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We analyze JWST Mid-Infrared Instrument/Medium Resolution Spectrograph integral field unit observations of three Seyferts from the Galactic Activity, Torus, and Outflow Survey (GATOS) and showcase the intriguing polycyclic aromatic hydrocarbon (PAH) and emission-line characteristics in regions of ∼500 pc scales over or around their active galactic nuclei (AGN). Combing the measurements and model predictions, we find that the central regions containing a high fraction of neutral PAHs with small sizes, e.g., those in ESO137-G034, are in highly heated environments, due to collisional shock heating, with hard and moderately intense radiation fields. Such environments are proposed to result in inhibited growth or preferential erosion of PAHs, decreasing their average size and overall abundance. We additionally find that the central regions containing a high fraction of ionized PAHs with large sizes, e.g., those in MCG-05-23-016, are likely experiencing severe photoionization because of the radiative effects from the radiative shock precursor besides the AGN. The severe photoionization can contribute to the ionization and further destruction of PAHs. Overall, different Seyferts, even different regions in the same galaxy, e.g., those in NGC 3081, can contain PAH populations of different properties. Specifically, Seyferts that exhibit similar PAH characteristics to ESO137-G034 and MCG-05-23-016 also tend to have similar emission-line properties to them, suggesting that the explanations for PAH characteristics of ESO137-G034 and MCG-05-23-016 may also apply generally. These results have promising application in the era of JWST, especially in diagnosing different (i.e., radiative and kinetic) AGN feedback modes.

Utilizing JWST MIRI/Medium Resolution Spectrograph integral field unit observations of the kiloparsec-scale central regions, we showcase the diversity of ionized gas distributions and kinematics in six nearby Seyfert galaxies included in the GATOS survey. Specifically, we present spatially resolved flux distribution and velocity field maps of six ionized emission lines covering a large range of ionization potentials (15.8–97.1 eV). Based on these maps, we showcase the evidence of ionized gas outflows in the six targets, and find some highly disturbed regions in NGC 5728, NGC 5506, and ESO137-G034. We propose active galactic nucleus (AGN)-driven radio jets plausibly play an important role in triggering these highly disturbed regions. With the outflow rates estimated based on [Ne V ] emission, we find the six targets tend to have ionized outflow rates converged to a narrower range than the previous finding. These results have an important implication for the outflow properties in AGN of comparable luminosity.

The superb image quality, stability, and sensitivity of JWST permit deconvolution techniques to be pursued with a fidelity unavailable to ground-based observations. We present an assessment of several deconvolution approaches to improve image quality and mitigate the effects of the complex JWST point-spread function (PSF). The optimal deconvolution method is determined by using WebbPSF to simulate JWST’s complex PSF and MIRISim to simulate multiband JWST/Mid-Infrared Imager Module (MIRIM) observations of a toy model of an active galactic nucleus (AGN). Five different deconvolution algorithms are tested: (1) Kraken deconvolution, (2) Richardson–Lucy, (3) the adaptive imaging deconvolution algorithm, (4) sparse regularization with the Condat–Vũ algorithm, and (5) iterative Wiener filtering and thresholding. We find that Kraken affords the greatest FWHM reduction of the nuclear source of our MIRISim observations for the toy AGN model while retaining good photometric integrity across all simulated wave bands. Applying Kraken to Galactic Activity, Torus, and Outflow Survey (GATOS) multiband JWST/MIRIM observations of the Seyfert 2 galaxy NGC 5728, we find that the algorithm reduces the FWHM of the nuclear source by a factor of 1.6–2.2 across all five filters. Kraken images facilitate detection of extended nuclear emission ∼2.″5 (∼470 pc, position angle ≃ 115°) in the SE–NW direction, especially at the longest wavelengths. We demonstrate that Kraken is a powerful tool to enhance faint features otherwise hidden in the complex JWST PSF.

What Is This Summary About?: Previous studies have shown that people living with multiple sclerosis (MS) treated with cladribine tablets have fewer relapses (where new symptoms occur or existing symptoms get worse for 24 hours or more) and delayed disability progression (slowing down of the disease getting worse). The CLASSIC-MS study looked at the long-term effectiveness of treatment with cladribine tablets in people living with MS who had taken part in the original CLARITY and CLARITY Extension clinical studies., What Were the Results?: Results showed that people treated with cladribine tablets maintained their mobility (the ability to move freely) for longer and experienced other positive effects long after their treatment ended, including being less likely to need further treatment for their MS., What Do the Results Mean?: The results obtained from CLASSIC-MS show that the benefits of taking cladribine tablets carry on even when patients stop taking the treatment.

Immune Cell Deconvolution methods utilizing gene expression profiling to quantify immune cells in tissues and blood are an appealing alternative to flow cytometry. Our objective was to investigate the applicability of deconvolution approaches in clinical trial settings to better investigate the mode of action of drugs for autoimmune diseases. Popular deconvolution methods CIBERSORT and xCell were validated using gene expression from the publicly available GSE93777 dataset that has comprehensive matching flow cytometry. As shown in the online tool, ~ 50% of signatures show strong correlation (r > 0.5) with the remainder showing moderate correlation, or in a few cases, no correlation. Deconvolution methods were then applied to gene expression data from the phase III CLARITY study (NCT00213135) to evaluate the immune cell profile of relapsing multiple sclerosis patients treated with cladribine tablets. At 96 weeks after treatment, deconvolution scores showed the following changes vs placebo: naïve, mature, memory CD4 + and CD8 + T cells, non-class switched, and class switched memory B cells and plasmablasts were significantly reduced, naïve B cells and M2 macrophages were more abundant. Results confirm previously described changes in immune cell composition following cladribine tablets treatment and reveal immune homeostasis of pro- vs anti-inflammatory immune cell subtypes, potentially supporting long-term efficacy., (© 2023. The Author(s).)

