Alterations in the innate and adaptive immune system in a real-world cohort of multiple sclerosis patients treated with ocrelizumab.

B cell depletion by the anti-CD20 antibody ocrelizumab is effective in relapsing-remitting (RR) and primary progressive (PP) multiple sclerosis (MS). We investigated immunological changes in peripheral blood of a real-world MS cohort after 6 and 12 months of ocrelizumab. All RRMS and most PPMS patients (15/20) showed treatment response. Ocrelizumab not only reduced CD20+ B cells, but also numbers of CD20+ T cells. Absolute numbers of monocytes, dendritic cells and CD8+ T cells were increased, while CD56hi natural killer cells were reduced after ocrelizumab. The residual B cell population shifted towards transitional and activated, IgA+ switched memory B cells, double negative B cells, and antibody-secreting cells. Delaying the treatment interval by 2-3 months increased mean B cell frequencies and enhanced naive B cell repopulation. Ocrelizumab reduced plasma levels of interleukin(IL)-12p70 and interferon(IFN)-α2. These findings will contribute to understanding ineffective treatment responses, dealing with life-threatening infections and further unravelling MS pathogenesis.

Design and analysis of graphene- and germanium-based plasmonic probe with photonic spin Hall effect in THz frequency region for magnetic field and refractive index sensing.

In this work, we analyze the design of a graphene- and germanium-based plasmonic sensor with photonic spin Hall effect (PSHE) for detection of refractive index (RI) of a gas medium and magnetic field (B) applied to the graphene monolayer in THz frequency region. The PSHE phenomenon is studied in both conventional as well as modified weak measurements. The effect of gaseous medium thickness (d4), transverse magnetic (TM) mode's order, and amplified angle parameter (Δ) is studied on the sensor's performance. Parameters such as sensitivity, resolution, and figure of merit have been considered for sensor's performance evaluation. The results indicate that in the conventional weak measurements, for a TM1 mode (with d4 = 20 µm, B = 0, and Δ = 0.1°), an RI resolution of 2.32 × 10-12 RIU is achievable for gas medium in the range 1-1.1 RIU. In the modified weak measurements, for a TM3 mode (with d4 = 100 µm, B = 0, and Δ = 0.1°), the RI resolution close to 1.39 × 10-10 RIU is achievable for gas sensing. The same sensor design was also studied for magnetic field sensing while keeping the value of gaseous medium RI (n4) as 1. The results indicate that for a TM1 mode (with d4 = 20 µm and Δ = 0.1°), in the conventional weak measurements, a magnetic field resolution of 5.31 × 10-4 µT (i.e., 0.53 nT) is achievable for a range 0-1 T of B. Further, it is found that in contrast with the conventional case, the resolutions in the modified weak measurements are improved for large values of the Δ. Some of the results emerge better or comparable with the resolutions of RI and magnetic field measurement (5 × 10-9 RIU and 0.7 µT or 1.22 × 10-11 RIU and 1.46 × 10-2 µT) existing in the literature.

Factors associated with treatment escalation among MS specialists and general neurologists: Results from an International cojoint study.

BACKGROUND: Previous studies in multiple sclerosis (MS) showed that therapeutic inertia (TI) affects 60-90% of neurologists and up to 25% of daily treatment decisions. The objective of this study was to determine the most common factors and attribute levels associated with decisions to treatment escalation in an international study in MS care. METHODS: 300 neurologists with MS expertise from 20 countries were invited to participate. Participants were presented with 12 pairs of simulated MS patient profiles described by 13 clinically relevant factors. We used disaggregated discrete choice experiments to estimate the weight of factors and attributes affecting physicians' decisions when considering treatment selection. Participants were asked to select the ideal candidate for treatment escalation from modest to higher-efficacy therapies. RESULTS: Overall, 229 neurologists completed the study (completion rate: 76.3%). The top 3 weighted factors associated with treatment escalation were: previous relapses (20%), baseline expanded disability status scale [EDSS] (18%), and MRI activity (13%). Patient demographics and desire for pregnancy had a modest influence (≤ 3%). We observed differences in the weight of factors associated with treatment escalation between MS specialists and non-MS specialists. CONCLUSIONS: Our results provide critical information on factors influencing neurologists' treatment decisions and should be applied to continuing medical education strategies.

