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MRI and clinical features of myelin oligodendrocyte glycoprotein (MOG)-antibody disease may overlap with those of other inflammatory demyelinating conditions posing diagnostic challenges, especially in non-acute phases and when serologic testing for MOG antibodies is unavailable or shows uncertain results. We aimed to identify MRI and clinical markers that differentiate non-acute MOG-antibody disease from aquaporin 4 (AQP4)-antibody neuromyelitis optica spectrum disorder and relapsing remitting multiple sclerosis, guiding in the identification of patients with MOG-antibody disease in clinical practice. In this cross-sectional retrospective study, data from 16 MAGNIMS centres were included. Data collection and analyses were conducted from 2019 to 2021. Inclusion criteria were: diagnosis of MOG-antibody disease; AQP4-neuromyelitis optica spectrum disorder and multiple sclerosis; brain and cord MRI at least 6 months from relapse; and Expanded Disability Status Scale (EDSS) score on the day of MRI. Brain white matter T2 lesions, T1-hypointense lesions, cortical and cord lesions were identified. Random forest models were constructed to classify patients as MOG-antibody disease/AQP4-neuromyelitis optica spectrum disorder/multiple sclerosis; a leave one out cross-validation procedure assessed the performance of the models. Based on the best discriminators between diseases, we proposed a guide to target investigations for MOG-antibody disease. One hundred and sixty-two patients with MOG-antibody disease [99 females, mean age: 41 (±14) years, median EDSS: 2 (0–7.5)], 162 with AQP4-neuromyelitis optica spectrum disorder [132 females, mean age: 51 (±14) years, median EDSS: 3.5 (0–8)], 189 with multiple sclerosis (132 females, mean age: 40 (±10) years, median EDSS: 2 (0–8)] and 152 healthy controls (91 females) were studied. In young patients (

Background and ObjectivesRelapsing-remitting multiple sclerosis (RRMS), aquaporin-4 antibody–positive neuromyelitis optica spectrum disorder (AQP4-NMOSD), and myelin oligodendrocyte glycoprotein antibody–associated disease (MOGAD) may have overlapping clinical features. There is an unmet need for imaging markers that differentiate between them when serologic testing is unavailable or ambiguous. We assessed whether imaging characteristics typical of MS discriminate RRMS from AQP4-NMOSD and MOGAD, alone and in combination.MethodsAdult, nonacute patients with RRMS, APQ4-NMOSD, and MOGAD and healthy controls were prospectively recruited at the National Hospital for Neurology and Neurosurgery (London, United Kingdom) and the Walton Centre (Liverpool, United Kingdom) between 2014 and 2019. They underwent conventional and advanced brain, cord, and optic nerve MRI and optical coherence tomography (OCT).ResultsA total of 91 consecutive patients (31 RRMS, 30 APQ4-NMOSD, and 30 MOGAD) and 34 healthy controls were recruited. The most accurate measures differentiating RRMS from AQP4-NMOSD were the proportion of lesions with the central vein sign (CVS) (84% vs 33%, accuracy/specificity/sensitivity: 91/88/93%,p< 0.001), followed by cortical lesions (median: 2 [range: 1–14] vs 1 [0–1], accuracy/specificity/sensitivity: 84/90/77%,p= 0.002) and white matter lesions (mean: 39.07 [±25.8] vs 9.5 [±14], accuracy/specificity/sensitivity: 78/84/73%,p= 0.001). The combination of higher proportion of CVS, cortical lesions, and optic nerve magnetization transfer ratio reached the highest accuracy in distinguishing RRMS from AQP4-NMOSD (accuracy/specificity/sensitivity: 95/92/97%,p< 0.001). The most accurate measures favoring RRMS over MOGAD were white matter lesions (39.07 [±25.8] vs 1 [±2.3], accuracy/specificity/sensitivity: 94/94/93%,p= 0.006), followed by cortical lesions (2 [1–14] vs 1 [0–1], accuracy/specificity/sensitivity: 84/97/71%,p= 0.004), and retinal nerve fiber layer thickness (RNFL) (mean: 87.54 [±13.83] vs 75.54 [±20.33], accuracy/specificity/sensitivity: 80/79/81%,p= 0.009). Higher cortical lesion number combined with higher RNFL thickness best differentiated RRMS from MOGAD (accuracy/specificity/sensitivity: 84/92/77%,p< 0.001).DiscussionCortical lesions, CVS, and optic nerve markers achieve a high accuracy in distinguishing RRMS from APQ4-NMOSD and MOGAD. This information may be useful in clinical practice, especially outside the acute phase and when serologic testing is ambiguous or not promptly available.Classification of EvidenceThis study provides Class II evidence that selected conventional and advanced brain, cord, and optic nerve MRI and OCT markers distinguish adult patients with RRMS from AQP4-NMOSD and MOGAD.