Background: CLASSIC-MS evaluated the long-term efficacy of cladribine tablets in patients with relapsing multiple sclerosis., Objective: Report long-term mobility and disability beyond treatment courses received in CLARITY/CLARITY Extension., Methods: This analysis represents CLASSIC-MS patients who participated in CLARITY with/without participation in CLARITY Extension, and received ⩾1 course of cladribine tablets or placebo ( N  = 435). Primary objective includes evaluation of long-term mobility (no wheelchair use in the 3 months prior to first visit in CLASSIC-MS and not bedridden at any time since last parent study dose (LPSD), i.e. Expanded Disability Status Scale (EDSS) score <7). Secondary objective includes long-term disability status (no use of an ambulatory device (EDSS < 6) at any time since LPSD)., Results: At CLASSIC-MS baseline, mean ± standard deviation EDSS score was 3.9 ± 2.1 and the median time since LPSD was 10.9 (range = 9.3-14.9) years. Cladribine tablets-exposed population: 90.6% ( N  = 394), including 160 patients who received a cumulative dose of 3.5 mg/kg over 2 years. Patients not using a wheelchair and not bedridden: exposed, 90.0%; unexposed, 77.8%. Patients with no use of an ambulatory device: exposed, 81.2%; unexposed, 75.6%., Conclusion: With a median 10.9 years' follow-up after CLARITY/CLARITY Extension, findings suggest the sustained long-term mobility and disability benefits of cladribine tablets.

Background: In the CLARITY (CLAdRIbine Tablets treating multiple sclerosis orallY) study of patients with relapsing-remitting multiple sclerosis, treatment with cladribine tablets 3.5 mg/kg (CladT) significantly reduced the annualised relapse rate (ARR) versus placebo; this effect was sustained in CLARITY Extension, without further treatment., Objective: To assess the frequency and severity of relapses in patients treated with CladT versus placebo in CLARITY over 2 years and evaluate the durability of effect in patients who received no further treatment for 2 years in CLARITY Extension., Methods: In this post hoc analysis, ARRs were calculated for qualifying and all relapses, and qualifying and all severe relapses (i.e. requiring steroid treatment or leading to hospitalisation) in patients treated with CladT ( n  = 433) and placebo ( n  = 437) in CLARITY, and those from the CladT group who received placebo in CLARITY Extension ( n  = 98)., Results: At Month 6, Year 1 and Year 2, patients receiving CladT had a significantly lower risk of qualifying or all relapses (all p  < 0.0001), and qualifying or all severe relapses (all p  < 0.005), compared with placebo. This effect was sustained in CLARITY Extension without further treatment., Conclusion: The results show durable efficacy of cladribine tablets 3.5 mg/kg for reducing frequency and severity of relapses in patients with relapsing-remitting multiple sclerosis.CLARITY: NCT00213135; CLARITY Extension: NCT00641537.

Background: Long-term safety data are of particular interest for any newly approved treatment in multiple sclerosis such as cladribine tablets 10 mg (MAVENCLAD®; 3.5 mg/kg cumulative dose over 2 years, referred to as cladribine tablets 3.5 mg/kg), which is approved in Europe and the USA. Here we provide the final report on the integrated analysis of the safety profile of cladribine tablets 3.5 mg/kg from the clinical development program, including final data from the PREMIERE registry., Methods: Safety data for cladribine tablets 3.5 mg/kg from three previously reported Phase III studies (CLARITY, CLARITY Extension and ORACLE-MS), as well as the prospective, observational PREMIERE registry (which ran from November 2009 to October 2018; consisting of patients who had participated in at least one of the Phase III trials) were combined to provide the Monotherapy Oral cohort. Serious adverse events (SAEs) and predefined SAEs of special interest were recorded. Observation-adjusted incidence rates per 100 patient-years (Adj-AE per 100 PY) were used to assess adverse events (AEs). Standardized incidence ratios for malignancies were calculated in relation to a matched GLOBOCAN reference population, and risk differences (cladribine tablets versus placebo) were estimated., Results: The Monotherapy Oral cohort comprised 923 patients who received cladribine tablets 3.5 mg/kg and 641 patients who received placebo. Overall, the reported number of SAEs was higher in the cladribine tablets 3.5 mg/kg group (133/923 [14.4%] patients with at least 1 SAE), versus the placebo group (68/641 [10.6%] patients with at least 1 SAE). Four patients in the cladribine tablets 3.5 mg/kg group had lymphopenia classified as a serious event (resulting in an Adj-AE of 0.10 per 100 PY) and 2 patients had serious herpes zoster (resulting in an Adj-AE of 0.05 per 100 PY). There were no cases in the corresponding placebo groups. There was no difference between the cladribine tablets 3.5 mg/kg group and placebo in the overall incidence of infections. However herpetic infection AEs occurred more frequently in the cladribine tablets 3.5 mg/kg group (driven primarily by herpes zoster, followed by oral herpes and herpes simplex). Overall, there was a numerical imbalance in malignancy incidence between cladribine tablets 3.5 mg/kg and placebo, with an Adj-AE of 0.26 and 0.12 per 100 PY, respectively; however the difference was not statistically significant. The rate of malignancies observed with cladribine tablets 3.5 mg/kg in the final integrated safety analysis was not different from the expected rate in the matched GLOBOCAN reference population (standardized incidence ratio, 0.88; 95% CI, 0.44-1.69)., Conclusion: Additional patient-years of observation do not significantly alter the conclusions of earlier interim analyses, and no new major safety findings were identified in this consolidated analysis of safety data of cladribine tablets 3.5 mg/kg monotherapy in patients with relapsing-remitting multiple sclerosis., (Copyright © 2020. Published by Elsevier B.V.)

