Periodic Bedrock Ridges at the ExoMars 2022 Landing Site: Evidence for a Changing Wind Regime.

Wind-formed features are abundant in Oxia Planum (Mars), the landing site of the 2022 ExoMars mission, which shows geological evidence for a past wet environment. Studies of aeolian bedforms at the landing site were focused on assessing the risk for rover trafficability, however their potential in recording climatic fluctuations has not been explored. Here we show that the landing site experienced multiple climatic changes in the Amazonian, which are recorded by an intriguing set of ridges that we interpret as Periodic Bedrock Ridges (PBRs). Clues for a PBR origin result from ridge regularity, defect terminations, and the presence of preserved megaripples detaching from the PBRs. PBR orientation differs from superimposed transverse aeolian ridges pointing toward a major change in wind regime. Our results provide constrains on PBR formation mechanisms and offer indications on paleo winds that will be crucial for understanding the landing site geology.

Evidence for improved systemic and local vascular function after long-term passive static stretching training of the musculoskeletal system.

KEY POINTS: Vascular function and arterial stiffness are important markers of cardiovascular health and cardiovascular co-morbidity. Transitional phases of hypoemia and hypermia, with consequent fluctuations in shear rate, occuring during repetitive passive stretching adminstration (passive stretching training) may constitute an effective stimulus to induce an amelioration in vascular function, arterial stiffness and vascular remodelling by improving central and local blood flow control mechanisms. Vascular function, arterial stiffness and vascular remodelling were evaluated before and after 12 weeks of passive stretching training and after 6 weeks from training cessation, in the femoral, popliteal (treated with stretching), and brachial arteries (untreated) of both sides. After passive stretching training, vascular function and arterial remodelling improved, and arterial stiffness decreased in all the arteries, suggesting modifications of both central and local blood flow control mechanisms. Passive stretching-induced improvements related to central mechanisms seemed to have a short duration, as they returned to pre-training baseline within 6 weeks from training cessation, whereas those more related to a local mechanism persisted in the follow-up. ABSTRACT: Acute passive stretching (PS) effects on blood flow ( Q̇ ), shear rate ( Ẏ ), and vascular function in the feeding arteries of the stretched muscle have been extensively investigated; however, few data are available on vascular adjustments induced by long-term PS training. We investigated the effects of PS training on vascular function and stiffness of the involved (femoral and popliteal) and uninvolved (brachial) arteries. Our hypothesis was that PS-induced changes in Q̇ and Ẏ would improve central and local mechanisms of Q̇ control. Thirty-nine participants were randomly assigned to bilateral PS (n = 14), monolateral PS (n = 13) or no PS training (n = 12). Vascular function was measured before and after 12 weeks of knee extensor and plantar flexor muscles' PS training by single passive limb movement and flow-mediated dilatation (FMD). Central (carotid-femoral artery PWV, PWVCF ) and peripheral (carotid-radial artery PWV, PWVCR ) arterial stiffness was measured by pulse-wave velocity (PWV), together with systolic (SBP) and diastolic (DBP) blood pressure. After PS training, increases of 30%, 25% and 8% (P < 0.05) in femoral Δ Q̇ , popliteal and brachial artery FMD%, respectively, occurred in both PS training groups. A decrease in PWVCF , PWVCR , SBP and DBP (-25%, -17%, -4% and -8%, respectively; P < 0.05) was noted. No changes occurred in controls. Vascular function improved and arterial stiffness reduced in the arteries involved and uninvolved with PS training, suggesting modifications in both central and local Q̇ control mechanisms. PS-induced improvements had a short duration in some of vascular function parameters, as they returned to baseline within 6 weeks of PS training cessation.

MicroRNAs expression in pituitary tumors: differences related to functional status, pathological features, and clinical behavior.