ObjectiveAssessing the risk of clinical and radiological reactivation during pregnancy and post partum in women with multiple sclerosis (MS) treated with natalizumab (NTZ) throughout pregnancy (LONG_EXP) compared with women interrupting treatment before (NO_EXP) and within >−30 days and ≤90 days from conception (SHORT_EXP), and describing newborns’ outcomes.MethodsMaternal clinical and radiological outcomes and obstetric and fetal outcomes were retrospectively collected and compared among groups (NO_EXP, SHORT_EXP, LONG_EXP). Predictors of clinical and radiological reactivation were investigated through univariable and multivariable analysis.Results170 eligible pregnancies from 163 women referring to 29 Italian MS centres were included. Annualised relapse rate (ARR) was significantly lower in LONG_EXP (n=66, 0.02 (0.001–0.09)) compared with NO_EXP (n=31, 0.43 (0.21–0.75), p=0.002) and SHORT_EXP (n=73, 0.46 (0.30–0.66), p=0.0004) during pregnancy, and in LONG_EXP (0.12 (0.05–0.24)) compared with SHORT_EXP (0.30 (0.17–0.50), p=0.008) during post partum. Gadolinium-enhancing (Gd+) lesions were less frequent in LONG_EXP (n=6/50, 2.00%) compared with NO_EXP (n=9/21, 42.86%) and SHORT_EXP after delivery (n=17/49, 34.69%, p=0.010).Delaying NTZ resumption after delivery significantly increased the risk of relapses (OR=1.29 (95% CI 1.07 to 1.57), p=0.009) and Gd+ lesions (OR=1.49 (95% CI 1.17 to 1.89, p=0.001). Newborns’ weight, length, head circumference and gestational age did not differ among groups after adjusting for confounders. Anaemia was tracked in 4/69 LONG_EXP newborns. Congenital anomaly rate was within the expected range for the untreated MS population.ConclusionsOur findings indicate that in women with MS treated with NTZ before conception, continuation of NTZ throughout pregnancy and its early resumption after delivery mitigate the risk of clinical and radiological reactivation. This approach has no major impact on newborns’ outcomes.

IntroductionNo evidence of disease activity (NEDA) is a treatment goal when using disease modifying therapy for treating relapsing remitting multiple sclerosis (RRMS).1 However, predicting which patients may achieve NEDA is challenging.ObjectiveTo identify the baseline clinical and MRI features that predict NEDA in patients initiating dimethyl fumarate (DMF).Method: In our observational study, we retrospectively collected clinical and radiological data acquired for patients with RRMS initiating DMF. Demographics and clinical details at MS onset and at DMF initiation (baseline) were evaluated. We investigated the associations between all the baseline clinical and MRI findings and NEDA at 24 months using a combined multiple logistic regression.ResultsWe had a total of 670 patients in our cohort and only 339 (50%) achieved NEDA at 24 months. Lower EDSS (Log odds[95%CI]= -0.19[-0.30 to -0.03], p=0.01), lower number of new MRI lesions at baseline (Log odds[95%CI]= -0.14[-0.32 to -0.04], p=0.01) and lower number of relapses in the previous 12 months (Log odds[95%CI]= -0.39[-0.77 to -0.26], p=0.0001) significantly predicted NEDA at 24 months.ConclusionSignificant predictors for achieving NEDA were the number of relapses in the previous year, the number of new MRI lesions and the EDSS at DMF initiation. This could be useful in clinical practice to counsel patients regarding their potential response to DMF.