Introduction: Although use of contraception was pre-specified during cladribine clinical trials for multiple sclerosis, some pregnancies did occur., Objective: This analysis reports on pregnancy outcomes in the cladribine clinical development program., Methods: Pregnancy outcomes in female patients (direct pregnancies) and those arising from partner pregnancies (i.e., female partners of male study participants with multiple sclerosis) were evaluated from an integrated safety analysis of ten studies of cladribine in multiple sclerosis (nine clinical trials and a long-term safety registry), with patients treated with cladribine tablets, parenteral cladribine, or placebo (all-exposed cohort; 1976 patients received cladribine and 802 received placebo). Pregnancies that occurred during the 'at-risk' period for cladribine (during treatment or within 6 months thereafter) are reported as a separate group., Results: In the all-exposed cohort, 70 direct pregnancies occurred among 62 female patients (cladribine, n = 49; placebo, n = 21). Pregnancy outcomes were: live births (cladribine, n = 19 [38.8%]; placebo, n = 9 [42.9%]), elective terminations (cladribine, n = 14 [28.6%]; placebo, n = 4 [19.0%]), spontaneous abortions (cladribine, n = 11 [22.4%]; placebo, n = 5 [23.8%]), and therapeutic terminations (cladribine, n = 5 [10.2%]; placebo, n = 2 [9.5%]); in the remaining placebo recipient, the pregnancy outcome was unknown. There were two reports of congenital malformations (cladribine, n = 1; placebo, n = 1), both of which occurred with pregnancies arising > 2 years after exposure to the last dose of study medication. Sixteen direct pregnancies occurred during the 'at-risk' period for cladribine; outcomes for these were: live births, n = 3 (18.8%); elective terminations, n = 10 (62.5%); spontaneous abortions, n = 2 (12.5%); and therapeutic terminations, n = 1 (6.2%). Corresponding findings for direct pregnancies among placebo recipients were (n = 11): live births, n = 5 (45.5%); elective terminations, n = 2 (18.2%); spontaneous abortions, n = 3 (27.3%); and unknown, n = 1 (9.1%). No cases of congenital malformation were reported for pregnancies during the 'at-risk' period. There were an additional nine partner pregnancies in female partners of cladribine-treated male patients, all of which resulted in live births; of these, two pregnancies occurred within the 'at-risk' period for cladribine., Conclusions: While limited by the small number of pregnancies and related data from the cladribine clinical development program, highlighting the need for further study, the observations made in the present analysis were generally consistent with epidemiological data on pregnancy outcomes for the general population or women with multiple sclerosis. There were no congenital malformations in pregnancies that occurred during cladribine treatment or within 6 months after the last dose. As the data available for cladribine-exposed pregnancies in patients with multiple sclerosis are limited, a non-interventional post-authorization safety study has been initiated to obtain more information on this subject., Clinical Trial Registration: CLARITY: NCT00213135; CLARITY Extension: NCT00641537; ORACLE MS: NCT00725985; ONWARD: NCT00436826; PREMIERE: NCT01013350.