Self-assembly of an organometallic Fe9O6 cluster from aerobic oxidation of (tmeda)Fe(CH2tBu)2.

Aerobic oxidation of (tmeda)Fe(CH2tBu)2 in toluene or THF solution leads to the self-assembly of a magic-sized all-ferrous oxide cluster containing the Fe9O6 subunit and bearing organometallic and diamine ligands. Mössbauer studies of the cluster are consistent with an all-ferrous assignment and magnetometry reveals complex intracluster and intercluster magnetic interactions.

Predicting clinical progression in multiple sclerosis after 6 and 12 years.

BACKGROUND AND PURPOSE: To predict disability and cognition in multiple sclerosis (MS) after 6 and 12 years, using early clinical and imaging measures. METHODS: A total of 115 patients with MS were selected and followed up after 2 and 6 years, with 79 patients also being followed up after 12 years. Disability was measured using the Expanded Disability Status Scale (EDSS); cognition was measured only at follow-up using neuropsychological testing. Predictors of interest included EDSS score, baseline brain and lesion volumes and their changes over 2 years, baseline age, clinical phenotype, sex and educational level. RESULTS: Higher 6-year EDSS score was predicted by early EDSS score and whole-brain volume changes and baseline diagnosis of primary progressive MS (adjusted R2  = 0.56). Predictors for 12-year EDSS score included larger EDSS score changes and higher T1-hypointense lesion volumes (adjusted R2  = 0.38). Year 6 cognition was predicted by primary progressive MS phenotype, lower educational level, male sex and early whole-brain atrophy (adjusted R2  = 0.26); year 12 predictors included male sex, lower educational level and higher baseline T1-hypointense lesion volumes (adjusted R2  = 0.14). CONCLUSIONS: Patients with early signs of neurodegeneration and a progressive disease onset were more prone to develop both disability progression and cognitive dysfunction. Male sex and lower educational level only affected cognitive dysfunction, which remains difficult to predict and probably needs more advanced imaging measures.

Endothelial progenitor cells populate the stromal stem niche of tympanum.

The tympanic membrane (TM) integrity is of utmost importance for the sense of hearing. Therefore, the intrinsic potential of the TM to regenerate and repair deserves complete characterisation. Existing studies brought evidence on the epithelial stem niche of the TM. However, the stromal compartment was not evaluated for harbouring a distinctive stem, or progenitor, niche. We aimed doing this in transmission electron microscopy. We used TMs dissected out from 3 male Oryctolagus cuniculus rabbits. Evidence of stromal quiescent stem cells was gathered. Moreover, endothelial progenitor cells were found in the TM, being accurately identified by two specific ultrastructural markers of the endothelial lineage: the Weibel-Palade bodies and the stomatal diaphragms of the subplasmalemmal caveolae. The stromal stem niche of the TM appears to be a distinctive contributor during physiological and pathological processes of the TM, such as cholesteatoma formation, at least as a biological support for processes of vasculogenesis. However, further characterisation of the molecular pattern of the stromal stem niche of the TM is mandatory.

Acute anterior uveitis and other extra-articular manifestations of spondyloarthritis.

