+ channels had a role as well. CONCLUSIONS: The obtained data showed the Ca2+ channel antagonism, potassium channel activation and antimuscarinic receptor-linked vasodilatory effects of diosmetin, which demonstrated its antihypertensive potential.

Analysis of the extent of limbic system changes in multiple sclerosis using FreeSurfer and voxel-based morphometry approaches.

BACKGROUND AND PURPOSE: The limbic brain is involved in diverse cognitive, emotional, and autonomic functions. Injury of the various parts of the limbic system have been correlated with clinical deficits in MS. The purpose of this study was to comprehensively examine different regions of the subcortical limbic system to assess the extent of damage within this entire system as it may be pertinent in correlating with specific aspects of cognitive and behavioral dysfunction in MS by using a fully automated, unbiased segmentation approach. METHODS: Sixty-seven subjects were included in this study, including 52 with multiple sclerosis (MS) and 15 healthy controls. Only patients with stable MS disease, without any relapses, MRI activity, or disability progression were included. Subcortical limbic system segmentation was performed using the FreeSurfer pipeline ScLimbic, which provides volumes for fornix, mammillary bodies, hypothalamus, septal nuclei, nucleus accumbens, and basal forebrain. Hippocampus and anterior thalamic nuclei were added as additional components of the limbic circuitry, also segmented through FreeSurfer. Whole limbic region mask was generated by combining these structures and used for Voxel-based morphometry (VBM) analysis. RESULTS: The mean [95% confidence interval] of the total limbic system volume was lower (0.22% [0.21-0.23]) in MS compared to healthy controls (0.27%, [0.25-0.29], p < .001). Pairwise comparisons of individual limbic regions between MS and controls was significant in the nucleus accumbens (0.046%, [0.043-0.050] vs. 0.059%, [0.051-0.066], p = .005), hypothalamus (0.062%, [0.059-0.065] vs. 0.074%, [0.068-0.081], p = .001), basal forebrain (0.038%, [0.036-0.040] vs. 0.047%, [0.042-0.051], p = .001), hippocampus (0.47%, [0.45-0.49] vs. 0.53%, [0.49-0.57], p = .004), and anterior thalamus (0.077%, [0.072-0.082] vs. 0.093%, [0.084-0.10], p = .001) after Bonferroni correction. Volume of several limbic regions was significantly correlated with T2 lesion burden and brain parenchymal fraction (BPF). Multiple regression model showed minimal influence of BPF on limbic brain volume and no influence of other demographic and disease state variables. VBM analysis showed cluster differences in the fornix and anterior thalamic nuclei at threshold p < 0.05 after adjusting for covariates but the results were insignificant after family-wise error corrections. CONCLUSIONS: The results show evidence that brain volume loss is fairly extensive in the limbic brain. Given the significance of the limbic system in many disease states including MS, such volumetric analyses can be expanded to studying cognitive and emotional disturbances in larger clinical trials. FreeSurfer ScLimbic pipeline provided an efficient and reliable methodology for examining many of the subcortical structures related to the limbic brain.

Effect of Deep Brain Stimulation on Cerebellar Tremor Compared to Non-Cerebellar Tremor Using a Wearable Device in a Patient With Multiple Sclerosis: Case Report.

Tremor of the upper extremity is a significant cause of disability in some patients with multiple sclerosis (MS). The MS tremor is complex because it contains an ataxic intentional tremor component due to the involvement of the cerebellum and cerebellar outflow pathways by MS plaques, which makes the MS tremor, in general, less responsive to medications or deep brain stimulation (DBS) than those associated with essential tremor or Parkinson's disease. The cerebellar component has been thought to be the main reason for making DBS less effective, although it is not clear whether it is due to the lack of suppression of the ataxic tremor by DBS or else. The goal of this study was to clarify the effect of DBS on cerebellar tremor compared to non-cerebellar tremor in a patient with MS. By wearing an accelerometer on the index finger of each hand, we were able to quantitatively characterize kinetic tremor by frequency and amplitude, with cerebellar ataxia component on one hand and that without cerebellar component on the other hand, at the beginning and end of the hand movement approaching a target at DBS Off and On status. We found that cerebellar tremor surprisingly had as good a response to DBS as the tremor without a cerebellar component, but the function control on cerebellar tremor was not as good due to its distal oscillation, which made the amplitude of tremor increasingly greater as it approached the target. This explains why cerebellar tremor or MS tremor with cerebellar component has a poor functional transformation even with a good percentage of tremor control. This case study provides a better understanding of the effect of DBS on cerebellar tremor and MS tremor by using a wearable device, which could help future studies improve patient selection and outcome prediction for DBS treatment of this disabling tremor.

In vitro cytotoxic and antimicrobial activities of Erythrina suberosa (Roxb) bark.