Background: Cladribine tablets 3.5 mg/kg cumulative over 2 years (CT3.5) had significant clinical/imaging effects in patients with clinically isolated syndrome (CIS; ORACLE-MS) or relapsing-remitting MS (RRMS; CLARITY and CLARITY Extension). This analysis compared the effect of cladribine tablets on the dynamics of immune cell reduction and reconstitution in ORACLE-MS, CLARITY, and CLARITY Extension during the first year of treatment (i.e. the first course of CT1.75) in patients randomized to CT3.5., Methods: Lymphocyte subtypes were analyzed using multiparameter flow cytometry. Changes in cell counts and relative proportions of lymphocytes were evaluated at weeks 5, 13, 24, and 48., Results: Across studies, consistent and comparable selective kinetics of immune cell populations occurred following the first treatment year with CT. A rapid reduction in CD16 + /CD56 + cells (week 5 nadir), a more marked reduction in CD19 + B cells (week 13 nadir), and a less-pronounced effect on CD4 + (week 13 nadir) and CD8 + T cells (week 24 nadir) was shown. There was little effect on neutrophils or monocytes. Lymphocyte recovery began after treatment with CT3.5. Regarding relative proportions of naïve and memory T-cell subtypes in ORACLE-MS, the proportion of naïve-like naturally occurring T-regulatory cells (nTregs) decreased, and the proportion of memory-like nTregs increased, relative to total CD4 + T cells., Conclusions: CT3.5 has comparable effects on the immune systems of patients with CIS or RRMS. The pronounced reduction and recovery dynamics of CD19 + B cells and relative changes in the proportion of some immune cell subtypes may underlie the clinical effects of CT3.5., Competing Interests: Conflict of interest statement: OS serves on the editorial boards of the Multiple Sclerosis Journal, and Therapeutic Advances in Neurological Disorders. He has served on data monitoring committees for Genentech-Roche, Pfizer, and TG Therapeutics without monetary compensation. He has advised EMD Serono, Celgene, Genzyme, and Serono. He currently receives grant support from Sanofi Genzyme. He received travel support from Shire PSS has served on advisory boards for Biogen, Merck KGaA, Novartis, Teva, MedDay Pharmaceuticals, and GSK; on steering committees or independent data monitoring boards in trials sponsored by Merck KGaA, Teva, GSK, and Novartis; has received speaker honoraria from Biogen Idec, Merck KGaA, Teva, Sanofi-Aventis, Genzyme, and Novartis. His department has received research support from Biogen, Merck KGaA, Teva, Novartis, Roche, and Genzyme. TL has received consultancy fees or clinical research grants from Acorda, Bayer, Biogen, Daiichi, EMD Serono, Novartis, ONO, Pfizer, and Teva Neuroscience. GG has received speaker honoraria and consulting fees from Abbvie, Actelion, Atara Bio, Almirall, Bayer Schering Pharma, Biogen Idec, FivePrime, GlaxoSmithKline, GW Pharma, Merck & Co., Merck KGaA, Pfizer Inc, Protein Discovery Laboratories, Teva Pharmaceutical Industries Ltd, Sanofi-Genzyme, UCB, Vertex Pharmaceuticals, Ironwood, and Novartis; and has received research support unrelated to this study from Biogen Idec, Merck & Co, Novartis, and Ironwood. YH, DD, FD, and UB are employees of EMD Serono Research & Development Institute Inc., a business of Merck KGaA, Darmstadt, Germany.

Background: Treating patients with relapsing multiple sclerosis (MS) with cladribine tablets (two times 4 or 5 days of treatment each year for 2 years) results in long-lasting efficacy, with continued stability in many patients for 4 or more years. Safety and tolerability outcomes from individual clinical studies with cladribine tablets have been reported previously., Objective: Report safety data from an integrated analysis of clinical trials and follow-up in patients with MS to further characterize the safety profile of cladribine tablets., Methods: Data for patients treated with cladribine tablets 10 mg (MAVENCLAD ® ; 3.5 mg/kg cumulative dose over 2 years, referred to as cladribine tablets 3.5 mg/kg) as monotherapy (n = 923) or placebo (n = 641) in Phase III clinical trials (CLARITY, CLARITY Extension and ORACLE-MS) and followed up in the PREMIERE registry were aggregated (Monotherapy Oral cohort). To better characterize rare events, additional data from earlier studies which involved the use of parenteral cladribine in patients with MS, and the ONWARD study, in which patients were given cladribine tablets in addition to interferon (IFN)-β or placebo plus IFN-β were included in an All Exposed cohort (cladribine, n = 1926; placebo, n = 802). Adjusted adverse events incidences per 100 patient-years (Adj-AE per 100 PY) were calculated for the integrated analyses., Results: The incidence rate of treatment-emergent adverse events (TEAEs) in the Monotherapy Oral cohort was 103.29 vs. 94.26 Adj-AEs per 100 PY for placebo. TEAEs that occurred more frequently with cladribine tablets were mainly driven by the TEAEs of lymphopenia (Adj-AE per 100 PY 7.94 vs. 1.06 for placebo) and lymphocyte count decreased (Adj-AE per 100 PY 0.78 vs. 0.10 for placebo) as anticipated due to the mode of action of cladribine. An increase in TEAE incidence rate was also observed in the cladribine tablets 3.5 mg/kg group vs. placebo for herpes zoster (Adj-AE per 100 PY 0.83 vs. 0.20, respectively). There were no cases of systemic, serious disseminated herpes zoster attributed to treatment with cladribine tablets. In general there was no increase in the risk of infections including opportunistic infections with cladribine tablets versus placebo, except for herpes zoster. Periods of severe lymphopenia (< 0.5 × 10 9 cells/L) were associated with an increased frequency of infections, but the nature of these was not different to that observed in the overall patient group treated with cladribine tablets 3.5 mg/kg. Within the constraints of a limited sample size, malignancy rates in the overall clinical program for cladribine in MS did not show evidence of an increase compared to placebo-treated patients and there was no increase in the incidence of malignancies over time in cladribine-treated patients., Conclusion: The AE profile for cladribine tablets 3.5 mg/kg as a monotherapy has been well-characterized in a pooled population of patients from early to more advanced relapsing MS. There was no increased risk for infections in general except for a higher incidence of herpes zoster. Lymphopenia was amongst the most frequently observed TEAEs that occurred at a higher incidence with cladribine relative to placebo. There was also no increase in malignancy rates for cladribine relative to placebo., (Copyright © 2018. Published by Elsevier B.V.)