BACKGROUND: MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression at post-transcriptional level, having a role in many biological processes, such as control of cell proliferation, cell cycle, and cell death. Altered miRNA expression has been reported in many neoplasms, including pituitary adenomas (PAs). PURPOSE: In this study, we aimed to evaluate the expression of 20 miRNAs involved in pathways relevant to pituitary pathophysiology, in PAs and normal pituitary tissue and to correlate their expression profile with clinical and pathological features. METHODS: Pituitary tumor samples were obtained during transphenoidal surgery from patients with non-functioning (NFPA, n = 12) and functioning (n = 11, 5 GH-, 3 ACTH-, 3 PRL-omas) PAs. The expression of selected miRNAs in PAs and in normal pituitary was analyzed by RT-qPCR. miRNAs expression was correlated with demographic, clinical, and neuroradiological data and with histopathological features including pituitary hormones immunostaining, Ki-67 proliferation index, and p53 immunohistochemistry evaluation. RESULTS: All evaluated miRNAs except miR-711 were expressed in both normal and tumor pituitary tissue. Seventeen miRNAs were significantly down-regulated in pituitary tumors compared to normal pituitary. miRNAs were differentially expressed in functioning PAs or in NFPAs, as in the latter group miR-149-3p (p = 0.036), miR-130a-3p (p = 0.014), and miR-370-3p (p = 0.026) were significantly under expressed as compared to functioning tumors. Point-biserial correlation analysis demonstrated a negative correlation between miR-26b-5p and Ki-67 (p = 0.031) and between miR-30a-5p and 'atypical' morphological features (p = 0.038) or cavernous sinus invasion (p = 0.049), while 508-5p was inversely correlated with clinical aggressiveness (p = 0.043). CONCLUSIONS: In this study, we found a significant down-regulation of 17 miRNAs in PAs vs normal pituitary, with differential expression profile related to functional status and tumor aggressiveness.

Changes in energy system contributions to the Wingate anaerobic test in climbers after a high altitude expedition.

PURPOSE: The Wingate anaerobic test measures the maximum anaerobic capacity of the lower limbs. The energy sources of Wingate test are dominated by anaerobic metabolism (~ 80%). Chronic high altitude exposure induces adaptations on skeletal muscle function and metabolism. Therefore, the study aim was to investigate possible changes in the energy system contribution to Wingate test before and after a high-altitude sojourn. METHODS: Seven male climbers performed a Wingate test before and after a 43-day expedition in the Himalaya (23 days above 5.000 m). Mechanical parameters included: peak power (PP), average power (AP), minimum power (MP) and fatigue index (FI). The metabolic equivalents were calculated as aerobic contribution from O2 uptake during the 30-s exercise phase (WVO2), lactic and alactic anaerobic energy sources were determined from net lactate production (WLa) and the fast component of the kinetics of post-exercise oxygen uptake (WPCr), respectively. The total metabolic work (WTOT) was calculated as the sum of the three energy sources. RESULTS: PP and AP decreased from 7.3 ± 1.1 to 6.7 ± 1.1 W/kg and from 5.9 ± 0.7 to 5.4 ± 0.8 W/kg, respectively, while FI was unchanged. WTOT declined from 103.9 ± 28.7 to 83.8 ± 17.8 kJ. Relative aerobic contribution remained unchanged (19.9 ± 4.8% vs 18.3 ± 2.3%), while anaerobic lactic and alactic contributions decreased from 48.3 ± 11.7 to 43.1 ± 8.9% and increased from 31.8 ± 14.5 to 38.6 ± 7.4%, respectively. CONCLUSION: Chronic high altitude exposure induced a reduction in both mechanical and metabolic parameters of Wingate test. The anaerobic alactic relative contribution increased while the anaerobic lactic decreased, leaving unaffected the overall relative anaerobic contribution to Wingate test.

Is corifollitropin alfa effective in controlled ovarian stimulation among all poor ovarian responders? A retrospective comparative study.