The MS-STAT2 study is a Phase III, 3 year multi-centre, randomised, placebo-controlled trial assessing the efficacy of 80mg simvastatin vs. placebo in secondary progressive multiple sclerosis (SPMS). Building upon the promising results of the MS-STAT1 study, it is an academically led study funded through a collaboration of the NIHR HTA, MS Society (UK), National MS Society (US), and the Rosetrees Trust.Here we will provide an update on the trial design and progress, including:The agreed trial extension periodAdaptations to recruitment targets and trial designAn update on trial sites where patients can be referredAn update on current trial progressthomas.williams@nhs.net

Background and aim There is increasing evidence suggesting that WHO body mass index (BMI) cut-off values are outdated and should not be applied to different population. To overcome misclassifications, direct measurements of percentage body fat (PBF) would be a better tool for preobesity and obesity diagnosis. The aim of this study was to analyze the body composition in a adult population in Centre-South of Italy, by age and gender, and to verify the accordance between BMI and PBF cut-off points for health status classification. Methods The total subject pool cover a total of 4408 participants adults. A completed screening of anthropometry and body composition by Dual X-ray Absorptiometry, (DXA) was assessed on 3.258 subjects. Results Distributions and quantitative reliable estimates of PBF, total body fat and lean, according to gender and age are provided. The prevalence of "at risk" subjects (preobese and obese) was 69% and 85%, for men and women respectively, according to PBF cut-off points. The agreement of BMI and PBF categories resulted low for the total and male population, even scarce for female population (all P≤0.001). The false negative classification of BMI was stronger for women than men and for younger than older subjects. Conclusions Screening for adiposity in subjects with a normal BMI could better identify those at higher risk for cardiometabolic disturbances and cardiovascular mortality. The herein used cut-offs points of PBF, by age and gender, may provide a useful reference in clinical settings and public health services, in particular for the Italian Caucasian population.

Tumor necrosis factor (TNF)-α is a pro-inflammatory cytokine associated with psoriasis pathogenesis. Anti-TNF-α therapies are effective in psoriasis. A significant weight gain has been reported in patients treated with anti-TNF-α agents. The aim of the present study was to evaluate the body composition changes in psoriatic patients receiving anti-TNF-α therapies according with disease phenotype. Forty patients affected with psoriasis were followed up for 24 weeks and divided into two groups: psoriasis vulgaris (PsO) and psoriatic arthritis (PsA). Anthropometric, blood biochemical, body composition parameters, resting metabolic rate, and disease activity indexes were measured at baseline and at week 24. After 24 weeks of anti-TNF-α administration, the disease activity indexes and concentration of inflammatory markers were significantly decreased. Seventy-five percent of PsO and 60% of PsA patients had an increase in body weight. Weight changes correlated with fat mass gain in the PsO group, and with fat and lean mass gain in the PsA group. In the present study, we demonstrated that a blockage of TNF-α bioactivity is related with fat and lean mass gain in both PsO and PsA subjects. The anti-TNF-α therapies could play a key role in the cross talk between adipose tissue and skeletal muscle, mediated by the reduction of TNF-α and interleukin-6 production.

Background Although TNF-α blockade is a very effective therapy for psoriasis, not all patients achieve a favorable outcome. The association between IL-6 and psoriasis has been investigated but no papers have focused on the pharmacogenetics of IL-6. Objective To examine whether the G or the C allele, at position -174 in the promoter of IL-6, influences the relationships between body weight, body composition, and therapeutic response to TNF-α blockers in psoriasis. Methods Sixty patients with psoriasis were studied, at baseline and 6-month follow-up after therapy. Assessment of the -174G/C IL-6 polymorphism, Psoriasis Area and Severity Index and Disease Activity Score-28 scores, body weight (kg), BMI, body composition by Dual-energy X-ray absorptiometry, and systemic inflammation was performed. Results Relevant body composition changes occurred after therapy. Normal weight participants showed a greater increase in fat mass than lean mass, compared with obese participants. According to their genotypes, C(+) carriers showed a greater increase in lean mass and fat mass, at the abdominal region, with respect to C(-) carriers. C(+) carriers outweighed C(-) carriers in the group of treatment responders. A higher number of responders were present among normal weight participants, with respect to obese participants. Obesity and the -174G/C IL-6 polymorphism predicted poor response to TNF-α blockers [odds ratio for C(-) carriers, obese: 2.00 (confidence interval: 1.19-3.38; P≤0.05)]. Conclusion Our data show that the G allele of the -174G/C IL-6 polymorphism and obesity can be considered as risk factors for the prognosis and management of psoriasis. This is the first study to suggest the -174G/C IL-6 polymorphism as a novel genetic marker of responsiveness to TNF-α blockers in psoriasis.