Background: Staphylococcus aureus is a common pathogen among humans worldwide, with an increasing prevalence of multidrug resistance. The understanding of virulence factors inducing pathogenicity is still incomplete, and thus far the transfer of results from animal studies into successful clinical trials has been difficult., Methods: In this study, we established an S. aureus infection model in mice engrafted with a human immune system, compared it with infected wild-type and nonhumanized mice, and investigated pathogenesis in these models., Results: Staphylococcus aureus infection was aggravated in humanized mice, compared with wild-type or nonengrafted mice. The humanized mice displayed a significantly reduced survival percentage, increased weight loss, and a more-rapid increase in bacterial burden. In addition, S. aureus infection induced T-cell activation, apoptosis, and Fas receptor expression in humanized but not wild-type mice., Conclusions: Our findings demonstrate the different pathogenetic mechanisms in wild-type and humanized mice and the possible benefit of including humanized mice in future studies involving S. aureus as a prior step to human clinical trials., (© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Objectives: The objective of the Therapy Optimization in MS (TOP MS) Study was to prospectively assess the relationship between MS disease-modifying therapy (DMT) adherence and MS relapse risk over 2 years., Methods: Potential participants were recruited for TOP MS by specialty pharmacies who dispensed glatiramer acetate and beta interferons for MS nationwide. Signed IRB-approved informed consents were returned to the pharmacies. TOP MS used electronic data capture with monthly patient entries. Adherence, measured by medication possession ratio (MPR), was derived from pharmacy shipment records. Logistic regression examined the association between protocol-defined relapses and DMT MPR (<0.5; >0.5-<0.9; >0.9)., Results: TOP MS enrolled 3151 persons with MS, and 2410 completed the full 2 years. Across all therapies, the mean MPR for the 2-year completer cohort of 2049 who maintained the same DMT was 0.9+0.2 (range: 0.1-1.0), with 63.8% reaching a 2-year MPR >0.9. Evaluated by categories of MPR, the proportion of participants remaining relapse-free for 24 months increased with increasing MPR, and the proportion with >1 relapses declined with increasing levels of MPR (p<0.0008). Regression analysis revealed the odds of relapse for a patient in the MPR >0.9 MPR group was 64% that of a patient in the MPR <0.5 category (p=0.02). Use of >1 DMT prior to the current one was an independent predictor of relapse., Conclusions: The study provides class III evidence that improvement in adherence to DMT for MS is associated with improved clinical outcomes as measured by relapse reduction., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Data sources for MS research are numerous but rarely provide an objective measure of drug therapy compliance coupled with patient-reported health outcomes. The objective of this paper is to describe the methods and baseline characteristics of the Therapy Optimization in MS (TOP MS) study designed to investigate the relationship between disease-modifying therapy compliance and health outcomes., Methods: TOP MS was designed as a prospective, observational, nationwide patient-focused study using an internet portal for data entry. The protocol was reviewed and approved by Sterling IRB. The study was registered with ClinicalTrials.gov. It captured structured survey data monthly from MS patients recruited by specialty pharmacies. Data collection included the clinical characteristics of MS such as MS relapses. Disability, quality of life and work productivity and activity impairment were assessed quarterly with well-validated scales. When events like severe fatigue or new or worsening depression were reported, feedback was provided to treating physicians. The therapy compliance measure was derived from pharmacy drug shipment records uploaded to the study database. The data presented in this paper use descriptive statistics., Results: The TOP MS Study enrolled 2966 participants receiving their disease-modifying therapy (DMT) from specialty pharmacies. The mean age of the sample was 49 years, 80.4% were female, 89.9% were Caucasian and 55.7% were employed full or part time. Mean time since first symptoms was 11.5 years; mean duration since diagnosis was 9.5 years. Patient-reported EDSS was 3.5; 72.2% had a relapsing-remitting disease course. The most commonly reported symptoms at the time of enrollment were fatigue (74.7%), impaired coordination or balance (61.8%) and numbness and tingling (61.2%). Half of the sample was using glatiramer acetate and half was using beta-interferons., Conclusion: Demographic and clinical characteristics of the TOP MS sample at enrollment are consistent with other community-based MS samples, and the sample appears to be representative of DMT users in the US. TOP MS data can be used to explore the associations between disease-modifying therapy compliance and health outcomes., Trial Registration: ClinicalTrials.gov (NCT00819000).

Multiple sclerosis (MS) affects an estimated 300,000 individuals in the United States. No cure exists and although there is a lack of consensus on management, strategies to modify disease course are available. These strategies involve initiating disease-modifying therapies that have been found to slow disease progression and prevent disability symptoms, thereby improving function for MS patients. The overall goal of early disease management is to intervene prior to irreversible neuronal destruction in order to delay disability progression and improve quality of life. Maintaining a lower level of disability for a longer period of time postpones and ultimately attempts to prevent reaching a level of immobility and irreversible disability. However, due to the complex nature of disease and its unique, individual patient course, no patient can be treated alike and no patient responds to therapy similarly. Therefore, MS research is continuous in its evolution of therapeutic development, focusing on neuroprotective effects and agents with distinctive mechanisms of action allowing for unique safety and efficacy profiles. Investigations include novel oral agents and monoclonal antibodies. Many of the approved agents also are continually being investigated in order to evaluate comparative data, the most appropriate means of implementing subsequent therapy upon failure, responsiveness to therapeutic agent when switched, and long-term safety and efficacy. This multimedia webcast educational activity will cover the current state of MS science, current therapies in MS, emerging treatments in clinical trials for MS as well as differences between physicians in diagnosis and management of MS and their evolving practices., (Copyright © 2014. Published by Elsevier Inc.)