Several studies have compared the effectiveness of corifollitropin alfa versus daily gonadotropins in poor ovarian responders (PORs) undergoing controlled ovarian stimulation (COS), showing conflicting results in terms of IVF outcomes. Given the heterogeneity of patients included in the classification of POR according to 'Bologna criteria', the aim of this study was to evaluate the impact of corifollitropin alfa in two different categories of POR distinguished according to patients' antral follicle count (AFC). We retrospectively evaluated 104 infertile POR, split into two groups according to AFC (Group A ≤ 5; Group B > 5) and subgroups according to the ovarian stimulation regimen (corifollitropin alfa plus daily gonadotropins (Subgroup 1) versus daily gonadotropins alone (Subgroup 2)). Outcome measures were total oocytes, MII oocytes, total embryos, follicular output rate (FORT), implantation rate (IR), clinical pregnancy rate (CPR), miscarriage rate (MR), and live birth rate (LBR). Subgroup A1 experienced a lower number of total oocytes, MII oocytes, total embryos, and FORT (p < .05) in comparison to Subgroup A2, while no difference was found when comparing Subgroups B1 and B2. No difference was found between subgroups even in terms of IR, CPR, MR, and LBR. In conclusion, corifollitropin alfa may be as effective as daily gonadotropins in POR with AFC > 5 undergoing COS, while it might be inferior to daily gonadotropins in POR with AFC ≤ 5.

Short communication: Activity of nisin, lipid bilayer fragments and cationic nisin-lipid nanoparticles against multidrug-resistant Staphylococcus spp. isolated from bovine mastitis.

Staphylococci are the main etiological agents of bovine mastitis. Bacteriocins and nanoparticles have emerged as promising alternatives for the future development of antimicrobial agents. This study evaluated the activity of the bacteriocin nisin and bicelles of the synthetic cationic lipid dioctadecyldimethylammonium bromide, alone and in combination, against multidrug-resistant Staphylococcus spp. strains isolated from bovine mastitis. In summary, cationic nisin/dioctadecyldimethylammonium bromide nanoparticles are shown to be a promising alternative for the control of mastitis caused by multidrug-resistant Staphylococcus spp.

Clinical response to Nabiximols correlates with the downregulation of immune pathways in multiple sclerosis.

BACKGROUND AND PURPOSE: Nabiximols (Sativex® ) is a cannabinoid-based compound used for the treatment of moderate to severe spasticity in multiple sclerosis (MS). The aim of the study was to investigate the effect of the administration of Nabiximols on blood transcriptome profile of patients with MS and to interpret it in the context of pathways and networks. METHODS: Whole-genome expression profiling was performed in whole blood of 33 subjects with MS at baseline and after 4 weeks of drug treatment. Patients were classified as responders (n = 19) and non-responders (n = 14). Pathway and network analyses on genes modulated by the drug were performed, followed by in vitro stimulation of peripheral blood mononuclear cells with pro-inflammatory agents to support the immunomodulatory properties of the drug. RESULTS: Individual effect size was modest; however, we observed a downregulation of several immune-related pathways after 4 weeks of treatment, which was more pronounced when restricting analyses to responders. Interesting hub molecules functionally related to the immune system emerged from network analysis, including NFKB1, FYN, MAP14 and TP53. The immunomodulatory properties of the drug were confirmed through in vitro assays in peripheral blood mononuclear cells collected from patients with MS. CONCLUSIONS: Our findings support the immunomodulatory activity of cannabinoids in patients with MS. Further studies in more specific cell types are needed to refine these results.

New TRAP1 and Hsp90 chaperone inhibitors with cationic components: Preliminary studies on mitochondrial targeting.

TRAP1 (Hsp75) is the mitochondrial paralog of the Hsp90 molecular chaperone family. Due to structural similarity among Hsp90 chaperones, a potential strategy to induce apoptosis through mitochondrial TRAP1 ATPase inhibition has been envisaged and a series of compounds has been developed by binding the simple pharmacophoric core of known Hsp90 inhibitors with various appendages bearing a permanent cationic head, or a basic group highly ionizable at physiologic pH. Cationic appendages were selected as vehicles to deliver drugs to mitochondria. Indeed, masses of new derivatives were evidenced to accumulate in the mitochondrial fraction from colon carcinoma cells and a compound in the series, with a guanidine appendage, demonstrated good activity in inhibiting recombinant TRAP1 ATPase and cell growth and in inducing apoptotic cell death in colon carcinoma cells.