Tumor necrosis factor (TNF)-α is a pro-inflammatory cytokine associated with psoriasis pathogenesis. Anti-TNF-α therapies are effective in psoriasis. A significant weight gain has been reported in patients treated with anti-TNF-α agents. The aim of the present study was to evaluate the body composition changes in psoriatic patients receiving anti-TNF-α therapies according with disease phenotype. Forty patients affected with psoriasis were followed up for 24 weeks and divided into two groups: psoriasis vulgaris (PsO) and psoriatic arthritis (PsA). Anthropometric, blood biochemical, body composition parameters, resting metabolic rate, and disease activity indexes were measured at baseline and at week 24. After 24 weeks of anti-TNF-α administration, the disease activity indexes and concentration of inflammatory markers were significantly decreased. Seventy-five percent of PsO and 60% of PsA patients had an increase in body weight. Weight changes correlated with fat mass gain in the PsO group, and with fat and lean mass gain in the PsA group. In the present study, we demonstrated that a blockage of TNF-α bioactivity is related with fat and lean mass gain in both PsO and PsA subjects. The anti-TNF-α therapies could play a key role in the cross talk between adipose tissue and skeletal muscle, mediated by the reduction of TNF-α and interleukin-6 production.

The Hepatitis C virus E1 and E2 envelope proteins are the major players in all events required for virus entry into target cells. In addition, the recently developed HCV cell culture system has indicated that E1E2 heterodimer formation is a prerequisite for viral particle production. In this paper, we explored a new genetic approach to construct intergenotypic 2a/1b chimeras, maintaining the structural region of the infectious strain JFH1 and substituting the soluble portion of E1 and/or E2 proteins. This strategy provides useful information on the role of the surface-exposed domain of the envelope proteins in virus morphogenesis and allows comparative analysis of different HCV genotypes. We found that substituting the E2 protein ectodomain region abolishes the production of chimeric infectious particles. Our data indicate that the soluble part of the E2 protein is involved in a genotype-specific interplay with remaining viral proteins that affect the HCV assembly process.

Hepatitis C Virus E1E2 heterodimers are components of the viral spike. Although there is a general agreement on the necessity of the co-expression of both E1 and E2 on a single coding unit for their productive folding and assembly, in a previous study using an in vitro system we obtained strong indications that E1 can achieve folding in absence of E2. Here, we have studied the folding pathway of unescorted E1 from stably expressing CHO cells, compared to the folding observed in presence of the E2 protein. A DTT-resistant conformation is achieved by E1 in both situations, consistent with the presence of an E2-independent oxidative pathway. However, while the E1E2 heterodimer is stable inside cells, E1 expressed alone is degraded within a few hours. On the other hand, the oxidation and stability of individually expressed E2 subunits is dependent on E1 co-expression. These data are consistent with E1 and E2 assisting each other for correct folding via different mechanisms: E2 assists E1 by stabilizing a semi-native conformation meanwhile E1 drives E2 towards a productive folding pathway.