BACKGROUND: The study was focused on evaluating cytotoxic and antimicrobial activities of Erythrina suberosa (Roxb.) bark through in vitro pharmacological screening. MATERIALS AND METHODS: The bark was extracted using different solvents, for example, dichloromethane, ethyl acetate, methanol, and aqueous for obtaining the organic fractions. These organic fractions were then evaluated for their cytotoxic and antimicrobial activity compared with the standard. Cefixime was used as the standard for antibacterial assay, whereas clotrimazole was used as the standard for antifungal activities. Bacterial strains used were Staphylococcus aureus and methicillin-resistant S. aureus (MRSA), whereas for antifungal activities Candida albicans, Candida parapsilosis, and Candida krusei strains were used. RESULTS: The organic fractions obtained were evaluated for their cytotoxic and antimicrobial activities. In cytotoxic assay (Brine shrimp lethality assay), dichloromethane fraction was the most potent with LD50 of 47.63, whereas aqueous, methanol, and ethyl acetate fractions showed LD50 of 121.74, 422.2, and 201.96, respectively. Similarly, for antibacterial assay, dichloromethane fraction showed 32.2mm zone of inhibition against MRSA in comparison with standard cefixime (zone of inhibition, 30.5mm). A minimal zone of inhibition with crude saponins (13.1 and 12.2mm) was observed against C. albicans in comparison to standard (cefixime) with a zone of inhibition of 28.5mm. No prominent results were observed against C. parapsilosis and C. krusei strains. CONCLUSION: The study was based on the plant from Indo-Pak origin, and it has shown some prominent cytotoxic and antibacterial activities. Although the results of this study have provided a basic idea about the efficacy of plant extract, still more explanatory and high-scale studies can be beneficial for elaborating the cytotoxic and antimicrobial activities of this plant.

Mechanisms underlying the wound healing and tissue regeneration properties of Chenopodium album.

In the current study, aerial parts (leaves, stem and shoots) of C. album were extracted with methanol and subjected to phytochemical and HPLC analysis. Agar well diffusion method was used for anti-bacterial activity against Gram-negative strains Escherichia coli, Salmonella typhi, Klebsiella, Pseudomonas aeruginosa and Gram-positive Bacillus cereus, Staphylococcus aureus, Methicillin-resistant Staphylococcus aureus. Burn was induced through flame heated metal rod on mice. C. album ointment (2% w/w), Vaseline (vehicle) and silver sulfadiazine (standard) were topically applied thrice daily for 15 days. Wound area was measured on day 0, 5, 10 and 15. On last day, the wound tissues were excised and subjected to histopathological, quantitative PCR and immunohistochemical analysis. Phenols, alkaloids, phytosterols, tannins, saponins, flavonoids, carbohydrates and glycosides were detected in phytochemical analysis. HPLC chromatogram displayed peaks for rutin, quercetin, ascorbic acid, gallic acid and various other phyto-constituents. The extract exhibited zone of inhibition in millimeter (mm) against E. coli (12.3 ± 0.57), S. typhyi (14.6 ± 1.52), Klebsiella (11.8 ± 0.76), P. aeruginosa (12.3 ± 0.57), B. cereus (12.5 ± 1.29), S. aureus (18.3 ± 2.08), and MRSA (11.8 ± 0.76). The wound area in C. album group was significantly (60%) reduced as compared to vehicle group (11%). Histological analysis showed complete re-epithelialization and fine tissue in extract treated group. qPCR data revealed up-regulation of EGF, PDGF and TGF-ß1 genes in extract treated group. Similarly, immunohistochemistry results confirmed heightened EGFR expression in extract treated group. Our findings suggest that C. album can promote wound healing and tissue regeneration through control of burns related infection and modulation of growth factors and its receptors.

COVID-19 in multiple sclerosis patients and risk factors for severe infection.

Multiple sclerosis (MS) patients have been considered a higher-risk population for COVID-19 due to the high prevalence of disability and disease-modifying therapy use; however, there is little data identifying clinical characteristics of MS associated with worse COVID-19 outcomes. Therefore, we conducted a multicenter prospective cohort study looking at the outcomes of 40 MS patients with confirmed COVID-19. Severity of COVID-19 infection was based on hospital course, where a mild course was defined as the patient not requiring hospital admission, moderate severity was defined as the patient requiring hospital admission to the general floor, and most severe was defined as requiring intensive care unit admission and/or death. 19/40(47.5%) had mild courses, 15/40(37.5%) had moderate courses, and 6/40(15%) had severe courses. Patients with moderate and severe courses were significantly older than those with a mild course (57[50-63] years old and 66[58.8-69.5] years old vs 48[40-51.5] years old, P = 0.0121, P = 0.0373). There was differing prevalence of progressive MS phenotype in those with more severe courses (severe:2/6[33.3%]primary-progressing and 0/6[0%]secondary-progressing, moderate:1/14[7.14%] and 5/14[35.7%] vs mild:0/19[0%] and 1/19[5.26%], P = 0.0075, 1 unknown). Significant disability was found in 1/19(5.26%) mild course-patients, but was in 9/15(60%, P = 0.00435) of moderate course-patients and 2/6(33.3%, P = 0.200) of severe course-patients. Disease-modifying therapy prevalence did not differ among courses (mild:17/19[89.5%], moderate:12/15[80%] and severe:3/6[50%], P = 0.123). MS patients with more severe COVID-19 courses tended to be older, were more likely to suffer from progressive phenotype, and had a higher degree of disability. However, disease-modifying therapy use was not different among courses.