BACKGROUND: Spondyloarthritis (SpA) is associated with an array of peripheral manifestations. Our study aims to evaluate extra-articular manifestations of SpA in a Romanian academic clinical setting and to observe their associations with different disease measures. METHODS: The study was designed to note the extra-articular manifestations of SpA patients in a cross-sectional and retrospective manner. Records included demographics, inflammation markers, SpA clinical characteristics, treatment regimes, associated osteoporosis and cardiovascular morbidity. Data were assessed by using appropriate non-parametric tests. RESULTS: A total of 126 SpA patients were included. The most common extra-articular manifestations were skin involvement in the form of psoriasis (34.1%), eye involvement in the form of acute anterior uveitis (8.7%) and dactylitis (7.2%). Compared to patients with no record of uveitis, uveitis-affected cases were more frequently males, more frequently diagnosed with ankylosing spondylitis, but less frequently dyslipidemic and diagnosed with psoriasis. Psoriasis-affected patients were older and had a higher prevalence of peripheral SpA diagnosis, but a lower prevalence of radiographic sacroiliitis. CONCLUSIONS: Acute anterior uveitis in SpA predominantly affects males with AS. This is relevant both to clinical and fundamental science, since its management requires both ophthalmology and rheumatology clinical settings. Psoriasis was associated more frequently with peripheral SpA. ABBREVIATIONS: AHT = arterial hypertension, AS = ankylosing spondylitis, ASAS = Assessment in SpondyloArthritis international Society, aSpA = axial spondyloarthritis, BASFI = Bath Ankylosing Spondylitis Functional Index, BASDAI = Bath Ankylosing Spondylitis Disease Activity Index, CRP = C-reactive protein, ESR = erythrocyte sedimentation rate, DM2 = type 2 diabetes mellitus, HLA = human leukocyte antigen, IBD = inflammatory bowel disease, MRI = magnetic resonance imaging, mSpA = mixed (peripheral and axial) spondyloarthritis, NSAIDs = non-steroidal anti-inflammatory drugs, pSpA = peripheral spondyloarthritis, PsA = psoriatic arthritis, ReA = reactive arthritis, SD = standard deviation, SI = sacroiliitis, SpA = spondyloarthritis, UDSpA = undifferentiated spondyloarthritis.

Clinical use of Bevacizumab in treating refractory glaucoma.

UNLABELLED: Bevacizumab is a recombinant humanized monoclonal antibody directed against vascular endothelial growth factor (VEGF). Though other VEGF inhibitors are being approved for the treatment of ophthalmological conditions, bevacizumab found its way into ophthalmology and clinical practice all around the world. The objective of this review is to present the ophthalmic dosage and administration pathways of bevacizumab in treating refractory glaucoma patients. ABBREVIATIONS: VEGF = vascular endothelial growth factor, FDA = Food and Drug Administration, AMD = age-related macular degeneration.

Hydroxyapatite ocular implant and non-integrated implants in eviscerated patients.

INTRODUCTION: This study compares the outcomes and complications of hydroxyapatite ocular implant and non-integrated ocular implants following evisceration. MATERIALS AND METHODS: This is a retrospective study of 90 patients who underwent evisceration for different ocular affections, in the Ophthalmology Department of the University Emergency Hospital Bucharest, between January 2009 and December 2013. The outcomes measured were conjunctival dehiscence, socket infection, implant exposure and extrusion rate. RESULTS: Forty-three patients had the hydroxyapatite implant (coralline-Integrated Ocular Implants, USA or synthetic-FCI, France) and forty-seven received non-integrated ocular implants (24 acrylic and 23 silicone). Five cases of socket infection, thirteen cases of extrusion and two cases of conjunctival dehiscence were encountered. CONCLUSIONS: There was a higher rate of conjunctival dehiscence with hydroxyapatite ocular implant, but implant extrusion and socket infection were found in non-integrated ocular implants.

The efficiency of subconjunctival bevacizumab in refractory glaucoma - case report.

Anti-vascular endothelial growth factor (anti-VEGF) therapy used as adjunctive to glaucoma filtration surgery may help filtering bleb survival because vascular endothelial growth factor has an important role in the angiogenesis of new vessels and in the fibrogenesis, which lead to scar formation and bleb failure. Bevacizumab is a non-selective monoclonal antibody against all isoforms of VEGF-A. We present the case of an inflammatory glaucoma of a 67-year-old female, with uncontrolled intraocular pressure on maximal tolerable medical treatment, who underwent trabeculectomy and received 1.25 mg/0.05 ml of bevacizumab (Avastin) subconjunctivally at the end of the surgery and an additional injection one month later. Right eye intraocular pressure (IOP) was 26 mm Hg at preoperative visit and after surgery, it decreased and remained normal at each postoperative examination with no additional IOP-lowering medication. A localized avascular bleb with moderate elevation was observed six months postoperatively.

What drives MRI-measured cortical atrophy in multiple sclerosis?