Preoperative MRI evaluation of lesion-nipple distance in breast cancer patients: thresholds for predicting occult nipple-areola complex involvement.

AIM: To identify clinically occult nipple-areola complex (NAC) involvement using preoperative magnetic resonance imaging (MRI), to inform selection of patients eligible for nipple-sparing mastectomy (NSM) or skin-sparing mastectomy (SSM). MATERIAL AND METHODS: This was a retrospective study of 195 patients, who had preoperative breast MRI (February 2011 to January 2017) before undergoing surgical treatments (NSM or SSM) for newly diagnosed breast cancer. Tumour features at MRI (mass or non-mass lesion, diameter, lesion-NAC distance [LND]) and pathology (lesion diameter, histopathological type, receptor status) were recorded, as well as the type of surgery (NSM/SSM) and presence (NAC+) or absence (NAC-) of tumour at intraoperative evaluation of retroareolar tissue. Mann-Whitney test, Fisher's exact test, logistic regression, and receiver operating characteristic (ROC) curve analysis were used for analysis of NAC+ versus NAC- to assess variables that predict NAC tumoural involvement. RESULTS: Over the study period, NAC+ was proven histologically in 71/200 (35.5%) surgical treatments, while there were 129/200 NAC- (72 NSM and 128 SSM performed). LND at MRI was statistically (p<0.001) lower in NAC+ patients than in NAC- patients. The area under the ROC curve (0.82, 95% confidence interval [CI]: 0.76-0.88) indicated 10 mm as the best cut-off, with sensitivity of 82%, specificity of 72%, and accuracy of 79%. A 5-mm cut-off enhanced sensitivity, whereas a 15-mm cut-off favoured specificity. CONCLUSIONS: MRI is a useful tool for identifying NAC+ patients; a 10-mm cut-off for LND assists selection of patients for NSM, although intraoperative retroareolar tissue examination remains mandatory.

Basal vitamin D levels and disease activity in multiple sclerosis patients treated with fingolimod.

BACKGROUND: Several studies have shown an association between 25-hydroxyvitamin D (25[OH]D) levels and multiple sclerosis (MS) susceptibility and/or level of disease activity in patients treated with first line drugs. AIMS: To investigate whether baseline 25[OH]D values could influence disease activity also during treatment with the second-line drug fingolimod (FTY). PATIENTS AND METHODS: We enrolled 176 MS patients who started FTY at the San Raffaele Hospital (OSR) MS center with available 25[OH]D measurement at the time of treatment start. We then prospectively followed them for 2 years with periodic clinical examinations and MRI scans. RESULTS: We found no linear correlation between baseline 25[OH]D levels and annualized relapse rate (ARR) or time to first relapse. However, we observed that patients with serum 25[OH]D ≥ 100 nmol/l showed a lower number of Gd+ and combined unique activity (CUA) lesions at baseline compared to patients with the lowest 25[OH]D levels (less than 50 nmol/l, p value < 0.05). Moreover, they showed fewer CUA lesions at 2-year follow-up also when accounting for baseline level of disease activity (p value < 0.05). CONCLUSIONS: In patients treated with FTY, those with the highest baseline 25(OH)D levels had a significantly lower number of active lesions at baseline; the same effect, even if weaker, was observed also at 2-year follow-up when adjusting for baseline disease activity. Given Vitamin D supplementation safety profile, also if a causal effect has not yet been shown, most of MS patients could probably benefit from 25[OH]D levels above those currently considered to be sufficient.

Evidence of balance training-induced improvement in soccer-specific skills in U11 soccer players.