Objective: To examine associations between multitasking ability defined by performance on a complex task integrating multiple cognitive domains and vocational functioning in multiple sclerosis (MS)., Design: Survey data collection., Setting: Laboratory with referrals from an outpatient clinic., Participants: Community-dwelling individuals with MS (N=30) referred between October 2011 and June 2012., Interventions: Not applicable., Main Outcome Measures: The modified Six Elements Test (SET) to measure multitasking ability, Fatigue Severity Scale to measure fatigue, several neuropsychological measures of executive functioning, and vocational status., Results: Among the sample, 60% of individuals have reduced their work hours because of MS symptoms (cutback employment group) and 40% had maintained their work hours. Among both groups, SET performance was significantly associated with performance on several measures of neuropsychological functioning. Individuals in the cutback employment group demonstrated significantly worse overall performance on the SET (P=.041). Logistic regression was used to evaluate associations between SET performance and vocational status, while accounting for neuropsychological performance and fatigue. The overall model was significant (χ(2)3=8.65, P=.032), with fatigue [Exp(B)=.83, P=.01] and multitasking ability [Exp(B)=.60, P=.043] retained as significant predictors., Conclusions: Multitasking ability may play an important role in performance at work for individuals with MS. Given that multitasking was associated with vocational functioning, future efforts should assess the usefulness of incorporating multitasking ability into rehabilitation planning., (Copyright © 2013 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Emotional processing styles appear to characterize various forms of psychopathology and environmental adversity in children. For example, autistic, anxious, high- and low-emotion conduct problem children, and children who have been maltreated, all appear to show specific deficits and strengths in recognizing the facial expressions of emotions. Until now, the relationships between emotion recognition, antisocial behaviour, emotional problems, callous-unemotional (CU) traits and early maltreatment have never been assessed simultaneously in one study, and the specific associations of emotion recognition to maltreatment and child characteristics are therefore unknown. We examined facial-emotion processing in a sample of 23 adolescents selected for high-risk status on the variables of interest. As expected, maltreatment and child characteristics showed unique associations. CU traits were uniquely related to impairments in fear recognition. Antisocial behaviour was uniquely associated with better fear recognition, but impaired anger recognition. Emotional problems were associated with better recognition of anger and sadness, but lower recognition of neutral faces. Maltreatment was predictive of superior recognition of fear and sadness. The findings are considered in terms of social information-processing theories of psychopathology. Implications for clinical interventions are discussed.

Geometric distortion caused by magnetic field inhomogeneity is generally an inevitable tradeoff for fast MRI acquisitions using echo-planar imaging. Most of the existing distortion-correction techniques require separate scans for field maps in order to correct the distortion contained in a measurement. A drawback of these current techniques is that the field map scans and the measurement can capture different patient positions, which invalidates the stationary condition. A new method was developed in this work to correct geometric distortion by using local phase shifts derived directly from the measurement itself, without the need of extra field map scans. This self-sufficient method takes advantage of parallel imaging and k-space trajectory modification to produce multiple images from a single acquisition. The measurement is also used to derive sensitivity maps for parallel imaging reconstruction. The derived phase shifts are retrospectively applied to the measurement for correction of geometric distortion in the measurement itself. The proposed method was successfully demonstrated using experimental data from a phantom and a human brain.

Observational cohort studies are a powerful tool to assess the long-term outcome in chronic diseases. This study design has been utilized in local and regional outcome studies in multiple sclerosis (MS) and has yielded invaluable epidemiological information. The World Wide Web now provides an excellent opportunity for an international, collaborative cohort study of MS outcomes. A web platform--MSBase--has been designed to collect prospective data on patients with MS. It is purely observational, enabling participating neurologists to contribute data on diagnosis, treatment and progress, to review anonymous aggregate data and to benchmark their patient population against other patient subsets or the entire dataset. MSBase facilitates collaborative research by allowing the online creation of investigator-initiated regional, national and international substudies. The registry aims to answer epidemiological questions that can only be addressed by prospective assessments of large patient cohorts. The registry is funded through the independent MSBase Foundation, and governed by an International Scientific Advisory Board. The MSBase Foundation commenced operations in July 2004 and since then, 22 neurologists from 11 countries have joined MSBase and are contributing 2400 patients to the total data pool.

The purpose of this open-label, crossover study was to determine the safety and efficacy of recombinant insulin-like growth factor-1 (rhIGF-1) using magnetic resonance imaging (MRI) and clinical measures of disease activity in seven multiple sderosis (MS) patients. Monthly clinical and MPI examinations were performed during a 24-week baseline and a 24-week treatment period with rhIGF-1. The primary outcome measure was contrast enhancing lesion (CEL) frequency on treatment compared to baseline. Secondary outcome measures included dinical and MRI measures of disease activity including: white matter lesion load (WMLL), magnetization transfer ratio (MTR), T1-Hypointensity volume, cervical spine cross-sectional area and proton magnetic resonance spectroscopic (MRS) imaging for determining regional metabolite ratios. rhIGF-1 (Cephalon) was administered at a dose of 50 mg subcutaneously twice a day for 6 months. rhIGF-1 was safe and well tolerated with no severe adverse reactions. There was no significant difference between baseline and treatment periods for any MRI or clinical measures of disease activity. Although rhIGF-1 did not alter the course of disease in this small cohort of MS patients, the drug was well tolerated. Further studies using rhIGF-1 alone or in combination with other therapies may be of value because of the proposed mechanism of action of this growth factor on the oligodendrocyte and remyelination.