There is growing evidence that interleukin-6 (IL-6) is linked to the regulation of fat mass (FM). Our previous data define the common -174GC IL-6 polymorphism as a marker for 'vulnerable' individuals at risk of age- and obesity-related diseases. An association between -174GC IL-6 polymorphism and weight loss after bariatric surgery has been demonstrated.We investigated the impact of -174GC IL-6 polymorphism on weight loss, body composition, fluid distribution and cardiometabolic changes in obese subjects, after laparoscopic adjustable gastric banding (LAGB) surgery.A total of 40 obese subjects were studied at baseline and at 6 months follow-up after LAGB surgery. Cardiometabolic and genetic assessment of -174GC IL-6 polymorphism, anthropometric, body composition and fluid distribution analysis were performed.After LAGB surgery, significant reductions in weight (Δ%=-11.66 ± 7.78, P0.001), body mass index (P0.001), total and trunk FM (kg, %) (Δ% of total FM=-22.22 ± 12.15, P0.01), bone mineral density (T-score) (P0.001), resting metabolic rate (RMR) (P0.01), and total body water and intracellular water (TBW, ICW) (P0.05) were observed. At baseline, C(-) carriers of IL-6 polymorphism had a significantly higher RMR (P0.05), free FM (kg), but less total and trunk FM (%), higher body cell mass (BCM), content of TBW (L) and ECW (extracellular water)/ICW ratio compared with C(+) carriers (P0.001). After LAGB, C(+) carriers had a significantly stronger reduction of total FM (kg), but lower bone density, compared with C(-) carriers (P0.05).Beyond the relationship between -174GC IL-6 polymorphism and body composition, this study provides first evidence about the association of IL-6 variant with fluid distribution, at baseline, and FM and bone density loss in obese subjects at 6 months follow-up after LAGB surgery. LAGB was less effective if the subjects were carrying risk genotypes, C(-) carriers, for obesity, suggesting a role of genetic variations on bariatric surgery outcomes.

The normal-weight obese (NWO) syndrome was identified in women whose body weight (BW) and BMI are normal but whose fat mass (FM) is30%. In these subjects, an early inflammatory status has been demonstrated. The aim was to verify whether oxidative stress occurs in NWO. Sixty age-matched white Italian women were studied and subdivided as follows: 20 normal-weight individuals (NW) (BMI25 kg/m(2); FM%30%); 20 NWO (BMI25 kg/m(2); FM%30%); 20 preobese-obese (OB) (BMI25 kg/m(2); FM%30%). Anthropometric, body composition (by dual-energy X-ray absorptiometry) variables, plasma levels of some cytokines, reduced glutathione (GSH), lipid hydroperoxide (LOOH), nitric oxide (NO) metabolites (NO(2)(-)/NO(3)(-)), antioxidant nonproteic capacity (ANPC) were measured and compared between groups. Glucose and lipid metabolism parameters were assessed. GSH and NO(2)(-)/NO(3)(-) levels resulted lower in OB and NWO compared to NW (P0.01). LOOH levels resulted higher in OB and NWO (P0.01). ANPC in NWO was lower than NW but higher with respect to OB (P0.01). Correlation analysis revealed strong associations between GSH levels and BW, BMI, FM% (R = -0.45, at least P0.05); waist circumference (W) (R = -0.33, P0.05); FFM% (R = 0.45, P0.01); IL-1α, IL-6, IL-10, IL-15 (R = -0.39, -0.33, -0.36 -0.34, respectively, P0.05); triglycerides (R = -0.416, P0.05). LOOH levels were negatively related to FFM% (R = -0.413, P0.05) and positively to FM%, IL-15, TNF-α, insulin, total cholesterol, low-density lipoprotein cholesterol, and triglycerides (R = 0.408, R = 0.502, R = 0.341, R = 0.412, R = 0.4036, R = 0.405, R = 0.405, respectively, P0.05). The study clearly indicates that NWO, besides being in early inflammatory status, are contextually exposed to an oxidative stress related to metabolic abnormalities occurring in obesity.

A detailed knowledge of the mechanism of virus entry represents one of the most promising approaches to develop new therapeutic strategies. However, viral fusion is a very complex process involving fusion glycoproteins present on the viral envelope. In the two hepatitis C virus envelope proteins, E1 and E2, several membranotropic regions with a potential role in the fusion process have been identified. Among these, we have selected the 314–342 E1 region. Circular Dichroism data indicate that the peptide exhibits a clear propensity to adopt a helical folding in different membrane mimicking media, such as mixtures of water with fluorinated alcohols and phospholipids, with a slight preference for negative charged bilayers. The 3D structure of E1314–342 peptide, calculated by 2D-NMR in a low-polarity environment, consists of two helical stretches encompassing residues 319–323 and 329–338 respectively. The peptide, presenting a largely apolar character, interacts with liposomes, as indicated by fluorescence and electron spin resonance spectra. The strength of the interaction and the deepness of peptide insertion in the phospholipid membrane are modulated by the bilayer composition, the interaction with anionic phospholipids being among the strongest ever observed. The presence of cholesterol also affects the peptide–bilayer interaction, favoring the peptide positioning close to the bilayer surface. Overall, the experimental data support the idea that this region of E1 might be involved in membrane destabilization and viral fusion; therefore it may represent a good target to develop anti-viral molecules.