The present study aimed to determine the role of balance training improving technical soccer skills in young players. Two U11 soccer teams were randomly assigned one to either balance training (BT; n = 22) or control group (Ctrl; n = 21). At the end of their habitual soccer training (identical in BT and Ctrl), BT underwent additional balance training for 12 weeks (3 sessions/week, 20 minutes per session), while Ctrl had a 20-minute scrimmage. Before and after the intervention, BT and Ctrl underwent two soccer-specific tests (Loughborough Soccer Passing, LSPT, and Shooting, LSST, Tests), and bipedal and unipedal balance evaluations. After intervention, both groups decreased the trials time and improved passing accuracy, with larger improvements in BT than Ctrl (LSPT penalty time [CI95% ]: -2.20 seconds [-2.72/-1.68]; ES [CI95% ]: -2.54 seconds [-3.34/-1.74]). Both groups improved balance ability, with BT showing larger increments in bipedal tests than Ctrl (static balance: -29 mm [-42/-16]; ES: -1.39 [-2.05/-0.72]; limit of stability: 4% [3/5]; ES 3.93 [2.90/4.95]; unipedal quasi-dynamic balance: 0.07 a.u. [0.03/0.11]; ES: 1.04 [0.40/1.67] and active range of motion: -5% [-8/-2]; ES -0.89 [-1.51/-0.26]). Low-to-moderate correlations between the players' technical level and unipedal balance ability were retrieved, particularly in the non-dominant limb (R from 0.30 to 0.48). Balance training improved some technical soccer skills more than habitual soccer training alone, suggesting that young soccer players may benefit from additional balance training added to their traditional training.

Evaluation of the impact of anthropogenic activities on arsenic, cadmium, chromium, mercury, lead, and polycyclic aromatic hydrocarbon levels in seafood from the Gulf of Naples, Italy.

The principal aim of this study was to monitor the occurrence of some metals and polycyclic aromatic hydrocarbons (PAHs) in fish and mussels from the Gulf of Naples. A comparison with previous researches of the same area was carried out, and the intakes of these compounds through the diet and their effect on the tolerable intake values (when available) were assessed. Cadmium (Cd), chromium (Cr), and lead (Pb) were detected by flameless atomic absorption spectroscopy (Cd, Cr, and Pb); arsenic (As) and mercury (Hg) were detected by applying the hydride method. PAHs were detected by high-performance liquid chromatography. Widespread contamination was found. Among the metals, Hg showed the highest maximum levels of 284.94 ng/g wet weight (ww) in fish and 480.00 ng/g ww in mussels. Chrysene, phenanthrene, fluoranthene, anthracene, and benzo[k]fluoranthene were the most common PAHs in fish, whereas benzo[a]anthracene, pyrene, phenanthrene, acenaphthylene, and acenaphthene were the most frequently occurring compounds in mussels. The concentrations of As, Cr, Hg, Pb, and PAHs in fish were found to decrease over a period of 30 years, whereas the Cd levels remained constant. The Hg, Pb, and PAH levels in mussels increased over the period 2010 to 2016. Finally, the average consumption of mussels led to the highest effect on the Tolerable Daily Intake of Hg, which was exceeded by 19%.

Pharmacogenetic study of long-term response to interferon-ß treatment in multiple sclerosis.

The aim of the study is the identification of genetic factors that influence the long-term response to interferon-ß (IFNß) (4-year follow-up). We performed a genome-wide association study in 337 IFNß-treated Italian multiple sclerosis patients at the extreme of treatment response, and we meta-analyzed association effects, integrating results with pathway analysis, gene-expression profiling of IFNß-stimulated peripheral blood mononuclear cells from 20 healthy controls (HC) and expression quantitative locus (eQTL) analyses. From meta-analysis, 43 markers were associated at P<10-4, and two of them (rs7298096 and rs4726460) pointed to two genes, NINJ2 and TBXAS1, that were significantly downregulated after IFNß stimulation in HC (P=3.1 × 10-9 and 5.6 × 10-10). We also observed an eQTL effect for the allele associated with favorable treatment response (rs4726460A); moreover, TBXAS1 appeared downregulated upon IFNß administration (ß=-0.39; P=0.02). Finally, we found an enrichment of pathways related to inflammatory processes and presynaptic membrane, the latter with involvement of genes related to glutamatergic system (GRM3 and GRIK2), confirming its potential role in the response to IFNß.