BACKGROUND: Cortical atrophy, assessed with magnetic resonance imaging (MRI), is an important outcome measure in multiple sclerosis (MS) studies. However, the underlying histopathology of cortical volume measures is unknown. OBJECTIVE: We investigated the histopathological substrate of MRI-measured cortical volume in MS using combined post-mortem imaging and histopathology. METHODS: MS brain donors underwent post-mortem whole-brain in-situ MRI imaging. After MRI, tissue blocks were systematically sampled from the superior and inferior frontal gyrus, anterior cingulate gyrus, inferior parietal lobule, and superior temporal gyrus. Histopathological markers included neuronal, axonal, synapse, astrocyte, dendrite, myelin, and oligodendrocyte densities. Matched cortical volumes from the aforementioned anatomical regions were measured on the MRI, and used as outcomes in a nested prediction model. RESULTS: Forty-five tissue blocks were sampled from 11 MS brain donors. Mean age at death was 68±12 years, post-mortem interval 4±1 hours, and disease duration 35±15 years. MRI-measured regional cortical volumes varied depending on anatomical region. Neuronal density, neuronal size, and axonal density were significant predictors of GM volume. CONCLUSIONS: In patients with long-standing disease, neuronal and axonal pathology are the predominant pathological substrates of MRI-measured cortical volume in chronic MS.

Accurate GM atrophy quantification in MS using lesion-filling with co-registered 2D lesion masks.

BACKGROUND: In multiple sclerosis (MS), brain atrophy quantification is affected by white matter lesions. LEAP and FSL-lesion_filling, replace lesion voxels with white matter intensities; however, they require precise lesion identification on 3DT1-images. AIM: To determine whether 2DT2 lesion masks co-registered to 3DT1 images, yield grey and white matter volumes comparable to precise lesion masks. METHODS: 2DT2 lesion masks were linearly co-registered to 20 3DT1-images of MS patients, with nearest-neighbor (NNI), and tri-linear interpolation. As gold-standard, lesion masks were manually outlined on 3DT1-images. LEAP and FSL-lesion_filling were applied with each lesion mask. Grey (GM) and white matter (WM) volumes were quantified with FSL-FAST, and deep gray matter (DGM) volumes using FSL-FIRST. Volumes were compared between lesion mask types using paired Wilcoxon tests. RESULTS: Lesion-filling with gold-standard lesion masks compared to native images reduced GM overestimation by 1.93 mL (p < .001) for LEAP, and 1.21 mL (p = .002) for FSL-lesion_filling. Similar effects were achieved with NNI lesion masks from 2DT2. Global WM underestimation was not significantly influenced. GM and WM volumes from NNI, did not differ significantly from gold-standard. GM segmentation differed between lesion masks in the lesion area, and also elsewhere. Using the gold-standard, FSL-FAST quantified as GM on average 0.4% of the lesion area with LEAP and 24.5% with FSL-lesion_filling. Lesion-filling did not influence DGM volumes from FSL-FIRST. DISCUSSION: These results demonstrate that for global GM volumetry, precise lesion masks on 3DT1 images can be replaced by co-registered 2DT2 lesion masks. This makes lesion-filling a feasible method for GM atrophy measurements in MS.

Oxysterols and cholesterol precursors correlate to magnetic resonance imaging measures of neurodegeneration in multiple sclerosis.

BACKGROUND: Cholesterol homeostasis is important for formation and maintenance of myelin and axonal membranes in the central nervous system (CNS). The concentrations of the brain specific cholesterol metabolite 24S-hydroxycholesterol (24OHC) and cholesterol precursors have been shown to be altered in multiple sclerosis (MS). However, how changes in sterol levels relate to the pathological processes in MS is not clear. METHODS: In this study, we compared serum and cerebrospinal fluid (CSF) sterol levels between 105 MS (51 relapsing-remitting (RR); 39 secondary progressive (SP) and 15 primary progressive (PP)) and 49 control patients. Sterol levels were correlated to magnetic resonance imaging (MRI) markers of disease activity. RESULTS: We found decreased serum 24OHC and 27-hydroxycholesterol (27OHC) and increased CSF lathosterol in MS patients compared to control patients (p=0.018, p=0.002 and p=0.002, respectively). Subgroup analysis showed that serum 24OHC levels were negatively correlated to normalized brain volume measurements in relapse-onset MS patients (r= -0.326, p=0.004). CONCLUSIONS: These results confirm that cholesterol homeostasis is disturbed in MS and suggest that changes in cholesterol synthesis are related to neurodegenerative pathological processes as seen on the MRI. The data seem to be in line with the recently reported observation that high dose statins may have a positive effect on clinical disability in secondary progressive MS.