Peroxynitrite has been implicated in the pathogenesis of multiple sclerosis (MS) and its animal model experimental allergic encephalomyelitis (EAE). Previously, we have shown that administration of uric acid (UA), a peroxynitrite scavenger, is therapeutic in EAE We have also shown that MS patients have lower levels of serum uric acid than healthy individuals or those with other neurological diseases. The aim of this investigation was therefore to raise serum UA levels in MS patients. Oral administration of UA failed to increase low serum UA levels, evidently due to its degradation by gastrointestinal bacteria. However, serum UA could be raised and maintained at elevated levels for a year and more without reported side-effects by oral administration of its precursor inosine. Three of 11 patients given inosine showed some evidence of clinical improvement and there was no sign of disease progression in the remaining patients. Gadolinium-enhanced lesions, observed in two patients before receiving inosine, could not be detected after either 10 or IS months inosine treatment These data provide evidence that serum UA levels can be readily manipulated and that the benefit of higher levels to individuals with MS should be studied further in greater number of patients.

Effects on adhesion molecules of immune cells might contribute to the mode of action of interferon-beta (IFN-beta) in multiple sclerosis (MS). We have serially monitored the cell surface expression of integrins CD49d (VLA-4) and CD11a (LFA-1) on fresh T lymphocyte subpopulations from 5 MS patients monthly for 2 months prior to treatment and for 3 months on treatment with IFN-beta1b. In parallel, we assessed inflammatory disease activity by monthly contrast-enhanced magnetic resonance imaging (MRI). IFN-beta treatment specifically downregulated CD49d expression on CD8+ and CD4+/CD45RO+ 'memory' T lymphocytes and differentially modulated the proportion of CD4+, CD8+ and CD27+ T cells. These effects may play an important role in the reduction of central nervous system cell trafficking and inflammation in MS.

Human T lymphotropic virus type I (HTLV-I) is the causative agent of an inflammatory neurological disease termed HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). An ongoing lymphocyte activation exists in patients with HAM/TSP, which was demonstrated by the spontaneous proliferation of their PBMC ex vivo. It was shown that spontaneous proliferation present in HAM/TSP is due, in part, to an IL-2/IL-2R autocrine loop. However, addition of Abs against IL-2 or IL-2R alpha only partially inhibited the spontaneous proliferation. Since IL-15 is a cytokine with similar functional characteristics to those of IL-2, we reasoned that IL-15 might be an additional growth factor that contributes to the spontaneous proliferation observed in HAM/TSP. In this study, we demonstrated that IL-15 mRNA expression was elevated in PBMC obtained from HAM/TSP patients when compared with those of the normal donors. Furthermore, we showed that the addition of blocking Abs against IL-15 or its receptor inhibited the spontaneous proliferation of HAM/TSP PBMC. Addition of Abs directed toward both IL-15 and IL-2, or their receptors, inhibited the proliferation almost completely. These data suggest the existence of two autocrine loops involving IL-15/IL-15R and IL-2/IL-2R, both contributing to the spontaneous proliferation of HAM/TSP PBMC.

Neutralizing polyclonal antibodies raised in rabbits against glycosylated natural human gamma-interferon (nIFN-gamma) and unglycosylated recombinant IFN-gamma (rIFN-gamma) were tested for their ability to bind to several polypeptides spanning the entire amino acid sequence of the rIFN-gamma molecule. Antibodies raised in four rabbits against rIFN-gamma all bound efficiently to relatively large polypeptides whose sequences started from the amino-terminus, rIFN-gamma 1-48, 1-59, 1-80, and the internal polypeptide IFN-gamma 81-120. These antibodies bound poorly or not at all to the following polypeptides: IFN-gamma 1-20, 24-59, 36-59, 87-96, 121-137, 121-146, 138-146. In contrast, antibodies raised in four rabbits against nIFN-gamma in general bound less well to IFN-gamma 1-48, 1-59, 1-80, and 81-120. In addition, all the other polypeptides cited above were recognized to some degree by anti-nIFN-gamma antibodies. These results suggest that the oligosaccharide side-chains of nIFN-gamma cover or perturb the structure of antigenic sites present in rIFN-gamma and thus significantly modify the antigenic properties of the IFN-gamma molecule.

Four oligopeptides corresponding to overlapping regions of the human leucocyte interferon alpha 1 (IFN) amino acid sequence have been synthesized by the solid-phase method. The physicochemical properties of these peptides were investigated by analytical ultracentrifugation and circular dichroism, absorbance, and fluorescence spectroscopies. IFNs 24-81 and 111-166 were shown to possess considerable ordered structure in solution. IFN 111-166 appeared to adopt a beta-stranded conformation, which could be reversibly unfolded by the addition of urea. Equimolar mixtures of IFNs 24-81 and 111-166 formed a noncovalent complex that was resistant to the formation of the Cys29-Cys139 disulfide bond found in native interferon alpha 1. Predictions of the secondary structure of interferon alpha 1 were made and the results compared to the measured properties of the fragments. In general, it was found that the prediction methods favored a highly alpha-helical conformation.