Baseline characteristics of participants in the Kerala Diabetes Prevention Program: a cluster randomized controlled trial of lifestyle intervention in Asian Indians.

AIMS: To describe the baseline characteristics of participants in the Kerala Diabetes Prevention Program. METHODS: The Kerala Diabetes Prevention Program is a cluster randomized controlled trial of lifestyle intervention for prevention of Type 2 diabetes mellitus in India. Participants in the study were those aged 30-60 years who had an Indian Diabetes Risk Score ≥ 60 and who were without Type 2 diabetes on oral glucose tolerance test. Data on demographic, lifestyle, clinical and biochemical characteristics were collected using standardized tools. RESULTS: A total of 2586 individuals were screened with the Indian Diabetes Risk Score, of these 1529 people (59.1%) had a score ≥ 60, of whom 1209 (79.1%) underwent an oral glucose tolerance test. A total of 202 individuals (16.7%) had undiagnosed Type 2 diabetes and were excluded, and the remaining 1007 individuals were enrolled in the trial (control arm, n = 507; intervention arm, n = 500). The mean participant age was 46.0 ± 7.5 years, and 47.2% were women. The mean Indian Diabetes Risk Score was 67.1 ± 8.4. More than two-thirds (69.0%) had prediabetes and 31.0% had normal glucose tolerance. The prevalence of cardiometabolic risk factors was high, including current tobacco use (34.4% in men), current alcohol use (39.3% in men), no leisure time exercise (98.0%), no daily intake of fruit and vegetables (78.7%), family history of diabetes (47.9%), overweight or obesity (68.5%), hypertension (22.3%) and dyslipidemia (85.4%). CONCLUSIONS: The Kerala Diabetes Prevention Program recruited participants using a diabetes risk score. A large proportion of the participants had prediabetes and there were high rates of cardiometabolic risk factors. The trial will evaluate the effectiveness of lifestyle intervention in a population selected on the basis of a diabetes risk score.

Default mode network changes in multiple sclerosis: a link between depression and cognitive impairment?

BACKGROUND AND PURPOSE: In multiple sclerosis (MS), depression is a common disorder whose pathophysiology is still debated. To gain insights into the pathophysiology of depression in MS, resting-state (RS) functional connectivity (FC) changes of the default mode network (DMN), salience network (SN) and executive control network (ECN) were assessed in a group of depressed MS (D-MS) patients and in appropriately matched control groups. METHODS: Sixteen D-MS patients, 17 non-depressed MS (ND-MS) patients, 17 non-depressed healthy controls and 15 depressed subjects (D-S), age, sex and education matched, cognitively preserved and non-fatigued, were enrolled. All participants underwent a neuropsychological evaluation and RS functional magnetic resonance imaging study. RESULTS: Comparing D-MS patients with D-S, within the DMN, a significant RS-FC suppression was found in the posterior cingulate cortex (PCC); comparing D-MS with ND-MS, FC was significantly increased in the anterior cingulate cortex and significantly reduced in the PCC. Within the SN increased FC in the right supramarginal gyrus and right middle frontal gyrus was found in D-MS patients compared to D-S and to ND-MS; within the ECN increased FC in the right inferior parietal cortex was found in D-MS patients compared to ND-MS patients. CONCLUSIONS: In cognitively preserved D-MS patients, FC derangement occurs in the SN, ECN and DMN. In the latter, changes occurring both in the anterior cingulate cortex and PCC suggest that depression in MS may be linked to MS itself and, in particular, to a peculiar pattern of network abnormalities favored by MS pathology through disconnection mechanisms. Reduced FC in the PCC, similar to MS patients with cognitive impairment, suggests a functional link between depression and cognitive impairment in MS.

Reactive, Inelastic, and Dissociation Processes in Collisions of Atomic Oxygen with Molecular Nitrogen.