The role of Spectral Domain Optical Coherence Tomography in monitoring uncontrolled hypertensive type 2 diabetic patients.

RATIONALE: The pathogenesis of diabetic retinopathy is multifactorial, and a range of hyperglycemia-linked pathways has been implicated in the initiation and progression of this condition. All the cells in the retina are affected by the diabetic milieu, and in view of such disease and tissue complexity, it is unlikely that any single process is solely responsible for the retinal pathophysiology. Dyslipidemia is considered a trigger to rapid worsening of the condition and its treatment is becoming a part of normal diabetes treatment. Nevertheless, as establishing causal mechanisms and related conditions remain an important research goal, also the means to follow up the impact on the retina and other ocular tissues are as important. OBJECTIVE: this retrospective study shows the progression of diabetic macular edema (DME) in patients with dyslipidemia related to poor glycemic and blood control in subjects with existing DME by measuring the total macular volume (TMV) and thickness through the spectral domain optical coherence tomography (SD- OCT). METHODS AND RESULTS: 30 uncontrolled cases of type 2 diabetes that were measured monthly by SD- OCT through a period of 3 months with correlation to the degree of dyslipidemia and hyperglycemia, were analyzed. CONCLUSION: The role of OCT in monitoring the progression of DME in patients with uncontrolled type 2 diabetes is essential and the collaboration between the ophthalmologist and endocrinologist is essential to monitor the course of disease in uncontrolled patients.

Comparison between the efficacy and side effects of intravitreal versus anterior chamber Bevacizumab injection in neovascular glaucoma patients.

Rationale. Neovascular glaucoma is the type of glaucoma most refractory to treatment. The most frequent causes are those associated with retinal hypoxia, which promotes the upregulation of the VEGF synthesis and produces fibrovascular membranes over the anterior chamber angle. Because the administration of anti VEGF products is still off label for neovascular glaucoma, there is not a single accepted way of treatment. There are differences between the site of administration (vitreal or anterior chamber or both at the same time), the dose or the setting of the procedure. Objective. The objective of our study was to asses the difference of efficacy and complications of bevacizumab injection for vitreal administration versus anterior chamber administration. Methods and results. Prospective study with 18 eyes from 18 patients with neovascular glaucoma associated with proliferative diabetic retinopathy or retinal vein occlusion. Group A (10 patients) received intravitreal injection with 0.05 ml Bevacizumab. Group B (8 patients) received anterior chamber injection with 0.03 ml Bevacizumab. There was a significant decrease of intraocular pressure (p<0.01 for group A, p<0.05 for group B) for both groups. Group A also had a statistically significant decrease of the macular edema (p<0.05). The side effects were reduced for both groups. Discussion. Our conclusion was that for the neovascular glaucoma, which associates significant macular edema, the intravitreal procedure should be performed, while for neovascular glaucoma patients without retinal edema, the anterior chamber procedure should be preferred because of reduced potential side effects.

Optimizing parameter choice for FSL-Brain Extraction Tool (BET) on 3D T1 images in multiple sclerosis.