The influence of major transplantation antigens on susceptibility to T cell-mediated disease caused by infection with the noncytopathic virus lymphocytic choriomeningitis virus (LCMV) was evaluated in B10 H-2-congenic mice. Susceptibility to early T cell-mediated liver cell destruction (day 7-9) and early mortality (before day 12) was H-2Dq linked and correlated directly with early (day 6-8) and high cytotoxic T cell activity. In contrast, susceptibility to become an LCMV carrier, inability to rapidly clear virus, or tendency to develop late hepatitis (day 14-17) was linked to Dk and correlated with absence of early cytotoxic T cell activity. Thus, H-2D-regulated T cell-immune responses controlling both virus spread and immunopathology may directly determine the type and severity of disease. The results illustrate that susceptibility to disease caused by one virus may be linked to distinct MHC alleles dependent upon the disease parameter studied.

The lymphocytic choriomeningitis virus (LCMV) isolates Docile (D) and Aggressive (A) of Pfau et al. were studied in various strains of mice. Disease susceptibility, assessed as mortality and time to death to LCMV-D or -A varied greatly amongst mouse strains, and all four possible susceptibility patterns were observed: susceptibility to both (e.g. SWR/J), resistance to both (e.g. DBA/2), susceptibility to A but resistance to D (C57BL/6), or vice versa (CBA/J). Irrespective of the virus isolate or the mouse strain tested, susceptibility correlated with both early and high cytotoxic T cell activity found in spleens or leptomeningeal infiltrates, and with early and high primary footpad swelling reaction after local infection. C57BL/6 mice infected with A or SWR/J infected with A or with D showed, in both test systems, early and high activities; in contrast, DBA/2 mice infected with either D or A, and C57BL/6 infected with D showed no or only slow and low responses in both tests. Early and high LCMV-specific cytotoxic T cell activity, and the rapidity and extent of the primary footpad reaction directly correlated with susceptibility to LCM and all were dominantly regulated by H-2D.

Synthetic polypeptides corresponding to hydrophilic regions of human interferon gamma (HuIFN gamma) based on the amino acid sequence of HuIFN gamma inferred from its cDNA sequence were used to produce antibodies in rabbits which reacted with the polypeptides and which might also be expected to recognise native HuIFN gamma. Groups of 3 or 4 rabbits were immunised with synthetic polypeptides corresponding to HuIFN gamma amino acid sequences 1-20, 1-59, 24-59, 36-59 and 87-96 which included major hydrophilic domains of the IFN gamma molecule. All the rabbits produced antibodies which recognised the polypeptide immunogen, but to date only 1 of 4 rabbits immunised with polypeptide 24-59 and 1 of 3 rabbits immunised with polypeptide 1-59 have produced antibodies which also recognise native HuIFN gamma. The positively reacting antiserum from the rabbit immunised with polypeptide 24-59 could only be shown to weakly bind to HuIFN gamma, whereas the positively reacting antiserum from the rabbit immunised with polypeptide 1-59 was shown to both weakly bind to HuIFN gamma and weakly neutralise its in vitro antiviral effect. The results so far obtained suggest that the amino acid sequences close to the N-terminus are important for biological activity.

A model for immunologically T cell-mediated hepatitis was established in mice infected with lymphocytic choriomeningitis virus (LCMV). The severity of hepatitis was monitored histologically and by determination of changes in serum levels of the enzymes alanine aminotransferase (ALT), aspartate aminotransferase (AST), glutamate dehydrogenase (GLDH), and alkaline phosphatase (AP). Kinetics of histological disease manifestations, increases of liver enzyme levels in the serum, and cytotoxic T cell activities in livers and spleens all correlated and were dependent upon several parameters: LCMV-isolate; LCMV-WE caused extensive hepatitis, LCMV-Armstrong virtually none. Virus dose. Route of infection; i.v. or i.p. infection caused hepatitis, whereas infection into the footpad did not. The general genetic background of the murine host; of the strains tested, Swiss mice and A-strain mice were more susceptible than C57BL or CBA mice; BALB/c and DBA/2 mice were least susceptible. The degree of immunocompetence of the murine host; T cell deficient nu/nu mice never developed hepatitis, whereas nu/+ or +/+ mice always did. B cell-depleted anti-IgM-treated mice developed immune-mediated hepatitis comparably or even more extensively than control mice. Local cytotoxic T cell activity; mononuclear cells isolated from livers during the period of overt hepatitis were two to five times more active than equal numbers of spleen cells. Adoptive transfer of nylon wool-nonadherent anti-Thy-1.2 and anti-Lyt-2 plus C-sensitive, anti-L3T4 plus C-resistant lymphocytes into irradiated mice preinfected with LCMV-WE caused a rapid time- and dose-dependent linear increase of serum enzyme levels. This increase was caused by adoptive transfer of lymphocytes if immune cell donors and recipient mice shared class I, but not when they shared class II histocompatibility antigens. The donor cell dose-dependent increase of these enzymes was first measurable 6-18 h after transfer with 2 X 10(8) cells or 3 X 10(6) cells, respectively. The time-dependent increase caused by the adoptive transfer of 1-2 X 10(8) cells was strictly linear during a period of up to 25-40 h. These results indicate single-hit kinetics of liver cell death and suggest that effector T cells destroy infected liver cells via direct contact rather than via soluble toxic mediators. The results may represent the best in vivo correlate of the in vitro 51Cr-release assay that has been analyzed so far, and strongly support the view that antiviral cytotoxic T cells are directly cytolytic in vivo.(ABSTRACT TRUNCATED AT 400 WORDS)