We report the results of detailed calculations of reactive, inelastic, and dissociative processes in collisions of atomic oxygen with molecular nitrogen in their respective electronic ground states. Cross sections are calculated as a function of collision energy in the range 0.001-10 eV, considering the whole rovibrational ladder. Some problems related to the vibrational energy levels of the asymptotes of 3A″ and 3A' potential energy surfaces used in this work are solved by an appropriate scaling at the level of cross sections. The results are compared with data in the literature, obtaining excellent agreement with experimental thermal data for reactive processes on a very large temperature range, and reasonable agreement with indirect dissociative data. Significant discrepancies are observed with previous reactive state-to-state results calculated on less detailed potential energy surfaces. Inelastic results are compatible with extrapolation of experimental thermal rate coefficient for temperatures higher than 4500 K but completely fail to reproduce experimental data at room temperature. The issue is discussed, indicating the reasons and possible solutions to the problem, and a resonable rate coefficient is obtained combining experimental and theoretical results in the range 300-20000 K. Complete, accurate fits are provided for both reactive and dissociative state-to-state rate coefficients to use them in applicative numerical codes concerning air kinetics.

Neuromyelitis optica spectrum disorders: long-term safety and efficacy of rituximab in Caucasian patients.

OBJECTIVE: To assess the long-term benefit-risk profile of repeated courses of rituximab in Caucasian patients affected by neuromyelitis optica (NMO) and related disorders, in everyday clinical practice. METHODS: This is a prospective observational study performed at San Raffaele Hospital, Milan, Italy. From February 2006, we recruited 21 patients affected by NMO and NMO spectrum of disorders (NMOSD) whom underwent at least one cycle of intravenous (i.v.) rituximab and then were followed for at least 2 years. RESULTS: At a mean follow-up time of 48 months, we observed a significant reduction of the annualized relapse rate (ARR), from 2.0 to 0.16 (p < 0.01); and of the median Expanded Disability Status Scale (EDSS), from 5.5 to 4.0 (p < 0.013). There were 12 patients (57%) who remained disease free during the follow-up period. Five patients (24%) reported mild hematological adverse events. Serious infectious adverse events were reported by another four patients: These were all wheelchair bound at the beginning of their rituximab treatment. CONCLUSIONS: A fixed treatment scheme of rituximab, with re-treatment every 6 months, was efficacious for NMO and NMOSD, with a good safety profile; however, to obtain an even better benefit-risk ratio, close monitoring of CD19(+) B cells should be performed before the re-treatment of patients with high-level disability, concomitant leukopenia and hypogammaglobulinemia.

Analysis of genes, pathways and networks involved in disease severity and age at onset in primary-progressive multiple sclerosis.

BACKGROUND: The role of genetic factors in influencing the clinical expression of multiple sclerosis (MS) is unclear. OBJECTIVE: The objective of this paper is to identify genes, pathways and networks implicated in age at onset (AAO) and severity, measured using the Multiple Sclerosis Severity Score (MSSS), of primary-progressive MS (PPMS). METHODS: We conducted a genome-wide association study (GWAS) of 470 PPMS patients of Italian origin:. Allelic association of 296,589 SNPs with AAO and MSSS was calculated. Pathway and network analyses were also conducted using different tools. RESULTS: No single association signal exceeded genome-wide significance in AAO and MSSS analyses. Nominally associated genes to AAO and MSSS were enriched in both traits for 10 pathways, including: "oxidative phosphorylation" (FDRAAO=9*10(-4); FDRMSSS=3.0*10(-2)), "citrate (TCA) cycle" (FDRAAO=1.6*10(-2); FDRMSSS=3.2*10(-3)), and "B cell receptor signaling" (FDRAAO=3.1*10(-2); FDRMSSS=2.2*10(-3)). In addition, an enrichment of "chemokine signaling pathway" (FDR=9*10(-4)) for AAO and of "leukocyte transendothelial migration" (FDR=2.4*10(-3)) for MSSS trait was observed, among others. Network analysis revealed that p53 and CREB1 were central hubs for AAO and MSSS traits, respectively. CONCLUSIONS: Despite the fact that no major effect signals emerged in the present GWAS, our data suggest that genetic variants acting in the context of oxidative stress and immune dysfunction could modulate the onset and severity of PPMS.