BACKGROUND: Brain atrophy studies often use FSL-BET (Brain Extraction Tool) as the first step of image processing. Default BET does not always give satisfactory results on 3DT1 MR images, which negatively impacts atrophy measurements. Finding the right alternative BET settings can be a difficult and time-consuming task, which can introduce unwanted variability. AIM: To systematically analyze the performance of BET in images of MS patients by varying its parameters and options combinations, and quantitatively comparing its results to a manual gold standard. METHODS: Images from 159 MS patients were selected from different MAGNIMS consortium centers, and 16 different 3DT1 acquisition protocols at 1.5 T or 3T. Before running BET, one of three pre-processing pipelines was applied: (1) no pre-processing, (2) removal of neck slices, or (3) additional N3 inhomogeneity correction. Then BET was applied, systematically varying the fractional intensity threshold (the "f" parameter) and with either one of the main BET options ("B" - bias field correction and neck cleanup, "R" - robust brain center estimation, or "S" - eye and optic nerve cleanup) or none. For comparison, intracranial cavity masks were manually created for all image volumes. FSL-FAST (FMRIB's Automated Segmentation Tool) tissue-type segmentation was run on all BET output images and on the image volumes masked with the manual intracranial cavity masks (thus creating the gold-standard tissue masks). The resulting brain tissue masks were quantitatively compared to the gold standard using Dice overlap coefficient (DOC). Normalized brain volumes (NBV) were calculated with SIENAX. NBV values obtained using for SIENAX other BET settings than default were compared to gold standard NBV with the paired t-test. RESULTS: The parameter/preprocessing/options combinations resulted in 20,988 BET runs. The median DOC for default BET (f=0.5, g=0) was 0.913 (range 0.321-0.977) across all 159 native scans. For all acquisition protocols, brain extraction was substantially improved for lower values of "f" than the default value. Using native images, optimum BET performance was observed for f=0.2 with option "B", giving median DOC=0.979 (range 0.867-0.994). Using neck removal before BET, optimum BET performance was observed for f=0.1 with option "B", giving median DOC 0.983 (range 0.844-0.996). Using the above BET-options for SIENAX instead of default, the NBV values obtained from images after neck removal with f=0.1 and option "B" did not differ statistically from NBV values obtained with gold-standard. CONCLUSION: Although default BET performs reasonably well on most 3DT1 images of MS patients, the performance can be improved substantially. The removal of the neck slices, either externally or within BET, has a marked positive effect on the brain extraction quality. BET option "B" with f=0.1 after removal of the neck slices seems to work best for all acquisition protocols.

Identification of biomarkers for diagnosis and progression of MS by MALDI-TOF mass spectrometry.

INTRODUCTION: Body fluid biomarkers for clinical subtyping and monitoring of disease progression are of considerable interest in multiple sclerosis (MS). Proteomics tools are optimal for the unbiased simultaneous detection of large series of peptides and proteins. OBJECTIVES: To identify novel candidate biomarkers discriminating patients with MS from patients with other neurological diseases (OND), and for subtyping of relapsing-remitting (RR), secondary progressive (SP) and primary progressive (PP) MS patients using a high-throughput MALDI-TOF-based mass spectrometry method. METHODS: Paired cerebrospinal fluid (CSF) and serum samples of 41 RRMS, 30 SPMS, 13 PPMS patients and 25 patients with OND were analysed. RESULTS: Out of a total of 100 detected peptides in CSF and 200 peptides in serum, 11 peptides were differentially regulated in serum and two in CSF between patients with MS and the OND control group. Eleven peptides were differentially regulated in both serum and CSF between relapse-onset MS and PPMS patients. Lastly, four peptides were differentially regulated in serum and two in CSF between RRMS and SPMS patients. Specific peaks regulated in MS were tentatively identified as fragments of secretogranin III and complement C3. The peak intensity of the CSF peptide ion with m/z value 8607.7 correlated to atrophy (r = -0.27, p < 0.005), black hole volumes (r = 0.31, p < 0.008) and total lesion load (r = 0.34, p < 0.003). A serum peptide with m/z value of 872.4 elevated in SPMS correlated to Expanded Disability Status Scale (r = 0.341, p < 0.005) and atrophy (r = -0.286, p < 0.028). CONCLUSIONS: Using high-throughput body fluid profiling by MALDI-TOF mass spectrometry, small proteins and peptides were detected as promising candidate biomarkers for diagnosis and disease progression of MS.

Heidelberg Retina Tomography analysis in optic disks with anatomic particularities.

Due to its objectivity, reproducibility and predictive value confirmed by many large-scale statistical clinical studies, Heidelberg Retina Tomography has become one of the most used computerized image analysis of the optic disc in glaucoma. It has been signaled, though, that the diagnostic value of Moorfieds Regression Analyses and Glaucoma Probability Score decreases when analyzing optic discs with extreme sizes. The number of false positive results increases in cases of megalopapillae and the number of false negative results increases in cases of small size optic discs. The present paper is a review of the aspects one should take into account when analyzing a HRT result of an optic disc with anatomic particularities.