Infection with hepatitis C virus (HCV) is still a major public health problem, and the events leading to hepatocyte infection are not yet fully understood. Combining confocal microscopy with biochemical analysis and studies of infection requirements using pharmacological inhibitors and small interfering RNAs, we show here that engagement of CD81 activates the Rho GTPase family members Rac, Rho, and Cdc42 and that the block of these signaling pathways drastically reduces HCV infectivity. Activation of Rho GTPases mediates actin-dependent relocalization of the HCV E2/CD81 complex to cell-cell contact areas where CD81 comes into contact with the tight-junction proteins occludin, ZO-1, and claudin-1, which was recently described as an HCV coreceptor. Finally, we show that CD81 engagement activates the Raf/MEK/ERK signaling cascade and that this pathway affects postentry events of the virus life cycle. In conclusion, we describe a range of cellular events that are manipulated by HCV to coordinate interactions with its multiple coreceptors and to establish productive infections and find that CD81 is a central regulator of these events.

Background/Aims The establishment of HCV replicon systems strongly improved the research on the replication processes but poorly advanced our knowledge on the subcellular localization of the structural glycoproteins, mainly due to their low expression. We sought to verify whether reinforcing E1E2 expression in the context of both HCV genomic and subgenomic replicon from either homologous or heterologous strains leads to formation of supramolecular structures including structural and nonstructural proteins. Methods Robust expression of HCV glycoproteins was achieved by stable expression of E1E2p7 from genotype 1a and 1b. Results In these cells, E1 and E2 triggered the formation of dot-like structures in which they co-localized with core and the nonstructural proteins NS3 and NS5A. Confocal microscopy analyses suggested that accumulation of HCV proteins occurs in an ER-derived subcompartment. Moreover, by labeling de novo-synthesized HCV RNA, we showed that these structures constitute a site of viral RNA synthesis. Conclusions Expression in trans of HCV glycoproteins in the context of replicative viral genome or subgenome generates accumulation of structural and nonstructural viral proteins in peculiar cytoplasmic structures. The simultaneous presence of viral RNA, structural and nonstructural protein suggests that these complexes represent not only sites of HCV replication but also potential places of viral pre-budding.

Background Mitoxantrone (MX) has been used as second line therapy for aggressive multiple sclerosis (MS). Potential cardiotoxic effects of MX limit its use; a cumulative dose of up to 100 mg/m2, has been long considered relatively safe. We calculated the frequency of cardiac side effects in MS patients treated with MX. Methods We performed a cohort study including all MS patients treated with MX at the Neurological Department of the University Hospital of Palermo, Italy. Two hundred-sixty-four MS patients diagnosed according to validated criteria were included and followed-up until the end of September 2010. Patients were treated with MX as a second line therapy if they had no previous heart diseases determined by clinical evaluation, electrocardiography, and echocardiography. Treatment administration was made at a monthly dose of 8 mg/m2 for the first three months and at a dose of 12 mg/m2 every three months. Echocardiography was routinely performed every six months. Treatment was stopped before reaching the final dose if signs had appeared of impaired heart function, confirmed left ventricular ejection fraction reduction lower to 50%, or a confirmed reduction of more than 10% with respect to the first examination. Results Heart involvement was observed in 12.4% of treated individuals, and symptomatic congestive heart failure occurred in 2.7% of the cohort. A patient had a myocardial infarction, and 3.1% showed electrocardiographic anomalies not present at baseline. Conclusion Our study confirms that cardiac adverse events associated with MX are more common than previously reported.